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 [Tmax ] 0.5-1 hour), rapid elimination (mean terminal half-lives 2.3-3.1 hours), and dose-proportional systemic exposures (peak serum concentration [Cmax ] and area under the serum concentration-time curve from time zero to infinity [AUC0-∞ ]). 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.

Development and validation of a rapid and sensitive UPLC–MS/MS assay for the quantification of tofacitinib in human plasma

“…This aspect is extensively studied using a 0.1–100 mg dose of TOF in healthy volunteers by Krishnaswami, Wang, et al (). The mean time point of maximum plasma concentration and half‐life ( t 1/2 ) values obtained for TOF were comparable with previous reports in healthy volunteers (Krishnaswami, Wang, et al, ; Krishnaswami, Boy, et al, ). Rapid systemic elimination of TOF with a short t 1/2 (2.83 h) is consistent with a previous report (Krishnaswami, Wang, et al, ).…”

“…For the extraction of TOF from various biological matrices all three conventional procedures were employed namely, protein precipitation (PPT) (Paniagua et al, ), liquid–liquid extraction (LLE) (Abdelhameed et al, ; Kadi et al, ; Kumar et al, ) and solid‐phase extraction (Dowty et al, ; Krishnaswami, Wang, et al, ; Krishnaswami, Boy, et al, ; Menon et al, ; Sharma et al, ). Initially, PPT was tried with acetonitrile and methanol in the presence of a base.…”

Evaluation of a Janus kinase 1 inhibitor, PF‐04965842, in healthy subjects: A phase 1, randomized, placebo‐controlled, dose‐escalation study

“…There were no deaths, serious AEs, temporary discontinuations or dose reductions due to AEs. The most frequent TEAEs were headache, diarrhoea and nausea, which have previously been reported in healthy volunteers treated with other JAK inhibitors . TEAEs were more common with the higher doses (single dose 800 mg and multiple dose 200 mg BID and 400 mg QD), but most were mild in severity.…”

“…Plasma PF-04965842 C max concentrations increased proportionally across the entire dose range, while exposure in terms of the AUC was greater than proportional at doses of 400 mg and 800 mg. A monophasic decline was observed in the disposition of PF-04965842 at the lower doses (3-30 mg) and a biphasic decline was observed at the higher doses, probably due to concentrations for the lower doses declining below the lower limit of quantification before the slower terminal phase was observed. In comparison, a median T max of 0.5-1 h followed by monophasic elimination was observed with single doses of tofacitinib (0.1-100 mg) in healthy volunteers [18]. Dose proportional systemic exposures and a mean t 1/2 of 2.5 h were observed for tofacitinib ≥3 mg [18].…”

“…In comparison, a median T max of 0.5–1 h followed by monophasic elimination was observed with single doses of tofacitinib (0.1–100 mg) in healthy volunteers . Dose proportional systemic exposures and a mean t 1/2 of 2.5 h were observed for tofacitinib ≥3 mg . Ruxolitinib was absorbed rapidly in healthy volunteers, typically attaining peak plasma concentrations within 2 h for single doses of 5–200 mg, and plasma concentration declined in a multiphasic manner with a mean terminal disposition t 1/2 of 3 h for the five lowest doses and 5 h for 200 mg .…”