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Hello everyone:
Could anyone give me some help for determining the minimum number of
samples (or subjects) needed for a population pharmacokinetics? Is
there an easy to estimate the number of samples needed using the
variability (for example, the %CV of important PK parameters is
around 100%)? Or I have to do some kind of simulation?
Thank you very much!
Best Regards,
Weijiang Zhang
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I DON'T THINK THERE IS A GOLD STANDARD BECAUSE EACH PROBLEM YOU ARE
DEALING with IS ASSOCIATED WITH A DIFFERENT KIND OF SENSITIVITY OF
THE PARAMETERS WITH RESPECT TO THE OBJECTIVE FUNCTION YOU ARE TRYING
TO OPTIMIZE. The type of model you are using is of course an
important component to take into consideration (1 compt model vs 2
compt model)but all other components are also
important(intraindividual noise, interindividual variability etc...).
Combination of simulation with subsequent fitting and reliability
procedures will help you to assess this kind of information for the
specific problem you are dealing with.
Serge Guzy, Ph.D.
Head of Pharmacometrics
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Weijiang,
> Could anyone give me some help for determining the minimum number of
> samples (or subjects) needed for a population pharmacokinetics?
This is not an uncommon question. There is no easy answer. It will
depend on the likely PK profile that you are expecting to see and on
why you are doing the PK study. In essence the more you look for the
more you will see - so intensive sampling may well reveal details
that sparse sampling cannot support. Therefore if you are in the
exploratory phase then you should try and aim for a more intensive
sampling strategy than if you are in a more confirming phase of
development (where 'sparser' sampling may be reasonable).
If you are thinking of simulating then you obviously have a good feel
for the data that you are likely to see and therefore could also
optimise the design using optimality-type procedures (DOE). The PFIM
functions in MATLAB and SPLUS can help here (see link from website
below).
As a general rule, for less intensive designs, you should always try
and set the *minimum* number of samples to be equal to the number of
fixed effect parameters to estimate; otherwise the efficiency of the
design may be considerably reduced. The number of patients and
number of occasions will depend on the variance models that you
believe are true.
Without more details it is hard to be more specific.
Regards
Steve
Stephen Duffull
School of Pharmacy
University of Queensland
Brisbane 4072
Australia
http://www.uq.edu.au/pharmacy/duffull.htm
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Weijiang,
You can find a way to answer such a problem in the following paper :
Bois, F. Y., T. J. Smith, et al. (1999). "Optimal
design for a study of butadiene toxicokinetics in humans."
Toxicological Sciences: an Official Journal of the Society of
Toxicology 49(2): 213-224.
This can help you to answer many questions.
Regards,
Sandrine.
Sandrine MICALLEF
Toxicology Lab
INERIS
Parc ALATA, PB2
60550 Verneuil en Halatte
FRANCE
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Thank you all for your response about my question. It helped me to
clear my mind and know where to start to think about this issue.
Thanks.
In fact, this is a pediatric pharmacokinetic study (for <1 year old
infant). The primary objective of the study is to get the general PK
profile in this population. Therefore I think I don't need to use
the mixed effect model to identify the covariate and residual
variability, probably naive pooled approach will be enough. Right?
This compound fits one compartmental model well in adults, the
sampling schedule in adults is 0, 0.5, 1, 1.5, 2, 3.5, 6, 9, and 12
hrs.
Any suggestions or comments will be highly appreciated.
Thanks.
Best Regards,
Weijiang
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[Three replies - db]
From: "Mishina, Elena V"
Date: Tue, 10 Sep 2002 14:26:14 -0400
To: david.at.boomer.org
Subject: RE: PharmPK Re: Sampling number for population pharmacokinetics
Dear Weijiang,
Usually when the drug is to be studied in pediatrics, the FDA requirement is
to have 4 groups of pediatric patients to include all ages from infants to
adolescents. If your study is planned as a one-site study to assess the PK
in infants as a part of multiple sites study you should not use a naive pool
approach for your group of children. Instead, you should have a few samples
taken from each patient and include your data into the population data
analysis for the whole pediatric population. It is very important to
evaluate the influence of the covariates on the PK parameters estimated for
the pediatric patients. This will help to make a decision on the dose
adjustment for children (if necessary).
Regards,
Elena Mishina, Ph.D.
Senior Clinical Pharmacologist
US Food & Drug Administration
---
From: Nick Holford
Date: Wed, 11 Sep 2002 07:01:50 +1200
To: david.-a-.boomer.org
Subject: Re: PharmPK Re: Sampling number for population pharmacokinetics
"Weijiang Zhang (by way of David Bourne)" wrote:
> In fact, this is a pediatric pharmacokinetic study (for <1 year old
> infant). The primary objective of the study is to get the general PK
> profile in this population. Therefore I think I don't need to use
> the mixed effect model to identify the covariate and residual
> variability, probably naive pooled approach will be enough. Right?
Wrong! In the 0 to 1 year age range is exactly the period of life
when major changes take place in PK parameters. There are very real
fixed (weight, age) and random (between subject variability) effects
that need to account for individual differences. A non-linear mixed
effect model is essential to be able to describe the changes
conditional on weight and age. A naive pooled analysis is guaranteed
to be misleading.
See Anderson BJ, van Lingen R, Hansen TA, Lin Y-C, Holford NHG.
Acetaminophen developmental pharmacokinetics in premature neonates
and infants. Anesthesiology 2002;96(6):1336-1345 for a recent example
and references to earlier literature.
--
Nick Holford, Divn Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand
email:n.holford.at.auckland.ac.nz
http://www.health.auckland.ac.nz/pharmacology/staff/nholford/
---
From: "Sam Liao"
Date: Tue, 10 Sep 2002 16:23:11 -0400
To: david.aaa.boomer.org
Subject: RE: PharmPK Re: Sampling number for population pharmacokinetics
Hi Weijiang:
You can use less frequent sampling schedule in your ped PK study if you use
the mixed effect model.
Such as 0, 1, 2, 4, 8, and 12 hr post-dose, which is more likely be
acceptable to the physician and parents.
Best regards,
Sam Liao, Ph.D.
PharMax Research
270 Kerry Lane,
Blue Bell, PA 19422
PharmPK Discussion List Archive Index page
Copyright 1995-2010 David W. A. Bourne (david@boomer.org)