Safety, tolerability, and pharmacokinetics of single oral doses of tofacitinib, a Janus kinase inhibitor, in healthy volunteers

Abstract Tofacitinib is an oral Janus kinase inhibitor. This randomized, double‐blind, parallel‐group, placebo‐controlled study was the first evaluation of tofacitinib in humans. The objectives were to characterize the safety and tolerability, pharmacokinetics (PK), and pharmacodynamics of escalating single tofacitinib doses in healthy subjects. Tofacitinib (0.1, 0.3, 1, 3, 10, 30, 60, and 100 mg) or placebo was administered as oral powder for constitution. For each dose, 7–9 subjects were randomized to tofacitinib and 3–5 subjects to placebo. Ninety‐five males and females (age range 19–45) completed the study. Forty‐nine treatment‐emergent all‐causality adverse events (AEs) were observed; nausea and headache were the most frequently reported. Tofacitinib PK was characterized by rapid absorption (time to peak serum concentration [T max ] 0.5–1 hour), rapid elimination (mean terminal half‐lives 2.3–3.1 hours), and dose‐proportional systemic exposures (peak serum concentration [C max ] and area under the serum concentration‐time curve from time zero to infinity [AUC 0–∞ ]). No appreciable correlation was observed between tofacitinib dose and lymphocyte subset counts. Single‐dose tofacitinib up to 100 mg in healthy subjects had a safety profile of mostly mild AEs, and no deaths, serious AEs, severe AEs or discontinuations due to AEs.