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Re: PD model

From: Paul Hutson <prhutson>
Date: Thu, 14 Jan 2010 09:24:15 -0600
Otilia makes useful recommendations, and I would just reinforce the caution of having a good baseline and an understanding of the individual's diurnal changes.  There is increasingly recognized to be a very large natural variability in QTc that will need to be considered.  Daily swings of 90msec are apparently not uncommon when 24 hr recordings are made in normal adults.

Dear Otilia,

Thank you very much for your suggestions. They are very helpful.



---------- Original Message ----------
From: Lillin - de Vries, O. -
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.
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
Y = QTC+EPS(1)

Otilia Lillin-de Vries, MSc
Modeling and Simulation Expert

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

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Received on Thu Jan 14 2010 - 10:24:15 EST

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