Modeling enantiomeric and racemic concentrations simultaneously

ProgId Word.Document Generator Microsoft Word 10 Originator Microsoft Word 10 Dear all, I have conducted a pharmacokinetic study in rat and I have a question about how to model enantiomeric and racemic concentrations simultaneously. The study design was as follows: Sparse data (2 - 3 plasma samples, n=10 rats) was collected for the two enantiomers, and rich data for the racemate (10-15 plasma samples, n=4 rats) following oral administration. I would like to build an individual model for each enantiomer and use the racemic data to stabilize the sparse data I have on the enantiomers. Do you have any suggestions how this could be done and how such a control-file should be written? Kind regards, Rasmus Jansson _____________________________________________ Rasmus Jansson Unit for Pharmacokinetics and Drug Metabolism Göteborg University P.O.Box 431, SE-405 30 Göteborg Sweden Phone: +46(0)31 786 3240 Fax: +46 (0)31 786 3284

Dear Rasmus, Below you will find a suggestion for how this could be coded in NONMEM. To simplify the code I have assumed i.v bolus dosing and one-compartment models for each enantiomer and no interconversion between the two enantiomers. I also assume that you know how much of each enantiomer the administered dose contains and that you in the data file specify this as two separate doses into separate compartments. If the ratio of the two enantiomers in the dose is not well defined a slightly different approach needs to be used. In case of any non-linear processes ADVAN 6 with defined differential equations ($DES) needs to be used instead of the suggested ADVAN5 (general linear model). Good luck! ; --------------------------------------------------------------------------------------------------------------- $PROBLEM Enantiomers and racemate $INPUT ID TIME AMT DV EVID CMT FLAG ; DV = S-enantiomer concentration => FLAG = 1 ; DV = R-enantiomer concentration => FALG = 2 ; DV = Racemic concentration => FLAG = 3 ; LOG transformed DV variable $DATA file.csv IGNORE=@ $SUBROUTINE ADVAN5 TRANS1 $MODEL COMP = (1_CENT_S) ; Obs S-enantiomer COMP = (2_CENT_R) ; Obs R-enantiomer $PK CLS = THETA(1) * EXP(ETA(1)) VCS = THETA(2) * EXP(ETA(2)) CLR = THETA(3) * EXP(ETA(3)) VCR = THETA(4) * EXP(ETA(4)) BIAS = 1 + THETA(5) ; Posible BIAS between non-enantiomer specific and specific ; analysis method. Drop this parameter if it is not needed. K10 = CLS/VCS K20 = CLR/VCR $ERROR CS = A(1)/VCS ; Plasma concentration of S-enantiomer CR = A(2)/VCR ; Plasma concentration of R-enantiomer CSR = (CS + CR) * BIAS ; Racemic plasma concentration IF(FLAG.EQ.1) THEN IPRED = LOG(CS) W = THETA(6) IRES = DV-IPRED IWRES = IRES/W Y = IPRED+W*EPS(1) ENDIF IF(FLAG.EQ.2) THEN IPRED = LOG(CR) W = THETA(7) IRES = DV-IPRED IWRES = IRES/W Y = IPRED+W*EPS(2) ENDIF IF(FLAG.EQ.3) THEN IPRED = LOG(CSR) W = THETA(8) IRES = DV-IPRED IWRES = IRES/W Y = IPRED+W*EPS(3) ENDIF $ESTIMATION POSTHOC MAXEVAL=9999 METHOD=1 ; --------------------------------------------------------------------------------------------------------------- Kind regards, Martin Bergstrand, MSc, PhD student ----------------------------------------------- Division of Pharmacokinetics and Drug Therapy Department of Pharmaceutical Biosciences Uppsala University ----------------------------------------------- P.O. Box 591 SE-751 24 Uppsala Sweden ----------------------------------------------- [EMAIL PROTECTED] ----------------------------------------------- Work: +46 18 471 4639 Mobile: +46 709 994 396 Fax: +46 18 471 4003

The code suggested by Martin seems reasonable (ADVAN7 is usually faster than ADVAN5). The only com ponent you would notbe sure about is the possibility of competetive interaction between enantiomers at the site of metabolism/clearance. Information (even preliminary) from drug-drug interaction studies would definitely help. The code that addresses PK interaction would include a component where clearance of one enantiomer is reduced/ enhanced by the concentration of the other. I hope this helps. Murad Melhem, Ph.D. Cognigen Corporation Buffalo, NY