Ron,
Truncation can also introduce bias so you should check for this in your simulations as well. Also, if your model based on 100 patients results in simulations of CL/F ranging from 1 300 L/hr but the post hoc estimates of CL/F range from 5 30 L/hr then you may want to further assess the appropriateness of your model before using it to conduct clinical trial simulations. Sounds like you are over-estimating the variance. You might want to look at a histogram of the ETAs for CL/F and look for departures from normality. Ken From: [EMAIL PROTECTED] [mailto:[EMAIL PROTECTED] On Behalf Of Nick Holford Sent: Tuesday, April 22, 2008 4:04 PM To: Ron Mathôt Cc: nmusers@globomaxnm.com Subject: 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 [EMAIL PROTECTED] tel:+64(9)373-7599x86730 fax:+64(9)373-7090 www.health.auckland.ac.nz/pharmacology/staff/nholford
