From: "R.A.A. Mathot" r.mathot@erasmusmc.nl
Subject: [NMusers] between-patient variability in PK and PD
Date: Wed, May 4, 2005 11:08 am
Dear all,
Currently, I am working on a PK-PD dataset of 250 patients. In the
study each patient received 4 different drug doses and effects were
recorded. PK were linear; between- and within-patient variability in
clearance were 35% and 20%, respectively. The relationship between
drug effect and AUC was described according to a sigmoidal Emax
model. Between-patient variability in AUC50 was large: ca 150%.
Since between-patient variability in PD is much larger than in PK, I am
wondering what the assessment of PK contributes to the evaluation of
the dose-respons relationships of this drug in this study. In fact more or
less comparable sigmoidal relationships were obtained when drug
effect was related to the administered dose: between-patient variability
in ED50 was 130%; the objective function was 50 points higher than
for the AUC-effect relationship indicating a worse fit; residual error was
similar.
I am wondering whether there are some objective criteria which may
be used to decide whether it is useful to include PK in future studies
of the dose-respons relationship of this drug.
I am looking forward to your comments.
======================================================R.A.A. Matht
Apotheek - Laboratorium
Erasmus MC
between-patient variability in PK and PD
From: "Bhattaram, Atul" BhattaramA@cder.fda.gov
Subject: RE: [NMusers] between-patient variability in PK and PD
Date: Wed, May 4, 2005 11:26 am
Hello Mathot
Couple of comments:
1. It is better to use concentrations rather than AUC in the model to derive
PK/PD relationships.
2. Even without the use of any model, just looking at the data do you think
that there is a lot of variability in the effects?
3. If PK is not very variable, but PD is highly variable then I would
suggest to look for sources to minimize this variability if possible.
4. Having reasonable information on drug concentrations in your registration
trials will always help you in identifying and justifying any findings which
you might not anticipated based on the limited experience from early
dose-response studies.
Venkatesh Atul Bhattaram
Pharmacometrics
US Food and Drug Administration
From: "Alice Nichols" NICHOLA2@wyeth.com
Subject: Re: [NMusers] between-patient variability in PK and PD
Date: Wed, May 4, 2005 12:09 pm
Its possible that effect is more related to overall exposure as opposed to
individual time-concentration values, also it needs to be considered whether
there is a delay between concnetrations and effect. Have you done hysteresis plots.
Alice I Nichols, PhD
Sr Director, Clinical Pharmacology
Wyeth Research
500 Arcola Rd
Collegeville, PA 19426
tel: 484-865-8741/ fax: 484-865-9075
nichola2@wyeth.com
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