RE: truncation & simulation
Dear Ron,
Your original dataset provided clearance estimates for 100 patients, which were
all within the range 5 to 30 L/h. When you simulated 4800 clearance values (=
2 cross-over observations/subject x 12 subject/trial x 200 trials), I would
expect to see a wider range of clearance values in the simulation dataset than
in the original analysis, simply because there are many more observations in
the simulation dataset.
However, arbitrarily truncating clearance to the range of 5 to 30 L/h may not
be wise. Consider the subject whose simulated clearance values are 30 L/h and
32 L/h, a 6.7% difference. If both of these values are truncated to 30 L/h,
then there is zero within-patient difference in clearance values (and zero
within-patient difference in AUC), and the truncation procedure both (1)
reduces the mean within-subject treatment difference and (2) reduces the
within-subject treatment variability. Either one of these effects would
arbitrarily increase the statistical power of attaining bioequivalence.
Statistical power for a bioequivalence test depends on the projected mean
within-subject treatment difference (say <=5%), the projected mean
within-subject variability (estimated in your original population PK analysis),
and the sample size. Instead of truncating clearance values, I think you
should examine the effects of larger sample sizes on the statistical power;
maybe run simulations with 16, 24, 36, and 48 subjects per study. In reality,
very few bioequivalence trials will be successful with only 12 subjects.
Good luck,
Steve
Steven Troy
Sr. Director,
Clinical Pharmacology and Pharmacokinetics
Shire Pharmaceuticals
Quoted reply history
-----Original Message-----
From: [EMAIL PROTECTED] [mailto:[EMAIL PROTECTED] On Behalf Of Ron Mathôt
Sent: Tuesday, April 22, 2008 3:18 PM
To: [email protected]
Subject: [NMusers] truncation & simulation
Dear NONMEM users,
Currently I am working on the simulation of a bio-equavalence trial. For
the reference compound a population PK model has been derived on basis
of data from 100 patients. Values for between-and within-patient
variability are available for all PK parameters. The simulation
comprises a randomized cross-over study with 12 patients taking the
test and reference compound. Two-hunderd trials are simulated and
summarized. During the simulations I noticed that truncation of the
simulated of PK parameters significantly influences the power of the
study to confirm bio-equivalence. For instance truncation of simulated
oral clearances of both compounds from a range of 1-300 L/hr to 5 - 30
L/hr doubled the number of positive trials (due to decreased within-
patient variability). Post-hoc estimates form the popPK study indicated
that clearance values of the reference compound are all within the
latter range of 5 to 30 L/hr. I expect that oral clearance of the test
compound will not differ more than 5% from the reference compound. In my
opinion simulation of trials with the smallest range will produce more
reliable estimates of the power to detect bio-equivalence.
I would greatly appreciate your comments on this subject.
Best regards,
Ron Mathôt
Department of Hospital Pharmacy and Clincal Pharmacology
Erasmus University Medical Center
Rotterdam
The Netherlands
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