Ron
I guess, the model over-estimates variances of the random effects (could
be due to non-normality of the distributions or some outliers in the data).
Instead of truncation, I would suggest to sample from the 100 subjects
that you have in your dataset:
For each study, randomly select 12 subjects (I would do it without
replacement) out of 100 that you have in your dataset. Use the PK
parameters of those subjects for simulations. If you expect population
of the BE trial to differ from the population of the trial that you had
in your model, use ETAs of those 100 patients (correlated, as a vector)
instead of PK parameters, and compute PK parameters based on the
expected patient covariates.
Leonid
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Leonid Gibiansky, Ph.D.
President, QuantPharm LLC
web: www.quantpharm.com
e-mail: LGibiansky at quantpharm.com
tel: (301) 767 5566
Ron Mathôt wrote:
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
