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Precise PK User Manual

1. 0 46 age in yr 9 x 0 57 x adjusted weight References this equation was written to smooth the transition between values for 71 children age 9 years and under to those of 12 year olds which appear to be equal to weight adjusted adult values based on data in reference 19 CL 6 months to 9 yr 0 46 x adjusted weight Reference 19 Volume of Distribution L CL over 6 months 2 7 x adjusted weight Reference 4 Bayes Parameters Coefficients of variation of pharmacokinetic parameters are as follows F 15 CL 45 Vd 40 CF 50 The time weighting factor is 1 005 Serum Level Range The therapeutic serum level range of quinidine is not firmly established and depends to a certain extent on the assay method used The range used in Precise PK 1 4 mg L is for unchanged quinidine and is most relevant for newer more specific assay techniques such as HPLC Older less specific assays such as the fluorescent assay also detect certain metabolites some of which may have partial activity The therapeutic range with these latter assays is accordingly higher 2 6 mg L The assay method and usual therapeutic range of users laboratory should be taken into account when using Precise PK Modifying Factors Congestive Heart Failure CHF decreases the volume of distribution by 32 and decreases nonrenal clearance by 46 or total clearance by an average of 34 Absorption rates are also affected as noted above
2. Cirrhosis Cirrhosis increases the volume of distribution by 50 Severe cirrhosis may also decrease nonrenal clearance by 46 but this factor is not included in Precise PK because is was derived in only three patients and older studies found no such decrement Amiodarone Amiodarone increases quinidine serum levels by perhaps as much as 100 The exact mechanism of this interaction is currently unknown Precise PK currently assumes that this is due to a 50 decrease in clearance Barbiturates Barbiturates increase clearance of quinidine by 2 5 times and increase the variability of clearance by 20 72 Cimetidine Cimetidine decreases quinidine clearance by 40 Phenytoin Phenytoin increases clearance of quinidine by 2 5 times and increases the variability of clearance by 20 Rifampin Rifampin increases clearance by 3 7 times It also decreases oral bioavailability as noted above Verapamil Preliminary evidence indicates that verapamil decreases quinidine clearance by 3596 79 References 1 Unpublished data by Riegelman 5 et al from a report submitted to the FDA September 1977 Obtained in a personal communication from Robert Upton Ph D University of California School of Pharmacy April 23 1986 2 Personal communication Mary Jo Brandt M D Lilly Research Laboratories February 13 1986 3 Ochs HR et al Clin Pharmacokinet 1980 5 150 68 4 Benet LZ Sheiner LB In Goodman AG et a
3. 5 Painter MJ et al J Clin Pharmacol 1994 34 312 7 6 Winter M Basic clinical pharmacokinetics 2nd ed Vancouver WA Applied Therapeutics 1988 237 7 Vanholder R et al Kidney Int 1988 33 996 1004 8 McCauley DL et al Ther Drug Monit 1989 11 540 2 9 Ratanakorn D et al J Neurol Sci 1997 147 89 92 10 Randinitis EJ et al Epilepsia 1990 31 458 64 11 Smith TC Kinkel A Clin Pharmacol Ther 1976 20 738 42 12 Jung D et al Clin Pharmacol Ther 1980 28 479 85 13 Grasela TH et al Clin Pharmacokinet 1983 8 355 64 14 Bauer LA Bluin RA Clin Pharmacokinet 1983 8 545 9 15 Abernethy DR Greenblatt DJ Arch Neurol 1985 42 468 71 68 Procainamide Procainamide Dosage Form Parameters Dosage Form F SD Refs Fast Release Capsules 0 83 0 166 2 1 2 Slow Release Capsules 0 83 0 166 04 1 3 4 Formulas Clearance L hr CL over 12 yr 2 7 x CLcr 3 9 x adjusted weight 0 06 References 2 CL 7 to 12 yr 1 94 x total body weight Reference 5 CL 6 months to 7 yr 7 3 1 86 x age in yr 0 5 x total body weight Reference this equation was written to make a smooth transition between age groups above and below CL under 6 months 7 3 x total body weight Reference 6 Volume of Distribution L Vd 18 yr and above 1 9 x adjusted weight References 2 Vd 12 to 18 yr 2 9 age in yr 12 x 0 166 x adjusted weight References this equation was written to make a smooth transition bet
4. Pharmacokinetic Parameters Population Bioavailability 100 00 Clearance L hr 4 72 Vol of Dist L 16 50 Half Life hr 2 42 Time to SS hr 9 69 Calculated Serum Level For Desired Dosage Regimen ENTERED DOSE 200 0 mg every 8 0 hours as an Intermittent Infusion infused o PREDICTED LEVELS mg L Population Custom Peak 31 73 11 73 Trough 1 58 1 58 Post 6 62 6 62 signatu Figure 2 7 1 Print Report Window The Print Report Window displays what the report looks like in real time User can select what content to be printed on the report and the preview of the report will update automatically based on what user selects By default all available selections are selected automatically User can change the default select on the program setting page i e don t select Least Square PK Parameters automatically When user needs to enter comment user can press the Comment button at the bottom left This will pop up a text area for user to enter comments There are also zoom in and zoom out buttons represented by magnifier with the plus and minus signs Press the print button will direct user to the printer setting page that allow user to print the report Comment will pop up a window that allow user to enter comment Print will lead user to the printer setting page that allow user to print the report 30 2 8 Program Settings one Settings General Setting Report Setting l Lice
5. 526225 tst heri ret esit ev de ue in e ec tdt est ts 39 TROUGH SERUM CONCENTRATION 2 2 0 enne nnn entes sensns stenst ts entes nei sins s seitens enin sss rnn nennen 39 AVERAGE CONCENTRATION neri epit T o epa aate te tele eed 39 LOADING DOSE tiet hp ton di ie nhi ee bee e 40 DOSAGEINTERVALS ion eret ete ee er t ei T ie Ene T 40 WHERE IS THE ABSORPTION RATE CONSTANT AND KD IS CL VD DOSAGE REQUIREMENT eee 41 STEADY STATE LEVELS WITH FIRST ORDER ABSORPTION esee eene nnne nnns nnns iniri inania 41 TIME 2 2 2 er eid ter rie eee ee Fr Ek ean den en ae de gest cese ee uda 42 TWO COMPARTMENT 43 5 i reete eset vt eee ine ar sonne de ee Pao ee dense 43 STEADY STATE CONCENTRATION AT TIME T cscssscssecscssccssccsseseceaecssesesusecssesesaecsssceseeeceasessessseaecseseseaecaaseaeeaeceaeeaees 43 NONSTEADY STATE CONCENTRATION AT TIME T sssccsscessesscesscssececesecssecsessecesecaessessaecsssessesecsascaeeeeceaecaessesascaseeaseass 43 MICHAELIS MENTEN FORMULAS 1 0 45 DOSAGE AT STEADY STATE 7 5 c eo Da te ben a e ede eoe 45 CONGENTRATION AT TIME Tz E ERE RUE EE 45 TIME TO REACH 90 OF STEADY STATE LEVEL iii 45 CH
6. License HP Database Software Version Convert Database Online Update It will restart the program after user update the license Once the program restarts the program will be in a full paid mode User will also see user management as this is to set up user accounts and password protect them etc To update the license user can go to program settings again and it will let user updates the license online Simply click on Online Update under license If the current license is already the latest it will show a message saying the current license 15 the latest Otherwise it will update the license to user s latest license If user updates a license with a different institution name the corresponding database will also re encrypt under the new license Each time a license is updated the program will always restart Database Setting and Convert Another important thing in a full paid version is the database You can also specify a common location for the database To do that you will go to program settings and go to database If you have an older TDMS database that you would like to use You will need to convert the database from the older version to the newer version by using the covert database tab under settings You simply enter the old database file path and the new database file path and it will import users data into the new format Database is encrypted under its own license Different
7. Oral DIOSVOUGDHIUY is 70 20 for patients 60 and younger and 87 5 20 in those over 60 The absorption rate constant is 1 5 Parenteral bioavailability is 100 5 Formulas Clearance L hr CL 18 years and over 1 97 x CLcr x 0 06 13 23 Reference 4 Volume of Distribution L Vd 18 years and over 2 0 x dosing weight Reference 6 7 Bayes Parameters Coefficients of variation of pharmacokinetic parameters are as follows Oral F 2096 IV CL 50 Vd 30 CF 50 The time weighting factor is 1 005 assay error is 10 and FE is 0 25 Modifying Factors The absorption of oral ciprofloxacin is quite susceptible to interference by divalent cations The amount of interference varies by product and amount contained These products generally should be taken 6 hours before or 2 hours after ciprofloxacin Aluminum and Magnesium Antacids Concurrent ingestion of these antacids reduces ciprofloxacin bioavailability by 60 per Nix DE et al Clin Pharmacol Ther 1989 46 700 5 Shiba K et al Antimicrob Agents Chemother 1992 36 2270 4 Flor S et al Antimicrob Agents Chemother 1990 34 2436 8 H ffken et al Rev Inf Dis 1988 suppl S 138 9 Cancer Chemotherapy Patients receiving cancer chemotherapy have ciprofloxacin bioavailability reduced by 47 per Johnson EJ et al J Antimicrob Chemother 1990 25 837 42 Cystic Fibrosis Cystic fibrosis patients have ciprofloxacin bioavailability increased by 50 40 per Criste
8. by 10 to 0 33 L kg Cystic Fibrosis Data are conflicting between studies on whether there are alterations in pharmacokinetic parameters in cystic fibrosis One factor may be that intrapatient parameters change as therapy progresses Precise PK increases the nonrenal clearance by 118 and increases the time weighting factor to 1 01 27 182028 Preterm Infants Two factors modify the clearance if the patient is a preterm infant Preterm infants less than 28 weeks gestational age have a clearance of 60 of full term infants which increases to meet that of full term infants at 2 months postnatal age Preterm infants between 28 and 34 weeks gestational age have a clearance of 80 of full term infants which increases to meet that of full term infants at 1 month postnatal age Patent Ductus Arteriosus PDA Newborns with uncorrected or recently treated patent ductus arteriosus have a larger volume of distribution than normal This factor is taken into account as noted above under Volume of Distribution ECMO This procedure increases the volume of distribution as noted above under Volume of Distribution and decreases the clearance to 0 04 L hr kg References Chung M et al Antimicrob Agents Chemother 1980 17 184 7 Lanao JM et al Int J Clin Pharmacol Ther Toxicol 1982 20 271 5 Mayer PR et al Drug Intell Clin Pharm 1986 20 611 5 Benet LZ Sheiner LB In Goodman AG et al eds The pharmacological basis of iheripeutics 7th e
9. follows salt fraction 1 bioavailability 100 5 and the IM absorption rate constant 18 1 9 hr in patients 75 and under and 2 7 in patients over 75 13 Formulas Clearance L hr CL over 6 months 0 82 x CLcr 0 11 x dosing weight x 0 06 Reference 4 CL over 6 months with cystic fibrosis 0 82 x CLcr 0 11 X dosing weight x 0 06 References 5 7 CL under 6 months 0 05 0 17 x age in years x total body weight calculation made only if Crs is less than 0 8 1 2 mg dL depending on the age of the infant References this equation written to smooth transition between age groups in references 5 11 Volume of Distribution L Vd over 6 months 0 3 x dosing weight Vd over 6 months to 1 yr lt IBW 0 3 x total body weight References 4 12 46 Vd 1 month to 6 month 0 52 0 44 x age in yr x total body weight References this equation written to smooth transition between age groups above and below Vd 1 month and under 0 52 x total body weight Reference 13 Vd 1 month and under receiving ECMO extracorporeal membrane oxygenation 0 52 x total body weight Reference 15 28 Bayes Parameters Coefficients of variation of pharmacokinetic parameters are as follows F 596 CL 50 Vd 30 in patients 65 and under and 50 in those over 65 CF 50 the time weighting factor is 1 005 In cystic fibrosis intrapatient variability may be increased tending towards more normal value
10. x total body weight Vd under 1 month full term 8 75 x total body weight Vd under 1 month premature 7 5 x total body weight Reference all pediatric data from reference 9 Equation for age group between 1 month and 2 years of age was derived to make a smooth transition between groups above and below Bayes Parameters Coefficients of variation of pharmacokinetic parameters are as follows F specified by product above CL 52 Vd 30 CF 50 The time weighting factor is 1 005 Modifying Factors A number of factors are known to affect digoxin bioavailability clearance and apparent volume of distribution These are used to modify the calculated population values for F CL and Vd if they are selected as being present The factors that are used and the references are given below Congestive Heart Failure CHF decreases digoxin renal and nonrenal clearance as noted above Thyroid Dysfunction Hyperthyroidism increased digoxin clearance by 30 and volume of distribution by 3096 Hypothyroidism decreases digoxin clearance by 3096 and volume of distribution by 30 Amiodarone Amiodarone decreases digoxin clearance by an average of 2896 and the volume of distribution by 1290 It also appears to increase oral bioavailability of digoxin by an average of 2596 The increased bioavailability factor is applied to the tablets and elixir only and not to the capsules 53 Diltiazem Diltiazem decreases the clearance of digoxin by 1
