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Pharmacokinetic Effects of Isavuconazole Coadministration With the Cytochrome P450 Enzyme Substrates Bupropion, Repaglinide, Caffeine, Dextromethorphan, and Methadone in Healthy Subjects
Author(s) -
Yamazaki Takao,
Desai Amit,
Goldwater Ronald,
Han David,
Howieson Corrie,
Akhtar Shahzad,
Kowalski Donna,
Lademacher Christopher,
Pearlman Helene,
Rammelsberg Diane,
Townsend Robert
Publication year - 2016
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.281
Subject(s) - dextromethorphan , cmax , pharmacology , medicine , cyp2b6 , repaglinide , bupropion , cyp2a6 , pharmacokinetics , drug interaction , cyp2d6 , cyp1a2 , cytochrome p450 , metformin , pathology , metabolism , insulin , smoking cessation
This report describes phase 1 clinical trials performed to assess interactions of oral isavuconazole at the clinically targeted dose (200 mg, administered as isavuconazonium sulfate 372 mg, 3 times a day for 2 days; 200 mg once daily [QD] thereafter) with single oral doses of the cytochrome P450 (CYP) substrates: bupropion hydrochloride (CYP2B6; 100 mg; n = 24), repaglinide (CYP2C8/CYP3A4; 0.5 mg; n = 24), caffeine (CYP1A2; 200 mg; n = 24), dextromethorphan hydrobromide (CYP2D6/CYP3A4; 30 mg; n = 24), and methadone (CYP2B6/CYP2C19/CYP3A4; 10 mg; n = 23). Compared with each drug alone, coadministration with isavuconazole changed the area under the concentration‐time curves (AUC ∞ ) and maximum concentrations (C max ) as follows: bupropion, AUC ∞ reduced 42%, C max reduced 31%; repaglinide, AUC ∞ reduced 8%, C max reduced 14%; caffeine, AUC ∞ increased 4%, C max reduced 1%; dextromethorphan, AUC ∞ increased 18%, C max increased 17%; R‐methadone, AUC ∞ reduced 10%, C max increased 3%; S‐methadone, AUC ∞ reduced 35%, C max increased 1%. In all studies, there were no deaths, 1 serious adverse event (dextromethorphan study; perioral numbness, numbness of right arm and leg), and adverse events leading to study discontinuation were rare. Thus, isavuconazole is a mild inducer of CYP2B6 but does not appear to affect CYP1A2‐, CYP2C8‐, or CYP2D6‐mediated metabolism.