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