PharmPK Discussion - Sample size for Intra-Patient variability

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On 27 Feb 2002 at 22:53:44, Rostam Namdari (chista90.-at-.yahoo.com) sent the message


The following message was posted to: PharmPK

Dear all,

What is the sample size (n=?) for examining intra-patient variability of
PK parameters?

Thanks

Rostam

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On 6 Mar 2002 at 10:17:16, Nick Holford (n.holford.-at-.auckland.ac.nz) sent the message

The following message was posted to: PharmPK

Rostam,

Rostam Namdari wrote:

>
>This is a liposomal drug given every 2 weeks. Based on limited PK data
from 4 patients we know that the t1/2 is about 10 hours (total drug
concentration is not detectable in plasma after 48 h). Plasma
concentration-time data from one patient for cycle 1 and 2 are very
similar and pre-dose sampling prior to cycle 2 does not show any
detectable drug as expected.
[stuff about lack of accumulation deleted]
>Any comment? Dose FDA need
>intra-patient variability data? What is the use of intra-patient
variability data?

I let those at FDA who read this to comment on their need for within
subject variability information.

The use of any kind of estimate of parameter variability depends on the
drug and
indication. For a drug with a high therapeutic index in which everyone
gets a reasonable response given the same dose there is no need to
describe PK variability
to use the drug. However, during drug development it is often useful to
have a full
description of the variability properties so that predictions can be
made e.g. using
clinical trial simulation to design a trial.

A practical use of knowing the relative size of between and within
subject variability [BSV - WSV - db] is to decide if target
concentration intervention [TCI] (aka TDM) can be of
benefit if a drug has a low therapeutic index. The impact of TCI is
limited to
reducing BSV. It cannot affect WSV. So if the WSV is too big for safe
and effective
use of the drug then there is no point hoping TCI will rescue the drug
and make it
safe to use.

Nick

Nick Holford, Divn Pharmacology & Clinical Pharmacology University of
Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand
email:n.holford.aaa.auckland.ac.nz
http://www.health.auckland.ac.nz/pharmacology/staff/nholford/

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