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[A few replies - db]
From:
Date: Tue, 11 Aug 1998 22:08:04 EDT
To: PharmPK.-at-.pharm.cpb.uokhsc.edu
Mime-Version: 1.0
Subject: Re: PharmPK PK Study design question
This sounds like a phase III study, so assume you have the OK from FDA.
Double blind your drug and placebo, irregardless healthy volunteers or
hyperuricemia patients.
Randomize subjects always, make their baseline and demographics as homogeneous
as possible.
If the drug is designed to lower the uric acid level, I doubt you will observe
effect on healthy normals, since there is not much uric acid to lower.
Anyway, you can do a paired t-test design. That is each individual serves as
their own control, measure UA level before and after the administration of
drug or placebo, then do a paired t-test.
Or if resource is limited, do a cross over repeated measurement design. Each
patient receives both drug and placebo, but the order is randomized. Analyze
your data accordingly.
Maybe you can also do it on the patients. Maybe more complicated, but a
controlled randomized clinical trial is the way to go, as long as the itt
patients have the similar baseline and demographics, medical histories, and
concurrent medications, etc.. are taken into account, the efficacy of the drug
could be determined.
I figure you could consult a statistician first, write up a protocol, and
statistical analysis plan, and do the trial.
This is the biostatistics student's answer, any comment? This is probably not
the way what a PK study should be done.
---
From: Nick Holford
Sender: nhol004.aaa.auckland.ac.nz
Reply-To: n.holford.at.auckland.ac.nz
To: PharmPK.-at-.pharm.cpb.uokhsc.edu
Subject: Re: PharmPK PK Study design question
Date: Wed, 12 Aug 1998 04:39:52 -0700 (Pacific Daylight Time)
Priority: NORMAL
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David,
The solution to your dilemma may become clearer if you are able to ask
yourself exactly what you are
trying to learn from your PKPD study. Let us assume that you already have a
pretty good idea of the
effective dose and tolerability because oxypurinol has been extensively
studied following
administration of the prodrug allopurinol. The PD of oxipurinol has been
studied (if my memory serves
me right) in patients (e.g. work done by Ric Day's group in Sydney). So the
major unknown is what is
the PK of oxipurinol. The idea is to understand the drug for use in real
patients not healthy
subjects. Real patients take other meds. So you need to study real
patients. There is no rule that
says they cannot be taking other meds. If you find big differences between
some individuals then you
might look closely at their meds to see if there is a clue about an
possible intereaction. You will
learn about such an interaction only by studying patients - not by studying
healthy subjects. But this
is fine tuning. The first questions must be about the behaviour of the drug
in real patients taking
their usual meds.
--
Nick Holford, Dept Neurology, L226
OHSU,3181 SW Sam Jackson Park Rd,Portland,OR 97201,USA
n.holford.at.auckland.ac.nz tel:+1 (503) 494-7228 fax:494-7242
http://www.phm.auckland.ac.nz/Staff/NHolford/nholford.htm
---
Date: Wed, 12 Aug 1998 10:14:10 -0500
From: Lydia Kaus
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To: PharmPK.-a-.pharm.cpb.uokhsc.edu
CC: Multiple recipients of PharmPK - Sent by
Subject: Re: PharmPK PK Study design question
This is just a general response to your questions:
The first thing to address is what is known about the toxicity of your
drug. Also consider the route of adminstration to which it is being given.
If all that is known is related to the parent compound, then you can still
get some information through an understanding of the exposure to the
metabolite (if this is the drug being studied), after administration of the
parent.
It is always a good idea to do a background search of the literature to get
information.
Use of a drug in oncology does not necessarily need the study to be done in
oncology patients. (You did not clearly say the objective of the sudy and
which hyperuricemic patient population you are considering for use of the
drug). This is dependent on what is known about the drug's toxicity/side
effects. After doing a study in healthy subjects (if appropriate),
eventually you may want to consider undertaking a PK-PD study in the patient
population. This study could be kept simple by including patients that are
on one drug, so in essence you would be studying the PK of your drug and
also be studying possible drug ineraction. You could get an early handle on
potential drug interactions by trying to determine all you can about the
drug's ADME , including in vitro metabolism studies. Another type of PK-PD
study would be using a sparse sampling strategy where a greater number of
patients would be involved but much fewer plasma samples could be taken.
This type of study has the potential to tell you a lot about your drug in
the patient population. Finally, the FDA has pharmacokinetic reviewers
that can help you design your study.
Lydia
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Dear David:
It is one thing to study the drug in healthy volunteers, and another to
study it in the actual patients who are being treated with it. You may well
need both groups, but you probably will need most to study its behavior in
the most relevant population, that of the patients being treated with it,
in the context of taking all their other meds, etc. This will give you the
most definitive info about the true behavior of the drug as it is actually
used. Don't worry about a washout if you don't need to for the actual
treatment. Study it in the context of the treatment. That would be my
suggestion.
Very best regards,
Roger Jelliffe
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USC Lab of Applied Pharmacokinetics
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