11. 2 4 1 Main Window Once user click continue from the Patient amp Case Window user will be lead to the Main Window Figure 2 4 1 which can be consider as the central panel of Precise PK The Main Window contains rich information related to patient and case also it is the place where user can see all the PK parameters Moreover user navigate at difference places from the Main Window The Main Window can be separated by three main areas On the top of the Main Window is group of buttons e Update Patient And Case Info will open the Patient amp Case Window which can allow user to update or change the patient or case information Note that once the patient has been saved or the case is loaded from database some values of patient and case are not changeable e Serum Level Forecast will open a Serum Level Forecast Window e Dosage Regimen Forecast will open a Dosage Regimen Forecast Window 22 e Dosage History will open the Dosage History Window e Graph Analysis will open the Graph Analysis Window Note that it is not available until user have entered the dosage history e Report will open the Print Report Window e Save will save the current patient and case information into the database It will not be available if there is no change after the last save operation In the middle of the Main Window displays the information about the patient and the case If user want to change any of them user can click the Update Patient And Case In
12. Capsules 0 92 1 0 1 3 Phenytoin Suspension 1 1 0 1 3 neonates 1 month 1 0 9 0 2 4 Phenytoin Tablets 1 1 0 1 3 Dosage expressed in phenytoin sodium equivalents PE 63 Phenytoin Plasma Protein Binding Group Unbound Fraction Refs Adults and Children CLer gt 25 mL min 1 1 albumin x 2 05 3 10 25 mL min 1 1 albumin x 1 0 07 x CLer 10 CLcr 10 mL min 1 1 albumin 3 Neonates 1 month 0 2 5 to fit unbound phenytoin levels enter 0 01 as the serum albumin concentration on the Patient Demographics screen equation to smooth transition between normal and uremic values Population Estimates Vmax mg day 11 5mg day Vmax 6 yr x total body weight References 3 4 Vmax 6 yr to 18 yr total body weight 805 25 x patient age 6 x EA 0 6 70kg Reference Ref 3 with equation written to smooth transition between upper and lower age groups and weight adjustment per ref 13 Vmax gt 18 yr total body weight 500 1 5 x patient age 18 x __ 70kg Reference Ref 3 with equation written to smooth transition between upper and lower age groups and weight adjustment per ref 13 Km mg L Km 1 month 5mg L Reference 4 Km 1 month to 6 months 5 0 3 x age in yr 0 083 Reference Equation written to smooth transition between upper and lower age groups 64 Km 6 months to 15 yr 6 4mg L Re
13. a demo license So user will see the following notification every time user starts the program with the demo license Notice This is a demo version Please visit PrecisePK com to purchase a license User can click ok and the program will start in demo mode User can only use three drugs and cannot use the database to save or load patients in the demo mode Precise EIE File Analysis Help Program Settings Update User Information X Precise 4 A pharmacokinetics amp a therapeutic WBA drug monitoring system by Healthware Inc lig y Formally known as T D M S 20007 New Patient Load Patient Precise PK DEMO VERSION Version v0 15 01 20 4 User can update license by going to Settings Program Settings Database Software Version Convert Database Under program settings go to License and then enter the following two strings in the License Name and License ID exactly as sent in user s email After entering the License Name and License ID click on Manual update On this page user can also specify the location that he she want his her license file to be as this can be a common location that various computers can point to so only one license file need to be updated and can be shared among multiple computers 49 General Setting Report Setting
14. a patient or group of patients in the database The Menu Bar contains various options that can lead user to almost all pages and windows User is able to access the Menu Bar in most of the time of using Precise PK 14 which allows user to have multi calculation and graph windows at the same screen Here are some brief description of the options File e New Patient Open a new Patient amp Case Window Open Patient Open a Load Patient Window Output File Outputs a csv Comma Separated Value file which contains the information of the current patient Not available until a patient is loaded Print Report Open a Print Report Windows Not available until a patient is loaded Log Out Log out the current user Exit Exit Precise PK Analysis Dosage Regimen Forecast Open a Dosage Regimen Forecast Window Not available until a patient is loaded Serum Level Forecast Open a Serum Level Forecast Window Not available until a patient is loaded Serum Level Analysis Open a Dosage History Window Not available until a patient is loaded Settings Program Setting Open a Program Setting Window which allows user to change the setting of Precise PK Available settings may vary depends on the Log In Role k Manage User Account Update User Information Open a User Management Window Administrator or a Profile Window Normal User which allows user to either manage all users account or update the information of current u
15. by capacity limited Michaelis Menten pharmacokinetics e g phenytoin Km X Dosage Rate C L gt 7 34 mg L Vmax Dosage Rate where 5 AWIE S x F x Dose AERE Dosage Interval Dosage at Steady State Vmax X Interval D osage Sx Fx Km Concentration at Time t Concentrations are calculated at 1 minute intervals throughout the time range of interest for both curve fitting an graphic display These thousands of calculations cause a slight delay in display of fitted values indicated by a horizontal progress bar Vmax R xt Km x Vmax 2 x Km Vmax R x C 0 Vd PUR x Km Vmax m R where R S x F x Daily Dosage 0 is the initial plasma concentration and C t is the concentration at time t Time to Reach 90 of Steady State Level _ Km x Vd x 2 3 x Vmax 0 9 x R NOU Vmax R where R S x Daily Dosage 45 CHAPTER 5 DRUG SPECIFIC PARAMETERS In this chapter the formulas used to calculate the estimated pharmacokinetic parameters for individual patients are provided In addition certain assumptions made in the program are mentioned Literature references are provided to document the formulas and values used Aminoglycosides All of the aminoglycosides are assumed to have the same clearance and apparent volume of distribution Parameters that are associated with aminoglycosides in the program are as
16. infusion time with IV doses and the time to peak at steady state for IM and oral doses Time to Peak Single Dose This formula calculates the time of the peak serum concentration following a single dose of a drug given PO or IM with an absorption rate constant of Ka and an elimination rate constant of Kd This time is used in the above formulas to approximate an infusion time t for IM and oral doses Formula In Ka Kd peak Racka 40 where Ka is the absorption rate constant and Kd is CL Vd Dosage Requirement These formulas calculate the dose required to achieve a desired peak given a clearance CL volume of distribution Vd salt fraction S bioavailability F and dosage interval J IV Formula peak x 1 7 Dosage 9 1 e Kd tinr where Kd CL Vd and 1 15 the infusion time PO IM Formula peak x Vd x 1 e Dosage x FxSx e KdxTMaxss where Kd CL Vd and TMax is the time to peak at steady state as calculated below under Steady State Levels With First Order Absorption Steady State Levels with First Order Absorption These equations calculate the steady state peak Peak and trough Trough concentrations for orally and intramuscularly administered doses D of drugs with a bioavailability fraction F salt fraction S volume of distribution Vd and absorption and elimination rate constants Ka amp Kd respectively at a given dosage interval The ti
17. interval t a starting concentration cp a Clearance CL and a volume of distribution Vd Formula 5 1 2 CL 1 where K dose t and Kd CL Vd Trough Serum Concentration This formula calculates the minimum serum concentration at steady state during an intravenous dosage regimen with a dosage interval of Formula Trough Peak tin where Kd CL Vd and t is the infusion time Average Concentration This equation is used to calculate the average steady state serum concentration with all routes of administration Formula Sx F X Kg AVgss CL 39 where K is either the infusion rate or the daily dosage as appropriate Loading Dose This formula calculates the loading dose needed to achieve a specified peak of an intravenous drug infused over time t given clearance CL initial serum concentration cp volume of distribution Vd salt fraction S and bioavailability F Formula CL x t x peak cp x e K t Loading dose Sx FX 1 e Kaxi where Kd CL Vd and t is the duration of the infusion with IV dosage or time to peak after a single dose with PO and IM administration Dosage Interval This formula calculates the dosage interval needed to achieve a desired trough given a desired peak an elimination rate constant of Kd and an infusion time of t Formula ln peak trough Interval t Kd where t is the
18. phenytoin levels during therapy especially if there are complicating factors Obtaining free unbound phenytoin levels are particularly recommended in the presence of drugs or conditions that affect protein binding Phenytoin injection should not be given intramuscularly because of its poor absorption and tissue toxicity Only the phenytoin prodrug fosphenytoin is allowed to be given IM by Precise PK It is converted to phenytoin in the body by a first order process Absorption Oral phenytoin absorption in adults is modeled as a constant 60 mg hour The concept of this absorption model was introduced by McCauley et al The value of 60 mg hour is an average derived from references 9 12 and data from patients at UC San Diego Medical Center In children under 18 years the absorption rate is modeled as 1 mg kg hour Intramuscular fosphenytoin absorption ref 1 has a Ka of 2 5 and intravenous fosphenytoin absorption has a Ka of 3 6 ref 2 which represents conversion to phenytoin The History Spreadsheet Screen Chapter 1 Figure 10 allows two oral dosage forms to be entered The regimen of each dosage form must be specified on separate lines using the letters Capsule Suspension or Tablet in the Route box of the spreadsheet to designate the corresponding dosage form Phenytoin Dosage Form Parameters Dosage Form 5 F SD Refs Fosphenytoin IM 0 92 1 0 1 1 Fosphenytoin IV 0 92 1 0 1 2 Phenytoin Injection IV 0 92 1 0 1 3 Phenytoin
19. remove from the database If user decide to delete a patient just single click a patient then click the delete button Note that deleting a patient will also deletes all the cases of that patient 20 The Open button behaves the same as the double click operation Selecting a patient and click Open will open a Patient amp Case Window with the patient information Similarly selecting a case and click Open will open a Patient amp Case Window with the patient information and the case information 21 2 4 Main Window F a s ebes File Analysis Settings Help Update Patient Serum Level Dosage Regimen And Case Info Forecast Forecast ML A JR Patient Case First Test Note Note Drug Amikacin Last Patient Hosp ID 111 ig Crs 10 4 Birthday 01 01 1991 Sex Male caladated 98 9 mL min Weight 85kg Height 165 cm Body Mass Index 31 22 kg m2 Body Surface Area 2 00 m2 Lean Body Mass 58 70 kg Ideal Body Weight 61 41 kg Population PK Parameters Least Squares PK Parameters Intermittent IV Injection MA Intermittent IV Injecion 7 M Value Range lalue Range Value Range F 100 00 5 00 F 100 00 5 00 F Vd 21 254 6 376 0 25 L kg d 21 254 6 376 0 25 L kg Vd l 5 271 2 635 L hr 5 271 2 635 L hi a CF 100 000 50 000 CF 100 000 f 50 000 CF kd 0 248 248 M kd hr t1 2 2 794 t1 2 2 794 hr reset t1 2 hr Figure
20. tinf dose D dosage interval t and steady state trough level troughss based on the on the intermittent infusion model where KO S x Fx CF x D tinf and kd CL Vd The calculation is made in two phases an approximation of the time that the serum concentration passes the MIC on the upswing 11 is subtracted from the time since the end of the infusion that the serum concentration passes the MIC on the downswing 6 For two compartment drugs e g vancomycin an iterative method is used to approximate the time above MIC to the nearest 0 1 hour One Compartment Formulas MIC Troughss ting ES xX t 17 Peakss Trough If t is less than 0 t is set to 0 In Peak MIC t5 Time above MIC t ting t1 X 24 1 81 Post MIC Ratio The post MIC ratio is defined as the ratio of the peak serum concentration drawn up to 1 hour after the end of the infusion divided by the MIC The greatest amount of experience with this value has been with the aminoglycoside antibiotics The rate of successful aminoglycoside treatment is improved with values over 6 mg L With infections in relatively protected or inaccessible sites such as the lung higher values may prove to be better Extending these findings the use of larger doses at longer dosage intervals has been explored Once daily use of aminoglycosides has been reported and may have equal or greater efficacy and lower toxicity than multiple daily dos
