Dear Kok-Yong Seng, Is the drug undergoing presystemic metabolism after oral administration? This might explain some differences in metabolic rate constants before and after oral administration. If your drug undergoes presystemic metabolism, metabolite concentrations may appear earlier in the systemic circulation than you would have expected based on your current PK model. A work-around is to use a more mechanistic-based model that incorporates both systemic and presystemic metabolism, e.g. as described by Levi et al in J Pharmacokinet Pharmacodyn. 2007 Feb;34(1):5-21..
Cheers, Rob ter Heine --- R. ter Heine, PhD, PharmD Hospital Pharmacist / Clinical Scientist / Clinical Pharmacologist Meander Medical Center, Amersfoort, The Netherlands T: +31-33-8502335 E: [email protected] -----Oorspronkelijk bericht----- Van: [email protected] [mailto:[email protected]] Namens Seng Kok Yong Verzonden: maandag 17 februari 2014 9:22 Aan: [email protected] Onderwerp: [NMusers] integrated parent-metabolite PK model from sequential iv and oral doses of parent drug Dear fellow NMusers, I'm trying to develop an integrated parent-metabolite PK model based on the plasma concentrations obtained from 40 subjects after sequential iv and oral administrations of the parent drug. The iv bolus was injected at time = 0 while the oral dose was administered at time = 4h. The most stable model so far is a two-compartment model for the parent drug (with first-order absorption) linked to a one-compartment metabolite model. However, in order to obtain reasonable parameter estimates and adequate goodness-of-fit plots, I needed to specify a "switch" in rate constant values and scaling factors at time = 4h (oral administration time), as defined in the control stream below. Without, this "switch", there was a very poor match between the measured and predicted metabolite concentration values. May I ask if my code below is correct for modelling the data at hand (assuming the abovementioned structural model)? If not, would you be able to suggest possible areas of model improvement? Thank you and best wishes, Kok-Yong SENG, PhD DSO National Laboratories Singapore ______________________ $PROB RUN# 1 parent-met data (nmol/L vs h) $INPUT ID NTIM TIME DV AMT ORAL CMT EVID MDV $DATA DATA.CSV IGNORE=C $SUBROUTINE ADVAN5 $MODEL NCOMP=4 COMP=(DEPOT) COMP=(CENTRAL, DEFDOSE) COMP=(METAB1) COMP=(PERIPM) $PK IIVCL = ETA(1) IIVF1 = ETA(2) IIVKA = ETA(3) IIVCL1 = ETA(4) IIVV3 = ETA(5) KA = THETA(1)*EXP(IIVKA) CL = THETA(2)*EXP(IIVCL) V2 = THETA(3) Q = THETA(4) V4 = THETA(5) F1 = THETA(6)*EXP(IIVF1) FMET = 0.6 CL1 = THETA(7)*EXP(IIVCL1) V3 = THETA(8)*EXP(IIVV3) IF (TIME.LE.4) THEN S2 = V2 S3 = V3 K12 = KA K20 = (1-FMET)*(CL/V2) K23 = FMET*(CL/V2) K24 = Q/V2 K42 = Q/V4 K30 = CL1/V3 ELSE S2 = V2/F1 S3 = V3 K12 = KA K20 = (1-FMET)*((CL/F1)/(V2/F1)) K23 = FMET*((CL/F1)/(V2/F1)) K24 = (Q/F1)/(V2/F1) K42 = (Q/F1)/(V4/F1) K30 = CL1/V3 ENDIF $ERROR ;ONLY OBSERVATIONS) IF (AMT.GT.0) TDOS=TIME TAD=TIME-TDOS IF (F.EQ.0) THEN IPRED=0 ELSE IPRED=LOG(F) ENDIF IRES=DV-IPRED IF(CMT.EQ.2) W2 = SQRT(THETA(9)**2 ) IF(CMT.EQ.3) W3 = SQRT(THETA(10)**2 ) IF(CMT.EQ.2) IWRES=IRES/W2 IF(CMT.EQ.3) IWRES=IRES/W3 IF(CMT.EQ.2) Y = IPRED + (W2)*EPS(1) ; IF(CMT.EQ.3) Y = IPRED + (W3)*EPS(2) $THETA $OMEGA $SIGMA 1 FIX 1 FIX $EST METHOD=1 INTER MAXEVAL=9999 PRINT=1 POSTHOC NOABORT MSFO=1.MSF SIGL=9 NSIG=3 $COV UNCONDITIONAL PRINT=E :::::DATA.csv::::: (for first two subjects) C Data Desc: parent-met data (dose in nmoles; time in hr; conc in nmol/L) CID NTIM TIME DV AMT ORAL CMT EVID MDV 101 0 0 0 2302.308 . 2 1 1 101 0 0 0 2302.308 . 2 1 1 101 0.25 0.25 5.430537181 . . 2 0 0 101 0.25 0.25 0.741358053 . . 3 0 0 101 0.5 0.5 4.799111134 . . 2 0 0 101 0.5 0.5 0.854669023 . . 3 0 0 101 0.75 0.75 4.55617397 . . 2 0 0 101 0.75 0.75 0.691490788 . . 3 0 0 101 1 1 4.106244674 . . 2 0 0 101 1 1 0.589508916 . . 3 0 0 101 1.5 1.5 3.822383616 . . 2 0 0 101 1.5 1.5 0.409972825 . . 3 0 0 101 2 2 3.652067835 . . 2 0 0 101 2 2 0.284763877 . . 3 0 0 101 2.5 2.5 3.346291176 . . 2 0 0 101 2.5 2.5 0.08938465 . . 3 0 0 101 3 3 3.121642304 . . 2 0 0 101 3 3 -0.090114893 . . 3 0 0 101 3.5 3.5 3.278754426 . . 2 0 0 101 3.5 3.5 -0.108362666 . . 3 0 0 101 4 4 . 4604.619 1 1 1 1 101 4 4 . 4604.619 1 1 1 1 101 4 4 3.44923847 . 1 2 0 0 101 4 4 -0.071713115 . 1 3 0 0 101 4.25 4.25 3.597385022 . 1 2 0 0 101 4.25 4.25 -0.048409056 . 1 3 0 0 101 4.5 4.5 3.716095668 . 1 2 0 0 101 4.5 4.5 1.175372119 . 1 3 0 0 101 4.75 4.75 4.154635181 . 1 2 0 0 101 4.75 4.75 2.212447576 . 1 3 0 0 101 5 5 4.08855346 . 1 2 0 0 101 5 5 2.253719503 . 1 3 0 0 101 5.5 5.5 3.726503911 . 1 2 0 0 101 5.5 5.5 1.86297201 . 1 3 0 0 101 6 6 3.52409438 . 1 2 0 0 101 6 6 1.48545147 . 1 3 0 0 101 7 7 -0.791943487 . 1 3 0 0 101 8 8 2.861295756 . 1 2 0 0 101 8 8 0.195365359 . 1 3 0 0 101 10 10 2.960551062 . 1 2 0 0 101 10 10 -0.709552271 . 1 3 0 0 101 12 12 2.164593204 . 1 2 0 0 101 12 12 -0.857712813 . 1 3 0 0 ***************************DISCLAIMER**************************** De informatie in dit e-mail bericht is uitsluitend bestemd voor de geadresseerde. Verstrekking aan en gebruik door anderen is niet toegestaan. Door de elektronische verzending van het bericht kunnen er geen rechten worden ontleend aan de informatie.
