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Evaluation of the effect of fluconazole and ketoconazole on the pharmacokinetics of tofacitinib in healthy adult subjects
Author(s) -
Gupta Pankaj,
Chow Vincent,
Wang Ronnie,
Kaplan Irina,
Chan Gary,
Alvey Christine,
Ni Grace,
Ndongo MarieNoella,
LaBadie Robert R.,
Krishnaswami Sriram
Publication year - 2013
Publication title -
clinical pharmacology in drug development
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.711
H-Index - 22
eISSN - 2160-7648
pISSN - 2160-763X
DOI - 10.1002/cpdd.71
Subject(s) - tofacitinib , ketoconazole , medicine , pharmacokinetics , fluconazole , pharmacology , cyp3a4 , drug interaction , janus kinase inhibitor , oral administration , antifungal , dermatology , cytochrome p450 , rheumatoid arthritis , metabolism
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.