Cytochrome P450 3A4 drug interaction profile of tofacitinib

Purpose: Tofacitinib is an oral Janus Kinase (JAK) inhibitor currently in development for the treatment of several inflammatory conditions including rheumatoid arthritis. Tofacitinib is primarily metabolized by the cytochrome p450 3A4 system (CYP3A4). The objective of these studies is to describe the potential drug-interaction profile of tofacitinib, focusing on the CYP3A4 isoenzyme.

Methods: Two separate open-label, pharmacokinetic studies were conducted in 12 healthy volunteers to determine the pharmacokinetic parameters of oral tofacitinib when administered with ketoconazole (potent CYP3A4 inhibitor), and rifampin (potent CYP3A4 inducer). In study 1, subjects received a single-dose of tofacitinib 10 mg in Period 1. In Period 2, subjects received ketoconazole 400 mg for 3 days followed by a single-dose of tofacitinib 10 mg on Day 3. In study 2, subjects received a single-dose of tofacitinib 30 mg in Period 1. In Period 2, subjects received rifampin 600 mg for 7 days followed by a single-dose of tofacitinib 30 mg on Day 8. In both studies, blood samples of tofacitinib were taken at 0, 0.5, 1, 2, 4, 6, 8, 12, 16, and 24 hours after tofacitinib dosing in Periods 1 and 2.

Results: Coadministration with ketoconazole increased tofacitinib AUCinf and Cmax by 103%, [ratio 203% (90% CI 191%-216%)] and 16% [ratio 116% (90% CI 105%-129%)], respectively. Mean t1/2 increased from 2.9 to 3.9 hours and median Tmax increased from 0.5 to 1.0 hours with ketoconazole administration. Coadministration of rifampin decreased mean tofacitinib AUCinf by 84% [ratio 16% (90% CI 14%-18%)] and Cmax by 74% [ratio 26% (90% CI 23%-31%)]. Mean t1/2 for tofacitinib decreased from 4.2 to 2.9 hours, however, median Tmax was similar with and without rifampin.

Conclusion: These results suggest that pharmacokinetic parameters of tofacitinib are altered when it is administered with ketoconazole (potent CYP3A4 inhibitor) or rifampin (potent CYP3A4 inducer).