Re: [NMusers] 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 mode=
l
can help eliminate non-physiologic parameter combinations.

For example, if CL and V are even somewhat correlated, simulating with a di=
agonal 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



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 dat=
a
> 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 instanc=
e
> 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. I=
n
> 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
>
>
>
>







Received on Tue Apr 22 2008 - 17:13:09 EDT