Bioequivalence of the pharmacokinetics between tofacitinib aspartate and tofacitinib citrate in healthy subjects

Abstract

Tofacitinib is an oral disease-modifying anti-rheumatic drug to selectively inhibit Janus kinases. Tofacitinib is a representative small molecule inhibitor that is used to treat many diseases including rheumatoid arthritis and various autoimmune conditions. Unlike biological agents, tofacitinib has several advantages, including the ability to be administered orally and a short half-life. This study aimed to evaluate the bioequivalence of the pharmacokinetics (PK) between tofacitinib aspartate 7.13 mg (test formulation) and tofacitinib citrate 8.08 mg (reference formulation; Xeljanz®) in healthy subjects. A randomized, open-label, single-dose, 2-sequence, 2-period, 2-treatment crossover trial was conducted in 41 healthy volunteers. A total of 5 mg of tofacitinib as the test or the reference formulation was administered, and serial blood samples were collected up to 14 hours after dosing for PK analyses. The plasma concentration of tofacitinib was determined by ultra-performance liquid chromatography-tandem mass spectrometry. A non-compartmental analysis was used to estimate the PK parameters. A total of 35 subjects completed the study and the study drug was well-tolerated. The mean maximum concentration (Cmax) and area under the concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast) for the test formulation were 52.67 ng/mL and 133.86 ng∙h/mL, respectively, and 50.61 ng/mL and 133.49 h∙ng/mL for the reference formulation, respectively. The geometric mean ratios (90% confidence intervals) of the Cmax and AUClast between the 2 formulations were 1.041 (0.944-1.148) and 1.003 (0.968-1.039), respectively. Tofacitinib aspartate exhibited bioequivalent PK profiles to those of the reference formulation.

Trial registration: ClinicalTrials.gov Identifier: NCT04278391.

Keywords: Bioequivalence; Pharmacokinetics; Tofacitinib.

Conflict of interest statement

Conflict of Interest: - Authors: KH Park, and H Shin are the employees of Daewoong Pharmaceutical Co., Ltd. The other authors report no conflicts of interest related to this work. - Reviewers: Nothing to declare - Editors: Nothing to declare

Copyright © 2020 Translational and Clinical Pharmacology.

Figures

Figure 1. Mean ± standard deviation plasma concentration-time profiles of Tofacitinib after single doses of the reference (white triangles) and test formulations (black circles) in healthy subject (A, linear scale; B, log scale).

Figure 2. Individual (A) Cmax and (B) AUClast of Tofacitinib after single doses of the reference and test formulations of Tofacitinib in healthy subjects.

Cmax, maximum plasma concentration of drug; AUClast, area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration.