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integrated parent-metabolite PK model from sequential iv and oral doses of parent drug

From: Seng Kok Yong <skokyong>
Date: Mon, 17 Feb 2014 08:22:29 +0000

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 or=
al 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-or=
der 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 contro=
l stream below. Without, this "switch", there was a very poor match betwee=
n the measured and predicted metabolite concentration values.

May I ask if my code below is correct for modelling the data at hand (assum=
ing the abovementioned structural model)? If not, would you be able to sug=
gest 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
Received on Mon Feb 17 2014 - 03:22:29 EST

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