21. yr or over 0 14 CLcr 0 06 0 006 x adjusted weight References 3 8 Volume of Distribution L Vd 12 yr to 70 yr 0 73 x IBW References 3 5 Vd over 70 yr 2 0 59 x IBW References 6 7 Bayes Parameters Coefficients of variation of pharmacokinetic parameters are as follows F specified by product above CL 5096 Vd 3096 CF 5096 The time weighting factor is 1 005 The time weighting factor is 1 005 56 Modifying Factors Acetazolamide or Sodium Bicarbonate Acetazolamide and sodium bicarbonate increase lithium clearance by about 30 per Pepin SM in Taylor WJ Caviness MHD eds A textbook for the clinical application of therapeutic drug monitoring Irving TX Abbott Laboratories Diagnostics Division 1986 435 65 Angiotensin Converting Enzyme ACE Inhibitors Numerous case reports of lithium toxicity have occurred with concurrent use of these agents However the cause of the toxicity has not been defined and it seems to happen only sporadically Monitor lithium serum levels especially carefully when administering an ACE inhibitor concurrently Ibuprofen or Piroxicam Average clearance is decreased by 33 and the coefficient of variation is increased to 43 per Ragheb M J Clin Psychiatr 1987 48 161 3 Ibuprofen decreases lithium clearance erratically Data on piroxicam are limited to case reports and changes in clearance are difficult to quantify It appears that clearance is decreased by at least 33 with piroxic
22. 0 57 Chapron DJ et al J Am Geriatr Soc 1982 30 651 5 Hardy BG et al J Clin Psychopharmacol 1987 7 153 8 Clericetti N et al Clin Nephrol 1991 36 281 9 58 Levofloxacin and Ofloxacin The salt fraction for ofloxacin is 1 for both the oral and injectable product Oral bioavailability is 100 10 The absorption rate constant is 3 0 Parenteral bioavailability is 100 5 Formulas Clearance L hr CL 18 yr or over 1 21 x CLcr 36 x 0 06 References 3 Volume of Distribution L Vd 18 yr or over 1 36 x dosing weight References 4 8 Bayes Parameters Coefficients of variation of pharmacokinetic parameters are as follows Oral F 10 IV F 5 CL 50 Vd 30 CF 50 The time weighting factor is 1 005 assay error is 10 and FE is 0 15 Modifying Factors The absorption of oral levofloxacin and ofloxacin is susceptible to interference by divalent cations The amount of interference varies by product and amount contained These products generally should be taken 6 hours before or2hours after lovofloxacin or ofloxacin Aluminum and Magnesium Antacids Concurrent ingestion of these antacids reduces ofloxacin bioavailability by 45 per Flor S et al Antimicrob Agents Chemother 1990 34 2436 8 H ffken et al Rev Infect Dis 1998 suppl 5138 9 abstract and decreases the Ka to 0 67 hr per Akerele JO Okhamafe AO J Antimicrob Chemother 1991 28 87 94 Oral Iron Oral iron decreases ofloxacin bioavai
23. 10 adjusted weight Reference this equation was written to make a smooth transition between age groups above and below as suggested by data in reference 12 CL 1 to 10 yr 0 084 x adjusted weight Reference 12 18 CL under 1 yr 0 018 0 066 x age in yr x adjusted weight 74 Reference this equation was written to make a smooth transition between the clearance of the age group above and the clearance of 0 018 x total body weight at birth per references 19 and 20 Theophylline Dosage Form Parameters Dosage Form Salt F SD Ka too Ref Elixir Syrup 1 1 0 1 2 3 1 2 Fast Release Solids 1 1 0 1 2 4 1 2 Theo 24 fasting 1 0 65 2 0 03 0 8 30 3 9 Theo 24 meal 1 1 0 125 20 9 Aminophylline Parameters Injection 0 79 1 10 Elixir Syrup 0 86 1 0 1 2 3 1 2 11 Fast Release Tablets 0 8 0 94 0 1 2 4 1 2 11 These products are erratically absorbed with large differences between the fasting and nonfasting states They are not included as menu selections in Precise PK for this reason Volume of Distribution L Vd under 1 month 0 77 x total body weight Reference 19 Vd 1 month to 1 yr 0 8 0 31 x age in yr x total body weight Reference this equation was written to make a smooth transition between age groups above and below Vd 1 yr and over nonobese 0 48 x total body weight Reference 13 17 Vd 1 yr and over obese 0 35 x total body weight Reference 13 17 Bayes Parameters Coeff
24. 5 8 Quinidine Quinidine decreases the volume of distribution of digoxin by 30 and decreases the clearance 50 Verapamil Oral verapamil decreases the nonrenal clearance by 43 during long term use During the first 4 weeks of therapy renal digoxin clearance is also decreased Therefore total digoxin clearance will be less initially than predicted by this correction Amiloride or Triamterene Amiloride and triamterene decrease nonrenal digoxin clearance by an average of 85 and increase renal clearance by 20 2 5 Spironolactone Spironolactone decreases digoxin clearance by 30 2025 26 References 1 Lanoxin product information 2 Winter ME Basic clinical pharmacokinetics 2nd ed page 148 3 Sheiner LB et al J Pharmacokinet Biopharm 1977 5 445 79 4 Morselli PL et al In Morselli PL et al eds Basic and therapeutic aspects of perinatal pharmacology New York Raven Press 377 92 5 Wettrell G et al Acta Paediatr Scand 1974 63 705 10 6 Gorodischer R et al Res Commun Chem Pathol Pharmacol 1977 16 363 74 7 Halkin H et al Eur J Clin Pharmacol 1978 13 113 7 8 Linday LA et al Clin Pharmacol Ther 1981 30 735 8 9 Wettrell G et al Ther Drug Monit 1986 8 129 39 10 Doherty JE et al Ann Intern Med 1966 64 489 507 11 Fenster JC et al J Am Coll Cardiol 1985 5 108 12 12 Nademanee K et al J Am Coll Cardiol 1984 4 111 6 13 Maragno I et al Int J Clin Pharmacol Res 1984 4 149 53 14 Kuhlmann J Cl
25. APTER 5 DRUG SPECIFIC PARAMETERS 4 eese eee eee seen eene enne nnne sn sa sens so sss assa ssassu senno 46 5 nt Padi NE sa 46 2 caen M 50 DIGOXIN m deteste sed darts na tee ds dei 52 iles iL ER 55 pee 56 LEVOFLOXACIN AND OFLOXACIN ssssssssssccccecsesessnareccecececssessnsnacsceececeesessnaeaceecscecsessnseaacaceececeesessnssaesececeses 59 2525 te 61 lid are teer 63 PROGAINAMIDE TD 69 enlm 71 THEQPHYLUINE 2 50 ERR 74 VANCOMYCIN assister 78 APPENDIX ANTIBIOTIC PHARMACODYNAMIICS 81 APPENDIX B CURVE FITTING eee eo oi 656 1 6006 aa ears e eere ep 06506660066 ec kan 84 CHAPTER 1 SYSTEM SETTING AND COMMON OPERATION Program Register and License Update The first time starting the program it will notify user that the program is running in demo mode since it is installed with
26. For intermittent administration enter the dosage regimen that user desire and the steady state serum levels predicted to be produced by this regimen are displayed For administration by continuous infusion simply enter the desired serum and the program will calculate the infusion rate needed to achieve this concentration For antimicrobial agents enter the minimum inhibitory concentration MIC of the organism to calculate pharmacodynamics values Post MIC Time Above MIC and AUIC at steady state 24 which are displayed at the bottom of the second column The bottom screen provides the graph using the entered dosage regimen The graph will originally start at concentration 0 and then simulate how this dosage regimen gets to the steady state Bar chart will provide a comparison between different PK for each value we calculate User can click on the legend of the graph to hide or show the corresponding set of value For example if I want to hide population graph just click on the Pop in the legend User can also set an initial concentration instead of using 0 by default and can also specify how many intervals doses the graph should draw By entering Time x value it will automatically show the corresponding level y value for each PK parameters a v gt m Figure 2 5 2 Dosage Regimen Forecast Window 25 This Serum Level Forecast Window Figure 2 5 2 allows user to predict the dosage regimen required to
27. J Clin Pharmacol 2001 41 927 34 20 Llopis Salvia P et al J Clin Pharm Ther 2006 31 447 54 21 Polard E et al Ther Drug Monit 1999 21 395 403 80 APPENDIX A ANTIBIOTIC PHARMACODYNAMICS There has been considerable work on the incorporation of microbial sensitivity data together with patient specific pharmacokinetics in order to optimize antimicrobial therapy The use of this method of integrating individual patient pharmacokinetics with the MIC of infecting organisms has been termed dual individualization The microbial pharmacodynamic parameter common to almost all methods is the minimum inhibitory concentration MIC of the infecting organism This is value obtained in vitro from bacterial cultures While not a flawless measure of bacterial sensitivity it is widely used and reported Potential pitfalls in the use of the MIC have been reviewed Since there is not currently general agreement on which if any value is the best overall Precise PK calculates the three most widely used pharmacodynamic values These values their methods of calculation and the experience with each are described Time Above the MIC This function is used with antibiotics to calculate the amount of time per day that the serum concentration is above the MIC of the organism being treated For one compartment drugs e g aminoglycosides values used include the clearance CL salt fraction S bioavailability F compliance factor CF infusion time
28. ORECAST e ee eese eene enean nasa nasa nasa sese sane 24 2 6 DOSAGE HISTORY amp GRAPHICAL ANALYSIS 4 annees n noon asa soes sena soto sea soto sesso eese aseo nenas 27 PAPA i diio K 30 2 8 PROGRAM SETTINGS iioi Le coena ra ER NERONE PY e EXE TREE ententes VR ER eS EEESR TE SEEN EY Re RUE 31 2 9 USER ACCOUNT P PR 33 CHAPTER 3 PHYSIOLOGIC PARAMETERS dei se ero o eo e na se o io eoo Eau aa sa sa aono sndsevedensdsvscancdandsedsaes 35 BODY 5 Me mc 35 eA cg M 35 MODIFIED WEIGHT na ess tete 35 LEAN BODY WEIGHT EET D D I ULT 36 DOSINGWEIGHT CPC Tu 37 ADJUSTED WEIGHT 333 2 52 2 aus ins pa yo E Repo eee vd ayer dosette uade 37 CREATININE CLEARANCE 3 s ves ons tester tentes ane dede den etes ten 37 CHAPTER 4 PHARMACOKINETIC 1 65 39 39 PEAK SERUM CONCENTRATION 5
29. Patient in the Welcome Window or in the Menu Bar user will see the Open Patient Window Figure 2 3 1 This screen allows user to search for a patient or group of patients in the database User can choose one of the following way to filter the search result by clicking the radio button Modified Between Dates Selecting start and end dates in the boxes of this screen will search users entire database to identify patient records that have not been modified since this time period Records from this time period that have been updated since the end of the time period are not included Patient s Last Name allows user to search for a patient by the last name Partial name searches are possible so entering the letter An will retrieve all patients whose last name starts with An User can also type in an empty Last Name which will then display all patients in the database Enter Patient ID Number allows user to search by the identification number user have stored in the database such as the patient s medical record number The Cancel button will lead user back to the pervious screen and cancel the search operation The OK button will lead user to the Search Result Window which displays the result of users search 19 FirstName Last Name i Sex Patient ID Last Update Drug Weight Unit Height Unit Crs Test LOUE SEE 1991 01 01 M 111 1 2015 01 21 14 20 15 Amikacin 85 165 cm 1 Double dick patient to op
30. Precise PK Formally known as T D M S 2000 Version v0 14 12 16 2015 For Windows THERAPEUTIC DRUG MONITORING SYSTEM USER MANUAL Copyright 1986 2014 Healthware Inc PO Box 221014 San Diego CA 92122 Phone FAX 858 452 0297 e mail Information TDMS2000 com www tdms2000 com Designed by Jenn Ting Pharm D Written by Philip O Anderson Pharm D Jenn Ting Pharm D Windows Programmer Anjum Gupta Ph D Xiaojian Chen Junrong Zhou The programs and equations contained in Precise PK were derived from the medical literature identified in the documentation provided with this program and are combined to provide a system that supplements the judgment of the clinician in dosing various drugs Precise PK is not intended to replace the sound clinical judgment of the user in the care of patients Neither Healthware Inc nor any of its employees shall be liable for any damages resulting from any use of this software package By the use of this software package the user waives all warranties expressed or implied including any warranties to the accuracy quality or suitability of Precise PK for any particular purpose either medical or nonmedical Healthware Inc provides a license to use Precise PK under the following conditions 1 You may make a copy of the program to a working diskette or hard disk as a backup to use on any machine owned by the purchaser so long as only the number of copies all
31. The following equations are used to calculate micro rate constants after establishment of clearance CL total volume of distribution Vd volume of distribution of the central compartment Vc and the transfer rate constant between the peripheral and central compartments K by population estimates Formulas CL Vc B CL Vdg a Kj X Kyg B Steady State Concentration at Time t This equation is used to predict the serum concentration at steady state Cp at time t during a dosage interval of drugs with a salt fraction S given IV at an infusion rate of K over an infusion time of and at a dosage interval of During the infusion ting and t are equal Formulas Ko 5 Ko 1 e xt Pss 1 9 Ky x S x B 1 Vc x B x a B x 1 Nonsteady State Concentration at Time t This equation is used to predict the serum concentration Cp at time t during a dosage interval of drugs with a salt fraction S given IV at an infusion rate of Ko over an infusion time of ting and a dosage interval During the infusion tint t 43 Formulas Kg xS x ac a x 1 A e Xtinr x Vc x a x a Ky X S x B X 1 eP tinr Vc x B x 44 MICHAELIS MENTEN FORMULAS This formula calculates the steady state serum concentration of a drug eliminated
