Re: [NMusers] truncation & simulation

Ron,

When you truncate the simulated parameter distribution it can lead to a
major violation of the assumptions of maximum likelihood i.e. that all
random effects are normally distributed. This means that the likelihood
ratio test will have a larger Type 1 error than expected from using the
chi-2 distribution assumption. You should use a randomization test in
order to determine what change in OFV is needed in order to reject the
null under your desired hypothesis.

Nick

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
>
>
>

--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand
n.holford_at_auckland.ac.nz tel:+64(9)373-7599x86730 fax:+64(9)373-7090
www.health.auckland.ac.nz/pharmacology/staff/nholford



Received on Tue Apr 22 2008 - 16:04:14 EDT