Dose response and pharmacokinetics of tofacitinib (CP-690,550), an oral janus kinase inhibitor, in the treatment of chronic plaque psoriasis

Abstract

Longitudinal nonlinear mixed effects modeling was used to characterize the dose-response profile of tofacitinib using data from a placebo-controlled dose-ranging study, where tofacitinib 2, 5, and 15 mg twice daily (b.i.d.) were evaluated for plaque psoriasis treatment. Bayesian estimation was applied with prior information derived from the literature: nonclinical and clinical data in psoriasis, as well as other indications. The probability to achieve a certain target effect associated with a given dose was calculated from the posterior samples. On the basis of these probabilities along with safety considerations, tofacitinib 5 and 10 mg b.i.d. were selected for further testing in confirmatory phase III clinical trials. Pharmacokinetics in patients with psoriasis was characterized using a population-based modeling approach, and body weight was identified as an important covariate. A subgroup analysis suggested reduced efficacy of tofacitinib with increasing body weight; however, it is unclear whether this trend could be explained by systemic exposure alone. © 2013 ASCPT All rights reserved.