32. Warning All incomplete rows will be erased Figure 2 6 2 Graphical Analysis Window also called Curve Fitting Analysis 28 The Graphical Analysis Window Figure 2 6 2 will display the result of curve fitting Entered levels are displayed as small rectangles on the graph Each set of PK is represented by its own color On the upper left corner program will explicitly tell the user which set of PK parameters is used The table on the upper right corner shows the serum level history and its fitted value using fitted parameters On the lower right corner user can select which set of values to be showed on the graph in the Graph Tool box In addition by clicking the Area of graph radio button it will highlight the area clearly on the graph User can also select the unit for x axis using the drop down menu in the Graph Tool box The reset button will reset everything and restore the screen to default state The program can also calculate the area of the graph by entering Time and Time2 in the Math Tool box By clicking the Show Legend check box it will show or hide the graph legend based on the checkbox status Reset will reset the screen to default state 29 2 7 Print Report PRECISE PK THERAPEUTIC DRUG MONITORING REPORT Amikacin Patient A Patient 0001 Date 01 21 Age 24 1 Years Height 170 0 cm 66 9 in Crs 1 00 mg dL Sex Male Weight 55 0 kg 374 8 1b Estimated CLcr
33. ability F and its coefficient of variation CV the absorption rate constant Ka and the time to 90 absorption t The values for specific products are listed in the table on the following page In Precise PK all oral dosage forms are modeled as if absorption were a first order process i e using Ka While some of the better slow release dosage forms approach true zero order absorption with the slow absorption rate constants used differences in predictions between the two models are clinically unimportant Absorption rate constants were primarily calculated from data that were visually obtained from Wagner Nelson absorption plots Both the time to 50 absorption 1 half life and the time to 90 absorption 3 5 half lives were read off the plots and the derived constants were averaged to produce the Ka In a few instances investigators reported the time to 50 absorption and this value was used to calculate Ka Whenever possible several studies and methods were used to derive Ka Average values of the best data are used for Ka in Precise PK The theophylline pharmacokinetic parameters used in PrecisePK M presented with references in tabular form below Formulas Clearance L hr CL over 60 yr 0 035 x total body weight Reference 12 CL 18 to 60 yr 0 04 x total body weight Reference 12 17 CL 18 to 60 yr obese 0 032 x total body weight Reference 14 16 CL 10 to 18 yr 0 084 0 0055 x age in yr
34. achieve the exact serum drug concentrations that user enter Results are calculated using all four types of pharmacokinetic values if available When user modified the Custom PK Parameters on the Main Window the corresponding values are also changed automatically User can select route and specific drug product from the drop down box on top of the screen Different route might have different user interface for entering the desired serum concentration After entering the desired serum concentrations and times the exact dosage regimen required to produce the serum drug concentrations user specify are displayed in the Steady State Dosage Regimen box User may enter further information in the Loading Dose Forecast box If the patient has been on the drug and user have a serum concentration drawn at a known time user can enter these and the program will calculate the dosage required to produce the desired level that user specified after the first dose Because calculations often result in impractical doses or frequencies the results obtained on this screen should be considered approximate dosage regimens The bottom screen provides the graph using the calculated dosage regimen The graph will originally start at concentration 0 and then simulate how this dosage regimen gets to the steady state Bar chart will provide a comparison between different PK for each value we calculate User can click on the legend of the graph to hide or show the corresponding s
35. acol 1982 23 87 92 Fernandez de Gatta MR et al Ther Drug Monit 1986 8 416 20 Beck DE et al Clin Pharm 1986 5 754 9 Davis AG et al Pediatrics 1981 68 824 7 Jalling B Develop Med Child Neurol 1974 16 781 93 10 Pitlick W et al Clin Pharmacol Ther 1978 23 346 50 11 Fischer JH et al Neurology 1981 31 1042 4 12 Painter MJ et al J Pediatr 1978 92 315 9 13 Boreus LO et al in Morselli PL et al eds Basic and therapeutic aspects of perinatology New York Raven Press 1975 14 Suganuma T et al J Pediatr 1981 99 314 7 15 Alvin J et al J Pharmacol Exp Ther 1975 192 224 35 16 Dam M et al Clin Pharmacokinet 1979 4 53 62 17 Pitlick W et al Clin Pharmacol Ther 1978 23 346 50 18 Alonso Gonzalez AC et al J Clin Pharm Ther 1993 18 267 70 CHNAARWNS 62 Phenytoin Phenytoin exhibits slow and erratic although usually complete oral absorption variable plasma protein binding and capacity limited Michaelis Menten elimination pharmaco kinetics All of these factors contribute to the great difficulty in predicting an individual patient s phenytoin dosage requirements Various condition and drugs are known to affect phenytoin s pharmacokinetics although the exact changes in parameters is often not known Because of these many factors and their uncertainty Precise PK groups some of these factors together and makes a single approximate change in pharmacokinetic parameters It is always important to measure serum
36. al basis of therapeutics 8th ed New York Macmillan 1990 1703 3 Tilstone WJ et al Eur J Clin Pharmacol 1978 14 261 5 4 Baker BA et al Clin Pharm 1988 7 135 8 5 Singh S et al Clin Pharmacol Ther 1982 32 607 11 6 Bryson SM et al DICP Ann Pharmacother 1991 25 68 71 70 Quinidine Quinidine has a number of factors associated with its bioavailability There are several salt forms each containing different amounts of quinidine base Each dosage form also has an associated absorption rate constant and bioavailability Certain factors can also affect these absorption parameters Oral Quinidine Parameters Dosage Form Salt Refs Quinidine Sulfate 0 83 0 8 1 8 1 4 nonsustained release tablets and capsules Cardioquin 0 6 0 8 1 15 1 Quinaglute 0 625 0 8 0 7 1 5 7 Duraquin 0 625 0 8 0 5 4 8 9 Quinidex 0 83 0 8 0 34 1 10 13 Intramuscular Quinidine Parameters Quinidine Gluconate 0 625 0 875 0 77 3 Quinidine Sulfate 083 0 875 077 3 Concurrent rifampin use increases the first pass metabolism of quinidine and decreases oral bioavailability by 41 Congestive heart failure decreases the rate of absorption of oral quinidine by 4590 7 IM quinidine absorption is slowed by 56 Formulas Clearance L hr CL over 60 yr and gt 50kg 0 0566 x CLcr 10 References 5 17 CL 12 to 60 yr or elderly adults lt 50kg 0 0566 CLcr 0 2 adjusted weight Reference 17 20 CL 9 to 12 yr
37. am possibly more per Walbridge DG et al Br J Psychiatr 1985 147 206 7 and Harrison TM et al Br J Psychiatr 1986 149 124 5 Diclofenac Indomethacin or Naproxen Diclofenac indomethacin and naproxen decrease lithium clearance by an average of 25 per Reimann IW et al Arch Gen Psychiatr 1983 40 283 6 Frolich JC et al Br Med J 1979 28 1115 6 and Ragheb M et al J Clin Psychopharmacol 1986 6 150 4 Low Sodium Diet A low sodium diet decreases lithium clearance by up to 50 per Atherton JC et al Kidney Int 1990 37 suppl 28 S36 8 Theophylline The clearance of lithium is increased proportionately to theophylline serum concentration An increase in lithium clearance of 5096 corresponds approximately to a theophylline level of 15 mg L per Holstad SG et al Psychiatry Res 1988 25 203 11 Thiazide Diuretics Thiazides in typically used doses decrease lithium clearance by an average of 2996 per Petersen V et al Br Med J 1974 2 143 5 Himmelhoch JM et al Clin Pharmacol Ther 1977 22 225 7 and Jefferson JW et al JAMA 1979 241 1134 6 References 1 Amdisen A Carson SW In Evans WE Schentag JJ Jusko WJ eds Applied pharmacokinetics principles of therapeutic drug monitoring 2nd Ed Spokane Applied Therapeutics 1986 978 1008 2 Vitiello B et al J Clin Psychopharmacol 1988 8 355 9 3 Groth U et al Clin Pharmacol Ther 1974 16 490 8 4 Mason RW et al Clin Pharmacokinet 1978 3 241 6 5 Hunter R Br J Clin Pharmacol 1988 25 375 8
38. an be skip then click Log In If user selected the Input option in Program Setting then the exact user name need to entered After the log in user can use Precise PK as either a Normal User or Administrator depends on the user s role User can also choose the click Guest button to use Precise PK as a Guest User Guest User has some restriction However no user name and password is required for Guest user Note that if some database errors such as failing to connect the database may cause user to be logged in as Guest User 34 CHAPTER 3 PHYSIOLOGIC PARAMETERS This chapter provides documentation of the formulas and methods used to estimate various physiologic parameters of the patient These in turn are used to estimate the pharmacokinetic parameters used in dosage regimen and serum level forecasts as well as starting points for the curve fitting routines Body Surface Area The body surface area BSA is calculated by the formula of Haycock GB et al J Pediatr 1978 93 62 6 Formula BSA weight 3 8 x height 3 64 x 0 024265 where BSA is in M5 weight is in kg and height is in cm Body Weight The patient s total body weight is entered in the Patient Demographic screen Precise PK will calculate the appropriate weight to use for the various calculations used in the program Modified Weight The modified weight of adults over 18 years of age is defined in Precise PK as the ideal body weight Devine BJ Drug In
39. ave amp Exit to apply the update To delete a user select the user on the list and click the minus button on the lower left corner A confirmation window will pop up If yes is clicked user will be deleted 12 As a Normal User User can only modify his her own information and cannot see add update delete other user About forgetting password user can click Forget Password and an tips window will pop up and give the user an instruction to reset the password password 13 CHAPTER 2 SYSTEM OVERVIEW 2 1 Welcome Screen and Manu Bar ren File Analysis Settings Help X Precise A pharmacokinetics 4 a therapeutic f drug monitoring system by Healthware Inc 27 72 Formally known as T D M S 2000 New Patient Load Patient Licensed to Hospital A Expires at 03 01 2015 Version v0 15 01 20 Figure 2 1 1 Welcome Screen and Menu Bar The Welcome Screen Figure 2 1 displays the program name version the name of user s institution and the expiration date of the current license as it is set in users computer In order to start any calculation user will need to select or create a patient There are two choices on the Welcome Screen New Patient will lead user to the which contains empty patient information Load Patient will lead user to the tient which allows user to specify the way user want to search for
40. ch decrease theophylline clearance by about 15 Thyroid Dysfunction Theophylline clearance is increased by 4046 in hyperthyroidism while hypothyroidism decreases clearance by 20 and increases volume of distribution by 4096 References 1 Fagerstrom PO et al Int J Clin Pharmacol Ther Toxicol 1983 21 359 62 2 Jonkman JHG et al Eur J Clin Pharmacol 1980 17 379 84 3 Hendeles L et al Clin Pharmacokinet 1984 9 95 135 76 eS ee 10 11 12 13 Upton RA et al J Pharmacokinet Biopharm 1980 8 131 49 Williams RL et al Curr Ther Res 1982 31 45 55 Williams RL et al J Asthma 1983 20 27 30 Saccar Cl et al Ann Allergy 1983 50 245 8 Pedersen S et al Pediatrics 1984 74 534 8 Hendeles L et al Chest 1985 87 758 65 Karim A et al Clin Pharmacol Ther 1985 38 642 7 American Hospital Formulary Service Drug Information 85 1675 7 Hendeles L et al Pharmacotherapy 1983 3 2 44 Benet LZ Sheiner LB In Goodman AG et al eds The pharmacological basis of therapeutics 7th ed New York Macmillan 1985 1663 733 14 15 16 17 18 19 20 21 Gal P et al Clin Pharmacol Ther 1978 23 438 44 Blouin RA et al Clin Pharmacol Ther 1980 28 619 23 Rohrbaugh TM et al Pediatr Pharmacol 1982 2 75 83 Jewesson PJ et al Ther Drug Monit 1985 7 197 201 Kubo M et al J Pediatr 1986 108 1011 5 Gilman JT et al Ther Drug Monit 1986 8 4 10 Nassif EG et al J Pediatr 1981 98 158 61 Peck CC et al Proceedings of
41. d New York Macmillan 1985 1663 733 Vogelstein et al J Pediatr 1977 91 333 9 Finkelstein E et al J Pediatr 1979 94 163 4 Letter Levy J et al J Pediatr 1984 105 117 24 Jusko WJ et al Kidney Int 1976 9 430 8 Berry PL et al Pediatr Pharmacol 1982 2 257 73 10 Rohwedder H J et al Dtsch Med Wochenschr 1970 95 1171 4 11 Kelman AW et al Br J Clin Pharmacol 1984 18 685 92 12 Tointon MM et al Clin Pharm 1987 6 160 2 13 Kelly HW et al Pharmacotherapy 1990 10 238 14 Cohen P et al Pediatr Infect Dis J 1990 9 562 6 15 Burton ME et al Clin Pharmacol Ther 1985 37 349 57 16 Zaske DE et al JAMA 1982 248 3122 6 ASNH 9 tA 48 17 18 19 20 21 22 23 24 25 26 21 28 29 Bosso JA et al Clin Pharm 1987 6 54 8 Munzenberger PJ et al Drug Intell Clin Pharm 1987 21 10A 1A Hoppe M et al Drug Intell Clin Pharm 1987 21 13A Horner GW et al Drug Intell Clin Pharm 1987 21 276 8 Fuhs DW et al Clin Pharm 1988 7 207 13 Dasta JF et al Crit Care Med 1988 16 327 30 Loirat P et al N Engl J Med 1978 299 915 9 Manny RP et al Clin Pharm 1986 5 629 32 Higa GM et al Clin Pharm 1987 6 963 6 Phillips JK et al N Engl J Med 1988 319 1290 Segal JL et al Drug Intell Clin Pharm 1988 22 461 5 Kearns GL et al J Pediatr 1986 108 847 53 Bhatt Mehta V et al Pharmacotherapy 1992 12 28 32 49 Ciprofloxacin The salt fraction for ciprofloxacin is 1 for both the oral and injectable product
