Here are my thoughts on this topic and the models:
I agree with the comments made about the baseline and the method to deal with estimating the baseline pattern of QTc. But, adding up concentrations of two different drugs should be the last resort, because it assumes that the drugs are equipotent (with respect to causing QT prolongation) and that they follow the same underlying shape of PK-QT relationship. This is an assumption that could be rarely the case in real life. I would first try a different model. What needs to be added up is the PD (i.e., QT prolongation) not the concentrations. If the individual PK-QT relationships for Drugs A, B and the metabolite C are sufficiently separated (i.e., different half-lives for the three compounds and have different PK-QT slopes or different EC50 and Emax values in the case of an Emax model), then you could try to fit a model like: EFFA = SLA*CPA ;Effect of drug A=SlopeA x Plasma concentrations of drug A EFFB= SLB*CPB ;Similar to above for drug B EFFC= SLC*CPC ;Similar to above for metabolite C EFF=EFFA+EFFB+EFFC ;Total drugs effect on QT QTC = QTC0+EFF ;QTC0 is the baseline QTc effect (could be a diurnal variation model, etc) Of course, the model requires enough data points and works if there is enough separation between the slopes of the PK-QT effects. If the above model does not fit, I would next use the pre-clinical data (e.g., hERG test) to eliminate at least one of the moieties for potential QT prolongation and that should simplify the model. Regards Parviz Ghahramani, PhD, PharmD, MSc, MBA Executive Director, Clinical Pharmacology and Drug Dynamics Forest Research Institute A Subsidiary of Forest Research Laboratories, Inc. Harborside Financial Center, Plaza V Jersey City, NJ 07311 201-427-8469 (office) 917- 828-3836 (cell) 201-427-8498 (fax) [email protected] Date: Thu, 14 Jan 2010 09:24:15 -0600 From: [email protected] Subject: Re: [NMusers] PD model CC: [email protected] Yuhong: 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. Paul [email protected] wrote: 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 From: [email protected] [mailto:[email protected]] On Behalf Of [email protected] Sent: Thursday, 14 January, 2010 2:45 To: [email protected] 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. 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 ____________________________________________________________ Diet Help Reach your goals of being healthier and happier. Click here for diet tips and solutions. This message and any attachments are solely for the intended recipient. 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