Dear Ron, Your original dataset provided clearance estimates for 100 patients, which were all within the range 5 to 30 L/h. When you simulated 4800 clearance values (= 2 cross-over observations/subject x 12 subject/trial x 200 trials), I would expect to see a wider range of clearance values in the simulation dataset than in the original analysis, simply because there are many more observations in the simulation dataset.
However, arbitrarily truncating clearance to the range of 5 to 30 L/h may not be wise. Consider the subject whose simulated clearance values are 30 L/h and 32 L/h, a 6.7% difference. If both of these values are truncated to 30 L/h, then there is zero within-patient difference in clearance values (and zero within-patient difference in AUC), and the truncation procedure both (1) reduces the mean within-subject treatment difference and (2) reduces the within-subject treatment variability. Either one of these effects would arbitrarily increase the statistical power of attaining bioequivalence. Statistical power for a bioequivalence test depends on the projected mean within-subject treatment difference (say <=5%), the projected mean within-subject variability (estimated in your original population PK analysis), and the sample size. Instead of truncating clearance values, I think you should examine the effects of larger sample sizes on the statistical power; maybe run simulations with 16, 24, 36, and 48 subjects per study. In reality, very few bioequivalence trials will be successful with only 12 subjects. Good luck, Steve Steven Troy Sr. Director, Clinical Pharmacology and Pharmacokinetics Shire Pharmaceuticals -----Original Message----- From: [EMAIL PROTECTED] [mailto:[EMAIL PROTECTED] On Behalf Of Ron Mathôt Sent: Tuesday, April 22, 2008 3:18 PM To: [email protected] Subject: [NMusers] 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 ______________________________________________________________________ This email has been scanned by the MessageLabs Email Security System. For more information please visit http://www.messagelabs.com/email ______________________________________________________________________ Please consider the environment before printing this e-mail This email and any files transmitted with it are confidential and may be legally privileged and are intended solely for the use of the individual or entity to whom they are addressed. If you are not the intended recipient please note that any disclosure, distribution, or copying of this email is strictly prohibited and may be unlawful. If received in error, please delete this email and any attachments and confirm this to the sender. www.shire.com