42. d by 50 if this option is selected Highly Protein Bound Drugs Drugs that are highly albumin bound can increase the free unbound fraction of phenytoin The free fraction is increased by 50 in Precise PK with valproic acid concentration over 70 mg L The value arises from the 50 change that occurs with moderate serum levels of valproic acid per Winter M in Murphy J ed Clinical Pharmacokinetics Pocket Reference 2005 267 85 Jaundice The free fraction is increased by 50 with a serum bilirubin gt 6 mg dL This value is estimated from the fact that a serum bilirubin of 6 mg dL is over 0 1 mmol L per Tozer TN Winter ME Chapter 25 Phenytoin In Applied pharmacokinetics 2nd ed Applied Therapeutics Vancouver WA 1986 Neurologic Injury Critically ill patients with head trauma have high phenytoin requirements This appears to be caused primarily by an increase in predicted Vmax by 40 Boucher BA et al Clin Pharmacol Ther 1988 44 675 83 and O Mara NB et al Crit Care Med 1995 23 1418 24 66 Tube Feeding Tube feeding has marked effects on phenytoin levels In Precise PK it is modeled as a decrease in F to 0 6 and an increase in its SD to 0 3 per the computer program Phenda Boucher BA et al Clin Pharm 1987 6 881 7 Other Factors Many other factors are known to affect phenytoin serum concentrations However the exact effects on pharmacokinetic parameters are not known They probably also increase the variability in t
43. deal body weight LBW Lean body weight MIC Minimum inhibitory concentration of a bacterium Peak The extrapolated serum concentration at the exact end of an IV infusion Post The serum concentration at a user specified time after the end of an infusion TBW Total body weight CHAPTER 1 SYSTEM SETTING AND COMMON OPERATION eene nenne enne nnne nennen nnn 6 PROGRAM REGISTER AND LICENSE UPDATE eene n nnn sess assess assess sess ssa 6 DATABASE SETTING AND CONVERT cecececececececececeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeseeeseeesesesesesesesesesesenesenesenenesenenenenens 9 PROGRAM UPDATE 5 5 sentent ee oye cuna ee eo eene e aee ee E be QE ue eene ee ed EU 11 ADD UPDATE DELETE USER AND FORGOT 5 1 1 12 CHAPTER 2 SYSTEM OVERVIEW iris eee eoa o eua rre o eo er au one sh caia e a Po SA ee aao AE apes aiaa 14 2 1 WELCOME SCREEN AND MANU sese sese sess sr P 14 2 2 PATIENT amp CASE WINDOW 16 2 3 LOAD PATIENT 8 SEARCH RESULT 19 2 4 MAIN WINDOW E t nets t sde 22 2 5 SERUM LEVEL FORECAST amp DOSAGE REGIMEN F
44. dosing weight References as recalculated in reference 2 3 4 10 13 Vdg adults with CLcr under 10 mL min 1 0 x dosing weight Reference 17 Vdg infants 6 months and under is calculated as follows kio CL Vc CLq 0 0334 X total body weight CLq Vc do kyo X k21 k10 a 4Aa4 4 X24g B 2 Vdg CL B Reference 19 Bayes Parameters Coefficients of variation of pharmacokinetic parameters are as follows CL 50 3296 in infants 6 months and under Vdg 3096 1696 in infants 6 months and under CF 5096 The time weighting or is 1 005 79 Modifying Factors Critically ICU Patients Critically ill and ICU patients have a larger volume of distribution than other patients and their variability over time is greater Vdg is increased by 13 in patients over 1 month of age and time weighting is increased to 1 0 Burn Patients Burn patients often have high creatinine and vancomycin clearances but the relationship between the two is essentially the same as in unburned patients Precise PK allows creatinine clearance to range as high as 265 mL min in this patient group and calculates vancomycin clearance as for other patients Gestational Age 28 Weeks Neonates with a gestational age less than 28 weeks have altered vancomycin clearance compared to other infants These are accounted for in the clearance equation above and applies only to infants 60 days of age o
45. e regimens The time above the MIC appears to be most useful for drugs that act on the bacterial cell wall e g B lactams vancomycin Maximizing time above the MIC with these antibiotics appears to improve their efficacy when used against susceptible organisms The concentration of drug in plasma should exceed the MIC for all or most of the 24 hour period daily for optimal efficacy with drugs having little or no post antibiotic effect against the organism e g B lactams against gram negative organisms However this alone may not be sufficient because some resistant organisms may require high peak levels for optimal killing AUIC Several slightly different methods of combining the area under the serum concentration time curve with the MIC have been reported to correlate with antimicrobial efficacy The method with the most study in humans is the area under the inhibitory curve AUIC The AUIC is a value derived by first calculating the area under the serum concentration time curve AUC AUC is then divided by the MIC of the organism to calculate the AUIC value which technically is dimentionless although the unit SIT or inverse serum inhibitory titer has been applied to this value It also is suggested that the time above the MIC should be maintained at 24 hours in seriously ill hospitalized patients while applying the AUIC method An AUIC value that appears to predict antimicrobial efficacy is 125 This value may apply acro
46. en new case with that patient Double dick a case to open the case Figure 2 3 2 Search Result The Search Result Window Figure 2 3 2 will display the patient records which fits users search filter and it will displays the record on the left area If no record fits the filter or there is no patient in the database then the area will be empty In this screen there are some operations user could choose to obtain different results Double click a Patient on the left will open a Patient amp Case Window with the patient information Single click a Patient on the left will show all the cases of that specific patient on the right area Also it will put that patient or case in the selected status Double click a Case on the right will open a Patient amp Case Window with the patient information and the case information Single click a Case on the right will put that case in the selected status On the bottom of the screen there are three buttons The Back button will lead user back to the Load Patient screen which user can reset the search filter and search again The other two buttons behavior will be different depends on the selected status of the patient on the left area and the case on right area The Delete button will delete the corresponding patient or case record which is under the selected status If user decide to delete a case just single click a case then click the delete button The selected case will then be
47. enicol cimetidine clarithromycin possibly disulfiram isoniazid especially in slow acetylators omeprazole sulfonamides ritonavir trimethoprim valproic acid possibly and zafirlukast possibly per Winter M in Murphy J ed Clinical Pharmacokinetics Pocket Reference 1993 193 209 amp Anderson PO Cytochrome P450 enzyme interactions In Anderson PO Knoben JE eds Handbook of clinical drug data 8th ed Stamford CT Appleton amp Lange 1997 694 6 Enzyme Inducing Drugs Drugs that induce hepatic cytochrome P450 metabolism of phenytoin increase Vmax and or decrease Km These drugs do not have adequate documentation to allow specific changes to phenytoin parameters in Precise PK Common drugs included in this category include carbamazepine phenobarbital usually an inducer but sometimes a competitive inhibitor and rifampin Winter M in Murphy J ed Clinical Pharmacokinetics Pocket Reference 1993 193 209 amp Anderson PO 67 Cytochrome P450 enzyme interactions In Anderson PO Knoben JE eds Handbook of clinical drug data 8th ed Stamford CT Appleton amp Lange 1997 694 6 References 1 Boucher BA et al J Pharm Sci 1989 78 929 32 2 Fierro LS et al Am J Health Syst Pharm 1996 53 2702 12 3 Tozer TN Winter ME Chapter 25 Phenytoin In Applied pharmacokinetics 4th ed Lippincott Williams amp Wilkins Baltimore 2006 4 Winter in Murphy J ed Clinical Pharmacokinetics Pocket Reference 1993 193 209
48. ents to the weight for subsequent calculations Entering the adjusted weight here may result in erroneous calculations After the Sex Birthday Weight and Height fields are entered The calculated Body Mass Index Body Surface Area Learn Body Mass and Ideal Body Weight will appear in the left column Patient Note will be stored with the Patient record in the database Information in this field will be retrieved whenever the Patient or any of the patient s Case records are retrieved In the right Case column user enter data about the particular course of drug therapy that user are studying Drug is selected from the drop down menu User may also type in the first letter of the drug name and the drop down menu will display the drug as soon as a match occurs Select a Maximum of 2 Applicable Factors Is this a critically ill or ICU patient 11 Is this a burn patient E Is this a hematology oncology patient Is this a spinal cord injury patient ET Is this a cystic fibrosis patient Figure 2 2 2 Drug Factors A Factor Window Figure 2 2 2 will appear if user click the Drug Factors Button after finishing filling or selecting the Birthday and Drug User can enter up to two factors 17 known to affect the pharmacokinetics by at least 10 of the drug being used in this Case Click on the check box to the left of any factor s that are applicable Once the appropriate factors have been checked c
49. et of value For example if I want to hide population graph just click on the Pop in the legend User can also set an initial concentration instead of using 0 by default and can also specify how many intervals doses the graph should draw By entering Time x value it will automatically show the corresponding level y value for each PK parameters 26 2 6 Dosage History amp Graphical Analysis f Dosage History Patient A Amikacin x Date 01 01 14 2015 00 100 02 01 15 2015 100 OD 103 01 15 2015 04 01 21 2015 BS overs 06 01 21 2015 07 01 21 2015 08 01 21 2015 09 01 21 2015 10 01 21 2015 01 21 2015 2 01 21 2015 Serum Level History Date Date Choose Prior PK Parameter Values for the 01 14 2015 7 01 21 2015 curve Fitting routine 01 21 2015 8 01 21 2015 Use Population PK Use Custom PK 01 21 2015 9 01 21 2015 01 21 2015 10 01 21 2015 01 21 2015 11 01 21 2015 01 21 2015 12 01 21 2015 E Figure 2 6 1 Dosage History Window This Dosage History Window Figure 2 6 1 allows user to enter the dosage history and serum level history for this case In Dosage History Window user should enter all the necessary information Routes are selected by the drop down menu For IV route user need to enter all the information and for other route infusion time can be omit
50. ference 14 weighted average of all groups Km gt 15 yr 5 7mg L Reference 13 Volume of Distribution L Vd lt 1 yr 1 x TBW 30 Reference 3 Vd gt 1yr if TBW IBW Vd 0 65 if TBW gt IBW Vd 0 65 x IBW 1 33 x TBW IBW Reference 3 15 Correction of Serum Levels and Vd to Normal Albumin Concentration and Affinity For CLcr lt 25 mL min Uncorrected Parameter Corrected P erea arx s rum 24 50 orrectea aramewer 0 48 x 1 a x serum albumin 4 4 a For CLcr gt 25 Uncorrected Parameter C ted P QUU ET MUTET ATEN 1 a x serum albumin 4 4 a Correction of Serum Level Range and Km for Altered Albumin Concentration and Affinity For CLcr lt 25 mL min Corrected Parameter Uncorrected Parameter 0 48 1 serum albumin 4 4 For CLcr gt 25 mL min Corrected Parameter Uncorrected Parameter x 1 serumalbumin 4 4 a Curve Fitting Curve fitting of phenytoin varies somewhat for phenytoin compared to other drugs in 65 Precise PK Because there is no direct mathematical method for calculating the concentration at any given time after a dose a unique iterative method is used see Michaelis Menten Formulas in Chapter 3 Pharmacokinetic Formulas Also because more parameters are fitted and the number of serum levels may be few and because most published reports in the literature use Bayesia
51. fo on the top At the bottom of the Main Window there four sets of PK parameters User can choose different routes in different set to show the corresponding parameters The Population PK Parameters cannot be change However user can use another set of parameters called Custom PK Parameters to compute different numbers The other two sets of PK parameters Bayesian PK parameters and Least Squares PK Parameters will be available once enough number of dosage history and serum level have been entered and analysis The Reset button under the set of Custom PK Parameters will resets all the customized PK parameters back to the last saved version By default if there no customized PK parameters us set for the patient then the Custom PK Parameters will be the same as Population PK Parameters 23 2 5 Serum Level Forecast amp Dosage Regimen Forecast Blood Level mg L Figure 2 5 1 Serum Level Forecast Window This Serum Level Forecast Window Figure 2 5 1 allows user to predict the serum drug concentrations achieved by dosage regimen that user enter Results are calculated using all four types of pharmacokinetic values if available When user modified the Custom PK Parameters on the Main Window the corresponding values are also changed automatically User can select route and specific drug product from the drop down box on top of the screen Different route might have different user interface for entering the dosage regimen
