Dear Otilia,
Thank you very much for your suggestions. They are very helpful.
Thanks,
Yuhong
---------- Original Message ----------
From: "Lillin - de Vries, O. \(Otilia\)"
<[email protected]>
To: <[email protected]>, <[email protected]>
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 what 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 need 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 effect, etc - see e.g. the
paper of V. Piotrovsky, Pharmacokinetic-Pharmacodynamic
Modeling in the Data Analysis and Interpretation
of Drug-induced QT/QTc Prolongation, AAPS Journal 2005).
If a combination of more
than 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 concentrations (see the Nonmem code below for your convenience,
without circadian 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 responsible for the QTc prolongation; a model can only quantify the
magnitude of the effect and give you a hint on which moiety is most
probably causing it.
You need to make assumptions
on physiological bases as well, and:
- check whether drugB
alone causes QTc prolongation (model 1b? litterature? previous studies
with limited ECG? ...) if yes, you need model 1c.
- check 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
describe the parent's effect on QTc (1a) and the concentrations in the
hypothetical compartment should agree with the metabolite profile. In
other words, you should be able to tell the effect from the
parent(s) and metabolite from each other.
Hope this helps.
Cheers,
Otilia
$PRED
OCC2=0
; steady state
IF
(DAY.EQ.11) OCC2=1
QTC0
= THETA(1)+ETA(1) ;baseline QTc
SHFT =
THETA(2) ;shift
factor placebo effect
QTCB
= QTC0+SHFT*OCC2+THETA(3)*GEN ;baseline
with placebo and gender effect
SL =
THETA(4)
; slope of drug effect
CP = CA +
CB ; add upp
concentrations causing the effect
EFF =
SL*CP
; linear direct effect
QTC =
QTCB+EFF
Y =
QTC+EPS(1)
IPRE = QTC
IRES =
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
[email protected]
MSD
Gasstraat Oost 10, 5349 AV, Oss
P.O.
Box 20, 5340 BH, Oss
The
Netherlands
www.merck.com
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. Drug 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 for drug A or B or the metabolite of drug A
(compound C). These three moieties will be present together in the
blood for most of the time. Is anyone has experience and would like to
share with us. Any comment will be greatly appreciated.
Best regards,
Yuhong
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