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RE: PD model

From: chenyuhong
Date: Thu, 14 Jan 2010 14:27:06 GMT

Dear Otilia,
Thank you very much for your suggestions. They are very helpful.

---------- Original Message ----------
From: Lillin - de Vries, O. - <otilia.lillin
To: <chenyuhong
Subject: RE: [NMusers] PD model
Date: Thu, 14 Jan 2010 11:45:16 +0100

Dear Yuhong, Here you have my 5 cents (in top-down fashion): 1. You need=
 a PK-PD model quantifying the QTc prolongation; since you don't know wh=
at causes the QTc prolongation, this breaks down to testing: 1a. DrugA=
 - QTc model 1b. DrugB - QTc model 1c. DrugA+DrugB - QTc model 1d.=
 DrugC - QTc model In order to be able to compare models 1a - 1d you nee=
d a good Baseline QTc model (i.e you need to describe well all non-drug =
related influences on QTc like gender, circadian rhythm, age, placebo ef=
fect, etc - see e.g. the paper of V. Piotrovsky, Pharmacokinetic-Pharmac=
odynamic Modeling in the Data Analysis and Interpretation of Drug-induce=
d QT/QTc Prolongation, AAPS Journal 2005). If a combination of more tha=
n one of your three moieties can be responsible for the effect on QTc (I=
 do not have experience with this case) I would simply add upp the conce=
ntrations (see the Nonmem code below for your convenience, without circa=
dian rhythm for keeping it simple). On the other hand be aware that a PK=
-PD model can not tell you for sure which one of the moieties is respons=
ible for the QTc prolongation; a model can only quantify the magnitude o=
f the effect and give you a hint on which moiety is most probably causin=
g it. You need to make assumptions on physiological bases as well, and:-=
 check whether drugB alone causes QTc prolongation (model 1b? litteratur=
e? previous studies with limited ECG? ...) if yes, you need model 1c.- c=
heck the time point at which you have the largest QTc prolongation: does=
 it occur at Tmax_drugA? then a direct effect model (1a or 1c) are most =
probable; does it occur at Tmax_drugC? since C is a metabolite, it takes=
 some time to be formed and probably Tmax_C > Tmax_A, this hints you in =
the direction of the metabolite and you need a delayed effect model to d=
escribe the parent's effect on QTc (1a) and the concentrations in the hy=
pothetical compartment should agree with the metabolite profile. In othe=
r words, you should be able to tell the effect from the parent(s) and me=
tabolite from each other. Hope this helps. Cheers,Otilia $PREDOCC2=
=0 ; steady s=
tate IF (DAY.EQ.11) OCC2=1 QTC0 = THETA(1)+ETA(1) =
              ;baseline QTcSHFT = THETA(2) =
                 ;shift factor placebo effect QTCB = QTC0+SHFT*OCC2+TH=
ETA(3)*GEN ;baseline with placebo and gender effect SL = THETA(4)=
                                                  ; slope of drug effect=
CP = CA + CB ; add up=
p concentrations causing the effectEFF = SL*CP =
                            ; linear direct effect QTC = QTCB+EFF Y ==
 QTC+EPS(1)IPRE = QTCIRES = DV-IPRE Otilia Lillin-de Vries, MSc
Modeling and Simulation Expert

Pharmacokinetics, Pharmacodynamics & Pharmacometrics (P3)
Department of Drug Metabolism and Pharmacokinetics
T: +31 412 669321 =

M: + 31 6 22004827 =

F: +31 412 662506 =


Gasstraat Oost 10, 5349 AV, Oss
P.O. Box 20, 5340 BH, Oss
The Netherlands =


From: owner-nmusers
 On Behalf Of chenyuhong
Sent: Thursday, 14 January, 2010 2:45
To: nmusers
Subject: [NMusers] PD model

Dear All,
I am looking for a help. Currently I am working on a population PD model=
 to evaluate the effects of drugs on QT prolongation. Drug A and drug B=
 are given to the study subjects (healthy volunteer) at the same time. D=
rug B is the inhibitor for the metabolism of drug A, also compound C is =
the metabolite of drug A. I am wondering how to evaluate the effects fo=
r drug A or B or the metabolite of drug A (compound C). These three moie=
ties will be present together in the blood for most of the time. Is anyo=
ne has experience and would like to share with us. Any comment will be g=
reatly appreciated.
Best regards,

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Received on Thu Jan 14 2010 - 09:27:06 EST

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