52. he factors they affect The following factors are not programmed into Precise PK but the user may consider manually adjusting these parameters and or increasing their SD in patients with one of these conditions Antacids or Sucralfate Antacids or sucralfate may decrease bioavailability F of phenytoin It is best to separate doses of phenytoin and antacids by 2 or more hours per Winter M in Murphy J ed Clinical Pharmacokinetics Pocket Reference 1993 193 209 Cirrhosis or Severe Liver Disease Liver diseases may reduce phenytoin s metabolism causing a decrease in Vmax per Tozer TN Winter ME Chapter 25 Phenytoin In Applied pharmacokinetics 4th ed Lippincott Williams amp Wilkins Baltimore 2006 Diarrhea Diarrhea may decrease the absorption F of phenytoin per Winter M in Murphy J ed Clinical Pharmacokinetics Pocket Reference 1993 193 209 Fluoxetine Fluconazole and Voriconazole These drugs have been relatively well document to increase phenytoin AUC by about 75 per Drug Interactions Facts Wolters Kluwer Health Inc 2008 This change is modeled as an increase in Km by 75 in Precise PK Other Enzyme Inhibiting Drugs Drugs that competitively inhibit hepatic cytochrome P450 metabolism of phenytoin increasing its Km These drugs do not have adequate documentation to allow specific changes to phenytoin parameters in Precise PK Common drugs included in this category include amiodarone fluvastatin possibly chloramph
53. icients of variation of pharmacokinetic parameters are follows F specified by product above CL 5096 Vd 2596 CF 5096 The time weighting factor is 1 01 2 75 Modifying Factors Congestive Heart Failure Congestive heart failure decreases theophylline clearance to 43 of normal Cirrhosis Cirrhosis decreases theophylline clearance by 509623 Chronic Obstructive Pulmonary Disease COPD decreases theophylline clearance to 80 of normal Smoking Smoking increases theophylline clearance to 1 6 times normal Cimetidine Cimetidine use decreases theophylline clearance to 75 of normal 225 Ciprofloxacin or Erythromycin Concurrent ciprofloxacin use decreases theophylline clearance by 2590 2928 Concurrent erythromycin use also decreases theophylline clearance by about 25 after 5 days of use Oral Contraceptives Oral contraceptives decrease theophylline clearance by 30 32 Phenytoin Concurrent phenytoin use increases theophylline clearance to 1 5 times normal 3 Rifampin Rifampin increases theophylline clearance by 4596 7 Mexiletine or Troleandomycin Concurrent mexiletine or troleandomycin use decreases theophylline clearance by about 50 239 Cystic Fibrosis Cystic fibrosis increases theophylline clearance by 1 8 times and increases volume of distribution by 3090 Phenobarbital Chronic phenobarbital use increases theophylline clearance by 3390 Diltiazem or Verapamil Diltiazem and verapamil ea
54. ied pharmacokinetics 3rd ed Spokane Applied Therapeutics 1992 18 1 13 Schentag JJ et al DICP Ann Pharmacother 1991 25 1050 7 Schentag JJ Scand J Infect Dis Suppl 1991 suppl 74 218 34 Deziel Evans LM et al Clin Pharm 1986 5 319 24 Moore RD et al J Infect Dis 1987 155 93 9 Drusano GL Antimicrob Agents Chemother 1988 32 289 97 Knoben JE Anderson PO eds Handbook of clinical drug data 7th ed Hamilton Drug Intelligence Publications 1993 334 7 8 Schentag JJ et al Dual individualization with antibiotics integrated antibiotic management strategies for use in hospitals In Evans WE Schentag JJ Jusko WJ eds Applied pharmacokinetics 3rd ed Spokane Applied Therapeutics 1992 17 1 20 9 Forrest A et al Antimicrob Agents Chemother 1993 37 1073 81 10 Schentag J Personal communication December 8 1993 11 Choi G et al Blood Purif 2010 30 195 212 83 APPENDIX B CURVE FITTING Precise PK uses both Bayesian and least squares curve fitting methods to adjust the population values of pharmacokinetic parameters F Vd CL CF as serum level data are obtained The Bayesian model used was originally described by Sheiner LB et al Comput Biomed Res 1972 5 441 59 and Clin Pharmacol Ther 1979 26 294 305 and is mathematically expressed as follows where N the number of parameters fitted N 4 for outpatient oral drugs N 3 for inpatient oral drugs N 2 for inpatient intravenous and i
55. ight References 6 10 CL 1 month and under 0 005 0 0325 x age in yr x total body weight References This equation was written to make a smooth transition between values for newborns and month old infants as suggested by data in references 17 and 18 Volume of Distribution L Vd over 1 month 0 6 x total body weight References 10 13 Vd 1 month and under 0 91 3 7 x age in yr x total body weight Reference this equation was written to make a smooth transition between Vd of 0 6 L kg above and neonatal Vd of 0 91 L kg per references 10 13 Bayes Parameters Coefficients of variation of pharmacokinetic parameters are as follows F 1096 CL 20 in adults and 40 in children under 13 and in those taking valproate Vd 10 in adults and 20 in children under 13 CF 50 The time weighting factor is 1 005 61 Modifying Factors Liver Disease Severe cirrhosis decreases phenobarbital clearance by one third while hepatitis decreases clearance by 17 Pregnancy Pregnancy increases clearance by an estimated 35 from data of reference 16 Valproic Acid Concurrent valproic acid use decreases phenobarbital clearance by 35 in adults and 55 in children under 16 44 References Wilensky AJ et al Eur J Clin Pharmacol 1982 23 87 92 Meyer MC et al J Pharm Sci 1984 73 485 8 Patel IH et al Clin Pharmacol Ther 1980 27 515 21 Nelson E et al J Clin Pharmacol 1982 22 141 8 Wilensky AJ et al Eur J Clin Pharm
56. in Pharmacol Ther 1985 37 150 6 15 Jones WN et al Eur J Clin Pharmacol 1986 31 351 3 16 Rameis H et al Clin Pharmacol Ther 1984 36 183 9 17 Beltrami TR et al J Clin Pharmacol 1985 25 390 2 18 Yoshida A et al Clin Pharmacol Ther 1984 35 681 5 19 Hager WD et al Engl J Med 1979 300 1238 20 Fenster PE et al Clin Pharmacol Ther 1984 36 70 3 21 Johnson BF et al Clin Pharmacol Ther 1987 42 66 71 22 Hedman A et al Clin Pharmacol Ther 1991 49 256 62 23 Pedersen KE et al Eur J Clin Pharmacol 1982 22 123 7 24 Waldorff S et al Clin Pharmacol Ther 1981 30 172 6 25 Waldorff S et al Clin Pharmacol Ther 1983 33 418 23 26 Waldorff S et al Clin Pharmacol Ther 1978 24 162 7 54 Flucytosine The salt fraction for flucytosine is 1 for both the oral and injectable investigational product Oral bioavailability is 84 15 and the absorption rate constant is 1 1 Parenteral bioavailability is 100 5 Formulas Clearance L hr CL 6 months and over 0 79 CLcr 0 01 adjusted weight References 1 3 Volume of Distribution L Vd 6 months and over 0 71 adjusted weight References 1 4 Bayes Parameters Coefficients of variation of pharmacokinetic parameters are as follows F 15 CL 50 Vd 30 CF 50 The time weighting factor is 1 005 Modifying Factors There are no well documented factors that affect flucytosine pharmacokinetics other than renal function which is accounted for in
57. institution will have its own encryption i e Institution A s license cannot open institution B s database 10 Program Update To update the whole program You can then also go Settings Program Setting and click on Software Version and click on Software Update If the current version is the newest program will show a message saying the current version is already the newest Otherwise the program will prompt a window and let the user to choose a place to store the updater Then the updater will be downloaded and run automatically and the program will restart after the update success 11 Add Update Delete User And Forgot Password There will always be a default user for the program with user name admin By default user will run the program using admin account with password disabled As an Administrator To manage user setting go Settings Manage Users Account a window will pop up like this Save amp Exit To add a user click the button on the lower left corner and then enter the corresponding user information User can choose to enable or disable the password option If password is disabled user can simply click login without entering anything After the information is filled out click Add or Save amp Exit will apply all the changes To update a user select the user on the list and that user s information will show up on the right side After finishing update click Apply or S
58. l eds The pharmacological basis of therapeutics 7th ed New York Macmillan 1985 1663 733 Ochs HR et al Am J Cardiol 1978 41 770 7 Spenard J et al Int J Clin Pharmacol Ther Toxicol 1983 21 1 9 Sirois G et al Biopharm Drug Disp 1980 1 167 77 Estimates from graphic data supplied by Parke Davis 9 Smith TC et al Curr Ther Res 1977 21 128 34 10 Wright GJ Unpublished bioavailability study Robins 11 Gibson DL et al Clin Pharm 1982 1 366 8 12 Sawyer WT et al Biopharm Drug Disp 1982 3 301 10 13 Mahon WA et al Clin Pharmacokinet 1987 13 118 24 14 Twum Barima Y et al N Engl J Med 1981 304 1466 9 15 Ueda CT et al Br J Clin Pharmacol 1981 11 571 7 16 Couthamel WG Am Heart J 1975 90 335 9 17 Fattinger K et al Br J Clin Pharmacol 1991 31 279 86 18 Ochs HR et al Am J Cardiol 1978 42 481 5 19 Szefler SJ et al Pediatrics 1982 70 370 5 20 Guentert TW et al J Pharmacokinet Biopharm 1979 7 315 30 21 Ueda CT et al Clin Pharmacol Ther 1978 23 158 64 22 Kessler KM et al Am Heart J 1978 96 627 35 23 Saal AK et al Am J Cardiol 1984 53 1264 7 24 Hansten PD Drug Interactions 5th Ed New York Macmillan 1985 25 Hardy BG et al Am J Cardiol 1983 52 172 5 26 Edwards DJ et al Clin Pharmacol Ther 1987 41 68 73 27 Trohman RG et al Am J Cardiol 1986 57 706 7 DNDN 73 Theophylline Absorption parameters for the theophylline derivatives include the salt form salt the bioavail
59. lability by 17 596 and increases the SD to 15 per Lehto P et al Br J Clin Pharmacol 1994 37 82 5 Martinez Cabarga M et al Antimicrob Agents Chemother 1991 35 2102 5 59 Sucralfate Sucralfate decreases ofloxacin bioavailability by 61 per Lehto P et al Antimicrob Agents Chemother 1994 38 248 51 References Yuk JH et al Antimicrob Agents Chemother 1991 35 384 6 Sanchez Navarro A et al Antimicrob Agents Chemother 1990 34 455 9 Lameire N et al Clin Pharmacokinet 1991 21 357 71 H ffler D Koeppe P Drugs 1987 34 suppl 1 51 5 Farinotti R et al Antimicrob Agents Chemother 1998 32 1590 2 Lode H et al Antimicrob Agents Chemother 1987 31 1338 42 Yuk JH et al Antimicrob Agents Chemother 1991 35 384 6 Sanchez Navarro A et al Antimicrob Agents Chemother 1990 34 455 9 Qo cgo eec par 60 Phenobarbital The salt fraction is 1 for the oral product and 0 91 for the injectable product Oral bioavailability is 100 10 while parenteral bioavailability is 100 5 Absorption rate constants are 1 5 hr for tablets 7 2 hr for the elixir and 1 1 hr for IM injections Formulas Clearance L hr CL over 13 yr 0 004 x total body weight References 3 6 CL 10 to 13 yr 0 0077 age in yr 10 x 0 0012333 x total body weight Reference this equation was written to make a smooth transition between age groups above and below as suggested by data in reference 7 CL 1 month to 10 yr 0 0077 x total body we
60. lick the Submit button at the bottom of the window and user will see the selected factors will appear on the right of the Patient amp Case Window The patient s creatinine clearance CLcr can be calculated from serum creatinine Crs or it can be entered directly if user have a measured value Select either Crs or CLer with the radio button and enter the value in the corresponding units in the box to the right of users selection Also Precise PK provides two options of Crs renal function User can choose either one of them by selecting the Crs radio button make the selection of which renal function user would like to use then in put the corresponding Crs values and or Time Interval in the proper fields Serum Albumin is only required when user have selected the drug phenytoin Otherwise this entry is skipped To fit unbound phenytoin levels enter 0 01 as the serum albumin concentration The date that this particular Case was updated is displayed on the top of the right column Case Note will be stored with the Case record in the database Information in this field will be retrieved whenever this Case record is retrieved The Cancel button at the bottom of this screen allows user to go back to the previous screen and discard all changes user have made for this patient or case The Continue button will proceed with analysis of this case 18 2 3 Load Patient amp Search Result Figure 2 3 1 Drug Factors If user select Load
61. llows Bioavailability Tablets 70 14 Capsules 95 5 Elixir 77 5 9 6 IV Injection 100 5 The oral absorption rate constant ka is set at 1 5 hr It should be noted that this rate constant has its primary use in determining the shape of curves plotted in the graphics portion of PrecisePK Although Ka is used during curve fitting serum digoxin levels should not be drawn before 6 8 hours after an oral dose when using a one compartment simulation Since absorption is complete by 6 8 hours after the dose the exact value of the absorption rate constant is not important during curve fitting Formulas Clearance L hr CL CHF over 10 yr 0 88 x CLcr 0 33 IBW x 0 06 CL nonCHF over 10 yr 1 02 x CLcr 0 8 IBW x 0 06 Reference 3 CL 6 months to 10 yr 1 4 x CLcr 0 7 x IBW x 0 06 References 4 8 CL under 6 months 3 2388 2 8777 x age in yr x TBW x 0 06 This equation was written to make a smooth transition between a neonatal clearance of 0 18 x total body weight and the clearance at six months CL under 1 month 0 18 x TBW CL under 1 month premature 0 12 x TBW calculation made only if Crs is less than 0 8 1 2 mg dL depending on the age of the infant Reference all data for children under 6 months from reference 9 52 Volume of Distribution L Vd 10 yr and over 3 12 x Clcr 3 84 IBW Reference 3 Vd 2 yr to 10 yr 16 x IBW Vd 1 month to 2 yr 8 44 age in yr x 3 78
