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Hi, colleagues,
I am currently trying to model plasma concentrations of parent and
metabolite with interconversion. (nmtran code is in the bottom).
The data came from a densely sampled PK study in healthy subjects.
I put the metabolite Vd identical to the parent Vd as recommended.
Then, I managed to obtain some estimates that make the individual
plots look nice.
However, I doubt whether we can get reliable estimates for K23 or K32 and
(hence, even K20 and K30 ) without urine concentration data and without any
priori knowledge on the metabolic ratios etc.
I suspect that the estimates of K23, K32, K20, K30 and V2 are all
interconnected as the Ka and Ke are in the flip-flop phenomenon - Am I wrong ?
Searching for some references for the metabolite PK modeling using NONMEM, I
found an article reporting detailed pop PK parameters of CPT-11 and its
metaolites in patients (Rujia Xie, Ron H.J. Mathijssen, Alex Sparreboom, Jaap
Verweij, and Mats O. Karlsson. Journal of Clinical Oncology, Vol 20, No
15 (August 1), 2002: pp 3293-3301)
In the paper, interconversion rate constants of interconverted
forms (CPT-11 lactone and CPT-11 carboxylate / SN-38 lactone and
SN-38 carboxylate ) were tabulated without using any urine data. -
If any of the authors comment on the method to obtain
reliable values using plasma concenentrations only, I would appreciate.
Any comments from nmusers other than above authors are also much welcomed !
Thanks !
Dong-Seok Yim
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$MODEL NCOMP=3
COMP=(DEPOT,DEFDOSE)
COMP=(PARENT)
COMP=(METABOLITE)
$PK
KA = THETA(1)*EXP(ETA(1))
K20 = THETA(2)*EXP(ETA(2))
V2 = THETA(3)*EXP(ETA(3)) ; V2 = parent Vd
K30 = THETA(4)*EXP(ETA(4))
V3 =
V2
; V3 = metabolite Vd
K23 = THETA(5)*EXP(ETA(5))
K32 = THETA(6)*EXP(ETA(6))
CL20 = K20*VS
CL30 = K30*VA
S2=VS
S3=VA
$DES
DADT(1)=-KA*A(1)
DADT(2)=KA*A(1)-K23*A(2)+K32*A(3)-K20*A(2)
DADT(3)=K23*A(2)-K32*A(3)-K30*A(3)
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Dong-Seok Yim M.D., Ph.D.
Associate Professor
Department of Pharmacology
College of Medicine
The Catholic University of Korea
505 Banpo-Dong, Seocho-Gu, Seoul 137-701, Korea
Tel +82-2-590-1201
Fax +82-2-536-2485
yi...@catholic.ac.kr
