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Identifiablity of parent / metabolite PK with interconversion

From: Dong-Seok Yim <yimds>
Date: Mon, 2 Feb 2009 21:10:08 +0900 (KST)


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Hi, colleagues,
I am currently trying to model plasma concentrations of parent and metabolite&nbsp;with interconversion. (nmtran code is in the bottom).&nbsp;
The&nbsp;data came from a densely sampled PK study in healthy subjects. I&nbsp;put the metabolite Vd identical to the parent Vd as recommended. Then,&nbsp;I managed to&nbsp;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. &nbsp;Journal of Clinical Oncology, Vol 20, No 15 (August 1), 2002: pp 3293-3301)&nbsp;
In the paper, interconversion rate constants&nbsp;of interconverted forms&nbsp;(CPT-11 lactone and CPT-11 carboxylate / SN-38&nbsp;lactone and SN-38 carboxylate )&nbsp;were tabulated without using any urine data. -
&nbsp;If&nbsp;any&nbsp;of the authors comment on the method&nbsp;to obtain reliable values using plasma concenentrations only, I would appreciate.
Any comments from nmusers other than above authors are also&nbsp;much welcomed !
Thanks !
Dong-Seok Yim
----------------------------------------
$MODEL NCOMP=3
&nbsp;COMP=(DEPOT,DEFDOSE)
&nbsp;COMP=(PARENT)
&nbsp;COMP=(METABOLITE)
&nbsp;
$PK
&nbsp;KA = THETA(1)*EXP(ETA(1))
&nbsp;K20 = THETA(2)*EXP(ETA(2))
&nbsp;V2 = THETA(3)*EXP(ETA(3))&nbsp;&nbsp; &nbsp;; V2 = &nbsp;parent Vd
&nbsp;K30 = THETA(4)*EXP(ETA(4))
&nbsp;V3 = V2&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; ; V3 = metabolite Vd
&nbsp;K23 = THETA(5)*EXP(ETA(5))
&nbsp;K32 = THETA(6)*EXP(ETA(6))
&nbsp;CL20 = K20*VS
&nbsp;CL30 = K30*VA
&nbsp;S2=VS
&nbsp;S3=VA
&nbsp;
$DES
&nbsp;DADT(1)=-KA*A(1)
&nbsp;DADT(2)=KA*A(1)-K23*A(2)+K32*A(3)-K20*A(2)
&nbsp;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

yimds




Received on Mon Feb 02 2009 - 07:10:08 EST

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