62. me to peak at steady state TMax s is calculated as an intermediate step for calculating Peaks Formulas SxFEFxD e KdXTMaxss PERDSRUXE A SxFXxD 7985 Ch xt In MERON SxFxDxkKa priu Troughs Vd x Ka Kd Gear ge Kax 41 Concentration at Time t These equations are used to calculate the serum concentration cp at a given time t after a dose where S is the salt fraction D is the dose CF is the compliance factor F is the bioavailability K is the infusion rate t 15 the infusion time Vd is the volume of distribution CL is the clearance and Kd is CL Vd They are used in both the curve fitting routines and in the graphics calculations The concentration during a multiple dose regimen is calculated by superposition 1 e addition of the contributions of all prior doses The superposition method is used in both the curve fitting and graphics portions of Precise PK to determine the serum concentration at times of interest IV Formulas IV Bolus CFXSXD C 2 Kdxt Res ye E During IV Infusion CF X S x K Cp x 1 e Kdxt CL After the End of An Infusion CF XS x K Cp T 257 1 e Kaxtiney x Dosage CF x S x F x Ka x dose e Kaxt g Kaxt Vd x Ka Kd 42 TWO COMPARTMENT Micro Rate Constants
63. n Pharmacol Ther 2007 82 505 8 This is in contrast to ideal body weight which includes a normal amount of body fat weight LBW Formulas 9270 total body weight kg LBW 1 6680 216 BMI 9270 total body weight kg LBW les 2 0 femen 8780 244 BMD Where total body weight in k BMI body mass index HAN Walenta height m 36 Dosing Weight A dosing weight is used for some calculations Dosing weight is defined as follows For patients at or below their IBW Dosing weight total body weightFor patients above their IBW Dosing weight IBW 0 4 total body weight IBW Adjusted Weight An adjusted weight is used for some calculations based on literature documentation Adjusted weight is defined as follows For patients at or below their IBW Adjusted weight total body weight For patients above their IBW but less than their LBW Adjusted weight IBW For patients in whom LBW gt IBW Adjusted weight LBW Creatinine Clearance The creatinine clearance CLcr calculation used depends on the age of the patient One of two formulas is used In patients 18 years of age or older the method of Cockroft and Gault Nephron 1976 16 31 41 The adjusted weight defined above is used in the calculations Ideal body weight IBW is used because it is a simple and widely accepted measurement with relatively good predictive ability Rosborough TK et al Pharmacothe
64. n methods Precise PK uses only Bayesian curve fitting least squares is not available In addition levels are not time weighted in order to preserve as much serum level data as possible Bayes Parameters Coefficients of variation of pharmacokinetic parameters are as follows F 10 Vmax 30 Km 50 Vd 20 CF 50 The assay error is 10 and FE is 0 75 Modifying Factors Ethnic Differences Metabolism of phenytoin is under genetic control Various ethnic groups appear to metabolize phenytoin differently However it is unclear the extent to which genetic and environmental e g diet pollution factors contribute to these differences which groups are affected and by how much The best studied group is Japanese patients in Japan who have a lower Km than Europeans Japanese Americans have not been studied Some evidence also exists that Blacks in southern Africa have similarly prolonged elimination African Americans appear to have metabolism more similar to Caucasians than to southern Africans Saudi Arabians metabolism seems to be similar to Caucasians Hvidberg EF Ethnic differences in reactions to drugs and xenobiotics Alan R Liss Inc 1986 279 87 Edeki TI Brase DA Drug Metab Rev 1995 27 449 69 Botha JH et al Clin Pharm 1991 10 928 31 Grasela TH et al Clin Pharmacokinet 1983 8 355 64 Precise allows selection of a slow metabolism factor for patients who have ethnically slow metabolism Km is decrease
65. nse t Database Software Version Convert Database J kg Background Color No Style Sky Blue Autumn Orange Grass Green Fire Red Display Users List When Log In List D Input Figure 2 8 1 Program Setting Window The Program Setting Window Figure 2 8 1 is the place where user can change the setting of Precise PK The window contains different pages and each one of them handles one area of the setting User can switch between different pages using the menu panel on the left side e General Setting e Height Unit and Weight Unit set the default units for new Patient e Background Color sets the color style of the program e Display Users List When Log In options changes the Log In Window setting when user log in e Report Setting This page sets the default values for report printing e License In this page user can set the path of the license file or update license e Database This page shows the current path of the database and which user makes the last modification User can change the path of the database by clicking 31 Change button Note that all Precise PK database are associated with a Precise PK license which means the change database operation might failed because the license is not match Software Update This page allows user to check and update to latest version of Precise PK Convert Database This page allows user to convert or import a Precise PK database to a Precise PK da
66. nsson BA et al Antimicrob Agents Chemother 1992 2512 7 Oral Didanosine This product has buffering agents included which decrease ciprofloxacin bioavailability by 98 per Sahai J et al Clin Pharmacol Ther 1993 53 292 7 Oral Iron Oral iron decreases ciprofloxacin bioavailability by 50 per Polk RE Antimicrob Agents Chemother 1989 33 1841 4 Shiba K et al Antimicrob Agents Chemother 1992 36 2270 4 Lehto P et al Br J Clin Pharmacol 1994 37 82 5 Sucralfate Sucralfate decreases ciprofloxacin bioavailability by 60 per Garrelts JC et al Antimicrob Agents Chemother 1990 34 931 3 Nix DE et al Pharmacotherapy 1989 9 377 80 VanSlooten AD et al DICP Ann Pharmacother 1991 25 578 82 Zinc Zinc alone or in multivitamins decreases ciprofloxacin bioavailability by 50 per Polk RE et al Antimicrob Agents Chemother 1989 33 1841 4 References Plaisance KI et al Antimicrob Agents Chemother 1990 34 1031 4 Ljungberg B Nilsson Ehle I Eur J Microbiol Infect Dis 1989 8 515 20 Hirata CAI et al Antimicrob Agents Chemother 1989 33 1927 31 Drusano GL et al Antimicrob Agents Chemother 1987 31 860 4 Yuen G et al Am J Med 1989 87 suppl 5a 70s Forrest A et al Antimicrob Agents Chemother 1993 37 1065 72 Allard 5 et al Clin Pharmacol Ther 1993 54 368 73 DII ues uk 51 Digoxin The various dosage forms of digoxin have different bioavailabilities and coefficients of variation associated with their absorption The values used are as fo
67. ntramuscular drugs For nonsteady state phenytoin N is one greater for each of these situations initial population estimates for each pharmacokinetic parameter P revised fitted estimates for each pharmacokinetic parameter SD variance of the pharmacokinetic parameter M the number of serum levels obtained M can range from 0 to 9 in Precise PK Cp the serum concentration predicted from initial parameter estimates SD j the predicted serum concentrations based on revised parameter estimates SDepj variance of the predicted serum level SDoyj Cp X SD FE 0 for drugs other than phenytoin For phenytoin Vmax Km and Vd have an SD coef ficient of variation FE x Qt SD Coefficient of variation of the assay error Bayes 0 1 10 least squares 0 01 1 FE fixed error due to unaccounted for variability such as model misspecification Bayes 5 of the midpoint value of the therapeutic serum level range least squares 0 84 Q time weighting multiplier With least squares fitting the coefficient of variation of the serum levels SD is changed to 1 and FE is changed to 0 causing population parameters to be virtually eliminated and only serum level data to be considered in arriving at the final estimate Q is a time weighting factor typically 1 005 or 1 01 and t is the time in hours between the time of the most recent serum level and the time of the serum level t ho
68. ol 1987 33 483 6 77 Vancomycin Vancomycin pharmacokinetics are assumed to conform to a two compartment open model in Precise PK To accomplish the fitting with a fewer number of levels during the distribution phase K and Vc are fixed and are not allowed to vary once the original population estimate is made Parameters that are assigned by the program are as follows salt fraction and bioavailability 100 The microrate constant is fixed by age group as follows Constants Ky 0 46 References 1 as recalculated in reference 2 3 4 Kio a and are calculated from Vc Vdg and CL using the formulas in Chapter 3 Formulas Clearance L hr CL 6 months and over 0 79 x CLcr 0 05 x adjusted weight x 0 06 References 3 13 CL under 6 months 0 006 total body weight x 0 028 Crs 0 046355 x age in yr x PNA 0 0123 x GA where PNA 1 if Crs 0 7 or PNA 0 if Crs gt 0 7 and GA 0 if the infant s gestational age lt 28 weeks and age lt 60 days or GA the infant s gestational age gt 28 weeks Reference 19 Volumes of Distribution L Central Vc 6 months or under is calculated as follows Vss 0 793 x total body weight 0 01 Vc 0 666 X Vss 78 Reference 19 Vc over 6 months 0 17 x dosing weight References as recalculated in reference 2 3 4 12 14 Vc adults with CLcr under 10 mL min 0 45 x dosing weight References 17 19 Total Vdg over 6 months 0 7
69. owed by the Precise PK protection scheme is not exceeded 2 Copies of Precise PK screens may be made for teaching or patient care purposes No copies of Precise PK screens may be made for any other purposes commercial or noncommercial without written permission of Healthware Inc 3 You may not modify copy or transfer Precise PK in any way except as provided for in this license Any other uses or copies of Precise PK are not allowed under this license and use of this program indicates users acceptance of these terms and conditions The Precise PK User Manual is copyright Healthware Inc 1986 2014 No part of this Manual may be reproduced in any form or by any means without permission in writing from Healthware Inc Precise PK and Precise PK are trademarks of Healthware Inc and all references to Precise PK or Precise PK in this manual refer to the trademark although they may not be designated as such ACKNOWLEDGEMENTS The authors would like to thank James Lane Jr Pharm D William Murray Pharm D Alex Dominguez Pharm D M A S BCPS and Edmund Capparelli Pharm D who have provided numerous pharmacokinetic insights and beta testing that improved the program Abbreviations and Definitions of Terms Used in the Precise PK User s Manual AUIC Area under the inhibitory curve Post MIC BMI Body mass index BSA Body surface error CLer Creatinine clearance Crs Serum creatinine in mg dL IBW I
70. r younger Patent Ductus Arteriosus PDA Limited data which are consistent with aminoglycoside data indicate that Vd is increased by 47 in infants with patent ductus arteriosus This effect probably persists for a few days after treatment with indomethacin This factor applies only to infants less than 30 days old who weigh less than 1 kg Reference 1 Schaad UB et al J Pediatr 1980 96 119 26 2 Baker D et al J Pediatr 1980 97 502 3 Letter 3 Rotschafer JC et al Antimicrob Agents Chemother 1982 22 391 4 4 Rodvold KA et al Antimicrob Agents Chemother 1988 32 848 52 5 Rodvold KA et al Ther Drug Monit 1989 11 269 75 6 Benet LZ Sheiner LB In Goodman AG et al eds The pharmacological basis of therapeutics 8th ed New York Macmillan 1990 1714 7 Gross JR et al Pediatr Pharmacol 1985 5 17 22 8 Reed MD et al Pediatr Res 1987 22 360 3 9 Lisby Sutch SM et al Eur J Clin Pharmacol 1988 35 637 42 10 Krogstad DJ et al J Clin Pharmacol 1980 20 197 201 11 Cutler NR et al Clin Pharmacol Ther 1984 36 803 10 12 Blouin RA et al Antimicrob Agents Chemother 1982 21 575 80 13 Garaud JJ et al J Antimicrob Chemother 1984 14 suppl D 53 7 14 Matzke GR et al Antimicrob Agents Chemother 1984 25 433 7 15 Brater DC et al Clin Pharmacol Ther 1986 39 63 1 4 16 Spivey JM et al Am J Dis Child 1986 140 859 17 Tan CC et al Ther Drug Monit 1990 12 29 34 18 Hoie EB et al Clin Pharm 1990 9 711 5 19 Capparelli EV et al
71. rapy 2005 25 823 30 In morbid obesity when LBW gt IBW LBW is used in the equation because it has better predictive value Demirovic JA et al Am J Health Syst Pharm 2009 66 642 8 In children from age 0 5 years to 18 years the method of Traub and Johnson Traub SL and Johnson CE Am J Hosp Pharm 1980 37 195 201 is used In children less than 0 5 years of age no calculation is made 37 Formulas Adults over 18 140 age x adjusted weight CLcr males 72 x Scr CLcr males 0 85 x above value where is in mL min weight is in kg and Crs is in mg dL Children 18 or Under 5 height CLcr mL min 1 73M 0 48 x This value is then multiplied by the child s BSA 1 73 to obtain the individual s CLcr value where height is in cm and Crs is in mg dL As a final check CLcr is not allowed to go above 90 mL min m in patients 5 or more years of age or over 58 mL min m in patients under 5 years of age These values are approximately 2 standard deviations above the mean in populations with normal renal function 38 CHAPTER 4 PHARMACOKINETIC FORMULAS This chapter provides the user with the equations used to calculate various serum level and dosage regimen data throughout the program ONE COMPARTMENT Peak Serum Concentration This equation calculates the steady state peak serum concentration for intravenously administered drugs that results from infusing a dose D over time ting with a dosage
