Evaluation of the effect of fluconazole and ketoconazole on the pharmacokinetics of tofacitinib in healthy adult subjects

Tofacitinib is a novel, oral JAK inhibitor that is being investigated as a targeted immunomodulator. Tofacitinib is predominantly metabolized by cytochrome P450 (CYP) 3A4 and to a lesser extent by CYP2C19. Two Phase 1, randomized, open-label, single sequence studies in 24 healthy subjects (12 per study) characterized the effects of fluconazole (moderate CYP3A4/potent CYP2C19 inhibitor) and ketoconazole (potent CYP3A4 inhibitor) on tofacitinib pharmacokinetics. In the fluconazole study, subjects received a single tofacitinib 30 mg dose. After 72 hours, subjects received fluconazole 400 mg, followed by 200 mg once daily (QD; days 2-7) plus tofacitinib 30 mg on day 5. In the ketoconazole study, a single tofacitinib 10 mg dose was administered. After 24 hours, subjects received ketoconazole (400 mg QD; days 1-3) plus tofacitinib 10 mg on day 3. Treatment comparisons were made using mixed-effect models. Tofacitinib area under the curve and maximal plasma concentration increased by 79% and 27%, respectively, with fluconazole co-administration and by 103% and 16%, respectively, with ketoconazole co-administration. Tofacitinib half-life increased by approximately 1 hour during co-administration with fluconazole or ketoconazole. Co-administration of moderate to potent CYP3A4 inhibitors is likely to increase the systemic exposure of tofacitinib and thus may warrant dosage adjustments or restrictions.