Re: Baseline as a covariate

Hi Pete, It all depends on the distribution in the baseline measurements. For the omalizumab-IgE model, Naoto, Stacey and I used measured baseline IgE as a covariate on IgE turnover. Baseline IgE was not normally distributed and was limited by inclusion criteria. The end result was that the baseline IgE (and bodyweight) predicted IgE production and elimination and the unexplained variation was minimised. However, the upshot of this was that for simulation we could not use a simple normal or log-normal distribution of baseline IgE, so either used the clinical trial database values if we wanted a full population, or produced simulations for narrow ranges of baseline IgE and bodyweight for specific regions of the dosing table. Interestingly, once we had loads of data, we discovered that the baseline IgE was also a significant covariate on the omalizumab-IgE binding constant (binding model equivalent of EC50 or IC50 in an indirect response model). Why is currently unknown, but may represent competition with other IgE binding entities such as FceR1 and CD23, which can vary in their expression levels. Best regards, Phil. Physiologist, biochemist; "Master Modeller" Novartis Pharma AG, WSJ-027.6.25, CH-4056 Basel, Switzerland Phone: +41 61 324 4676; Mobile: +41 79 349 7806; [email protected] "Peter Bonate" <[email protected]> Sent by: [email protected] 11/08/2010 17:50 To "'[email protected]'" <[email protected]> cc Subject [NMusers] Baseline as a covariate I'd like to get the group's opinion on something. I have a pharmacodynamic model and the baseline was shown to be a covariate on one of the model parameters. I was hoping to get general thoughts on the use of the baseline as a covariate. Is there a preference for using the observed baseline vs. NONMEM predicted baseline? And does your opinion change if you have a large residual error? Thanks Pete bonate Peter L. Bonate, PhD, FCP, FAAPS GlaxoSmithKline Clinical Pharmacology, Modeling, and Simulation 5 Moore Drive, 17.2259 Research Triangle Park, NC 27709 phone: 919-483-7534 fax: 919-483-8948 email: [email protected]