Re: PK simulation and replicates

Dear Marie, Someone else may comment on the regulatory guidelines, but before even getting into this here is something to think about. If you only intend to do simulations based on the point estimates of your population parameters (i.e. point estimates of THETA, OMEGA and SIGMA), then there is often no need to simulate a trial with replicates. For that case, just use a sufficient number of subjects for the statistic(s) you want to derive, or what you want to illustrate and simulate a single-replicate data set. One exception would be e.g. VPC, where you want to simulate replicate trials (all with the same set of population parameters) with the analysis data set, in order to establish CIs based on the data set at hand. This article may help you understand the number of replicates needed (Jonsson and Nyberg): https://pubmed.ncbi.nlm.nih.gov/35353958/ Similarly, if you want to also account for uncertainty in population parameters, the number of replicates needed depends on the confidence interval you want to report, and what precision you want to achieve. For example if you are interested in the group mean Ctrough,ss and also want to account for the uncertainty in this predicted value (by accounting for the uncertainty in population parameters): In general you would need more replicate trials in order to calculate the statistic with 99% CI as supposed to an 80% CI. And in all cases with replicate trials: you should calculate the statistic (e.g. a mean, or a percentile) separately for each replicate trial, not across all trials. I will stop there since I am not sure whether you are intend to simulate a single trial, or do the latter and account for the uncertainty as well. Best regards Jakob Jakob Ribbing, Ph.D. Principal Consultant & Client Operations Expert [email protected] +46(0)705-14 33 77 www.pharmetheus.com