Mixed effects modeling of weight change associated with placebo and pregabalin administration.

ABSTRACT

OBJECTIVE: To characterize change from baseline weight over time for pregabalin and placebo administration. METHODS: Asymptotic fraction of baseline weight was modeled with a nonmixture model and a mixture model as a function of baseline weight, exposure, time, covariate effects, and subject-specific random effects. Model fit was assessed using standard diagnostic plots. Predictive performance was assessed using both data similar to the original data, and open-label data. RESULTS: The nonmixture model indicated that a typical patient (baseline weight 82 kg) receiving placebo or 300 mg/day pregabalin approached an asymptotic fractional change from baseline weight of [mean (95% prediction interval for typical individual)] 0.7% (-5.5% to 7.4%) or 2.5% (-3.8% to 9.1%), respectively, with a half-life of 17 days. Substantial between-subject variability is observed, with some drug-treated subjects remaining weight neutral or losing weight, at all levels of exposure. Structural fixed effects parameters for the two submodels (mixture model) were in close agreement with each other and with those for the nonmixture model. The mixture model described two subpopulations differing in interindividual variability. No significant interindividual-varying covariates influencing the mixture probabilities were identified other than exposure. Both models had adequate fit; both models performed well during external validation. Predictive performance (nonmixture model) was adequate to ~900 days. CONCLUSIONS: The weight of a typical 82-kg patient receiving placebo or pregabalin (300 mg/day) approaches an asymptotic fractional change from baseline weight of 0.7%, or 2.5%, respectively, with a half-life of 17 days. Substantial between-subject variability remains unexplained.