Re: truncation & simulation
Dear Ron,
Do you have parameter covariances? or does your PK model have only diagonal
between-subject variability (OMEGA). Simulating from a full covariance model
can help eliminate non-physiologic parameter combinations.
For example, if CL and V are even somewhat correlated, simulating with a
diagonal variance matrix ignores this correlation.
The high and low CL (of your simulated subjects) may not be your "problem." It
could be the simulation of high CL (paired with unreasonably low Vol) or low CL
(paired with unreasonably high Vol)... for example.
I hope this helps,
Dave
Quoted reply history
On Tue, 22 Apr 2008, [ISO-8859-1] 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
>
>
>
>