72. s as infection resolves In these patients the time weighting factor is increased to 1 01 in Precise PK to more heavily weight the most recent serum levels Time weighting is also increased to 1 01 in critically ill and ICU patients 7 Modifying Factors Many factors have been found to alter aminoglycoside pharmacokinetics However only a few have been reliably quantified and confirmed Only those that have been well quantified are included in Precise PK Critically Ill or ICU Patients Numerous studies have documented that critically ill and ICU patients have a larger volume of distribution than other patients and their variability over time is greater Vd is increased by 13 to 0 34 L kg in patients over 1 month of age and time weighting is increased to 1 01 212 Burn Patients Burn patients often have higher dosage requirements than other patient groups A major reason for this is that glomerular filtration rate is dramatically increased in some burn patients Precise PK allows creatinine clearance to range as high as 265 mL min in this patient group and calculates aminoglycoside clearance as for other patients If a burn patient is critically ill the Critically Ill or ICU Patient factor should also be selected 47 Hematology Oncology Patients These patients have an expanded Vd which is modeled as an increase of 17 to 0 35 L kg 6 Spinal Cord Injury These patients have a larger Vd which is increased in Precise PK
73. ser About Open the Precise PK Information Page Software Update Open the Software update Page which allows user to check and download the latest version of Precise PK Manual Open the Manual Window which contains a abstract version of the Precise PK User Manual for simple reference 15 2 2 Patient amp Case Window Patient amp Case Dat Drug Factors J Crs Stable Renal Function 1 Crs value Crsi Crs2 mg dL Time hr Body Mass Index Body Surface Area Lean Body Mass Ideal Body Weight Figure 2 2 1 Patient amp Case Window After selecting a specific ase ora nt user will be lead to the Patient amp Case Window Figure 2 2 1 This screen is used to gather information about the patient and drug of interest In the first three fields of the left Patient column user may enter the patient s Last and First names and any Hospital Identification number These fields are used to store and later identify the patient in the database User may jump between fields with a mouse click or tab key 16 Birthday is entered as mm dd yyyy Sex is entered by clicking on the appropriate radio button Male or Female Weight and Height are entered as numbers and the correct units are selected using the buttons to the right of each box These fields default unit can be set in Program Setting Window The patient s total body weight should always be entered Precise PK will make the proper adjustm
74. ss antimicrobial classes Clinically a value of over 125 has been associated with success of ciprofloxacin although higher values appear to offer more rapid eradication of organisms The method of calculating AUC has varied with most of the work published by Schentag and colleagues using a rather complex method that calculated the area only during that the serum drug concentration exceeds the MIC i e between the times where the serum concentration first exceeds the MIC and first drops below the MIC as in the time above the MIC calculation However more recently most investigators including Schentag have standardized on using simpler calculation of the total AUC below AUIC Calculations 22 24 45 SAONE 42452 i GL MIC x t 82 Suggested Pharmacodynamic Targets Antibacterials Killing characteristics Pharmacokinetic targets Aminoglycosides Concentration dependent Peak MIC ratio 8 10 Beta lactams Time dependent Time above MIC 40 100 of dosage interval or 40 100 of dosing interval gt 5 times MIC Fluoroquinolones Concentration amp Post MIC ratio 6 8 time dependent AUIC Gram negatives 100 125 AUIC Streptococcus pneumoniae 34 Linezolid Concentration dependent AUIC Streptococcus pneumoniae 50 AUIC Staphylococcus aureus 82 Vancomycin Concentration dependent AUIC Staphylococcus aureus 400 References 1 Dudley MN Commentary on dual individualization In Evans WE Schentag JJ Jusko WJ eds Appl
75. tabase 32 2 9 User Account Precise PK have four types of users each one of have different levels of authorization and limitation User Type Limitation Demo No access to database Fixed Patient name Allow drug Vancomycin Theophyline Gentamicin Can only see the page of User Choice Drug but cannot summit Can update license Guest access to license Cannot read write database Can change database path Normal User Cannot add delete user Can only change current user s info Can update license Can access database Administrator No limitation User Accounts are created or managed inUser Account Manage Window By default Precise PK will be under Demo Mode which all users are Demo users when one but not only one of the following situation occurs e New download e License file is not found e License is expired e Unknown errors occurs Once user have register a valid license and configure the database correctly a default Administrator will be created with following information e ID 1 User name admin Name admin User type administrator Password no password If there is more than one users Normal User or Administrator or the only one user have set up the password then a Log In Window Figure 2 9 1 will appear every time Precise PK starts 33 Figure 2 9 1 Log In Window User can select the user name and input the password if no password then this step c
76. ted If a row is completed a green check sign will appear on the right side If the completed row shows some strange behavior the green check sign will become a yellow warning sign that indicates there MIGHT be something wrong but the program can still do the calculation 1 in this case infusion time is greater than interval There are two buttons at the end of each row The first one is Copy button and it will copy the previous row s value into the current row The second one is a Delete button and it will delete the value in the current row and restore it to default value In Serum Level History user will enter the measured level that the specific time A green 27 check will also appear if the row is complete and a yellow warning sign will appear if the row is complete but shows some strange behavior i e level is measured during infusion User can select which set of PK parameters is used in the analysis and curve fitting by selecting the radio buttons on the lower right corner Program will call the selected set as Prior PK Parameters Warning If there are multiple Non IV F values program will used the most recent selected route s F value as the based value for curve fitting As a result the analysis might not be very accurate Analysis will lead user to the graphical analysis screen Data entered in this screen will be transferred and used in the analysis Sort will sort the complete row in increasing time order
77. tell Clin Pharm 1974 8 650 5 if the patient s actual weight is greater than or equal to the ideal body weight but less than the lean body weight For morbidly obese patients whose lean body weight is greater than the ideal body weight the modified weight equals the lean body weight For patients less than their ideal body weight modified weight equals the actual total body weight The modified weight of children aged 1 to 16 years is defined as the ideal body weight Traub SL Kitchen L Am J Hosp Pharm 1983 40 107 10 and Traub SL Johnson CE Am J Hosp Pharm 1980 37 195 201 if the actual weight exceeds 1 2 times the ideal body weight otherwise the modified weight is the total body weight In adolescents aged 16 to 18 years of age who are over 5 ft the modified weight is the average of the ideal body weights calculated by the adult and pediatric formulas In infants under the age of 1 year the modified weight is the total body weight 35 Formula for IBW in kg Adults over 18 IBW males 50 0 2 3 height in inches 60 IBW males 45 5 2 3 height in inches 60 Children 18 or under height under 5 ft IBW kg 2 396 x 6001863 xheight in cm height 5 ft or over IBW in kg male 39 0 2 27 height in inches over 5 ft IBW in kg female 42 2 2 27 height in inches over 5 ft Lean Body Weight Lean body weight LBW is defined as the weight of the body minus the weight of body fat Han PY et al Cli
78. the Fourth Annual Symposium on Computer Applications in Medical Care 988 94 22 23 24 25 26 2T 28 29 30 31 32 33 34 35 36 37 38 39 39 40 41 42 43 44 45 Powell JR et al Am Rev Resp Dis 1978 118 229 Piafsky KM et al N Engl J Med 1977 296 1495 7 Jonkman JHG et al Clin Pharmacokinet 1984 9 309 34 Cohen et al Ther Drug Monit 1985 7 426 34 Schwartz J et al Antimicrob Agents Chemother 1988 32 75 7 Wijnands WJA et al Pharm Weekbl Sci 1987 9 suppl 72 5 Nix DE et al J Antimicrob Chemother 1987 19 263 9 Cummins DP et al Ann Allergy 1976 37 450 1 Kozak P et al Clin Immunol 1977 16 149 51 Prince RA et al J Clin Pharmacol 1989 29 650 Baciewicz AM Ther Drug Monit 1985 7 26 35 Ogilvie RI Clin Pharmacokinet 1978 3 267 93 Robson RA et al Br J Clin Pharmacol 1984 18 445 8 Straughn AB et al Ther Drug Monit 1984 6 153 6 Powell Jackson PR et al Am Rev Resp Dis 1985 131 939 40 Boyce EG et al J Clin Pharmacol 1986 26 696 9 Weinberger M J Allergy Clin Immunol 1977 59 228 31 Loi C H et al Clin Pharmacol Ther 1991 49 571 80 Isles A et al Am Rev Resp Dis 1981 127 417 21 Knoppert DC et al Clin Pharmacol Ther 1988 44 254 64 Nafziger AN et al J Clin Pharmacol 1987 27 862 5 Robson RA et al Br J Clin Pharmacol 1988 25 397 400 Sirmans SM et al Clin Pharmacol Ther 1988 44 29 34 Vozeh S et al Clin Pharmacol Ther 1984 36 634 40 Pokrajak M et al Eur J Clin Pharmac
79. the clearance calculation above However it has been observed by our consultants that flucytosine serum levels of infants in intensive care units are somewhat unpredictable and are often quite low It is not known if this is due to erratic oral absorption instability of extemporaneously compounded flucytosine suspensions or both Since there are no published pharmacokinetic studies on flucytosine in infants Precise PK should be used with caution in this age group References Cutler RE et al Clin Pharmacol Ther 1978 24 333 42 Dawborn JK et al Br Med J 1973 4 382 4 Wade DN Sudlow G Aust N Z J Med 1972 2 153 8 Sch enbeck J et al Chemotherapy 1973 18 321 6 xS ade uim 55 Lithium The various dosage forms of lithium salts have different bioavailabilities and absorption rate constants The absorption rate constant has its primary relevance in determining the shape of curves plotted in the graphics portion of PrecisePK Although it is used during curve fitting serum lithium levels are usually drawn 12 hours after a dose Since absorption is complete by about 10 hours after the dose the exact value of the absorption rate constant is not important during curve fitting when using a one compartment simulation Lithium Dosage Form Parameters Dosage Form F SD Ka Refs Syrup 1 0 0 1 3 6 1 Fast Release Capsules 1 0 0 1 1 2 1 Fast Release Tablets 1 0 0 1 1 2 1 Eskalith CR 097 01 05 1 Formulas Clearance L hr CL 12
80. urs previously The time weighting factor applies in both the Bayes and the least squares fitting routines except for phenytoin where it is not applied The effect of the time weighting factor is to cause earlier serum levels to have less weight or impact than more recent levels More recent levels should be a better reflection of the patient s current pharmacokinetic status than older ones The effect of this factor can be seen on the graphs where early levels sometimes seem to be further from the curve than more recent levels Drugs whose pharmacokinetic parameters changes more dramatically with time e g because of enzyme induction or disease state alterations are time weighted more heavily The table below shows the effect of some representative times on the weight of the levels Time Weighting Factors Time of Sample 1 005 1 01 Most recent 1 00 1 00 12 hours prior 0 94 0 89 1 day prior 0 88 0 79 2 days prior 0 79 0 62 3 days prior 0 70 0 49 4 days prior 0 62 0 38 5 days prior 0 55 0 30 10 days prior 0 30 0 09 20 days prior 0 09 0 01 85
81. ween age groups above and below Vd 12 yr and under 2 9 x total body weight References 5 6 69 Bayes Parameters Coefficients of variation of pharmacokinetic parameters are as follows F 20 CL 50 Vd 30 CF 50 The time weighting factor is 1 005 assay error is 10 and FE is 0 35 Modifying Factors Amiodarone Amiodarone decreases total drug clearance by 23 per Windle J et al Clin Pharmacol Ther 1987 41 603 10 and Saal AK et al Am J Cardiol 1984 53 1264 7 Cimetidine Cimetidine decreases renal clearance by 40 per nonrenal clearance per Bauer LA et al JAGS 1990 38 467 9 Somogyi A et al Eur J Clin Pharmacol 1983 25 339 45 Rodvold KA Ther Drug Monit 1987 9 378 83 Lai MY et al Int J Clin Pharmacol Ther Toxicol 1988 26 118 21 and Christian CD et al Clin Pharmacol Ther 1984 36 221 7 Trimethoprim or Septra Trimethoprim decreases procainamide renal clearance by 46 per Vlasses PH et al Arch Intern Med 1989 149 1350 3 Kosoglou T et al Clin Pharmacol Ther 1988 44 467 77 Impaired Cardiac Output Decreased cardiac output decreases total drug clearance by 35 per Winter M Basic clinical pharmacokinetics 2nd ed Vancouver WA Applied Therapeutics 1988 References 1 Coyle JD Lima JJ In Evans WE Schentag JJ Jusko WJ eds Applied pharmacokinetics principles of therapeutic drug monitoring 2nd Ed Spokane 199 22 3 to 22 33 2 Benet LZ Sheiner LB In Goodman AG et al eds The pharmacologic

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