Pharmacokinetic Effects of Isavuconazole Coadministration With the Cytochrome P450 Enzyme Substrates Bupropion, Repaglinide, Caffeine, Dextromethorphan, and Methadone in Healthy Subjects.
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 (Cmax) as follows: bupropion, AUC∞reduced 42%, Cmaxreduced 31%; repaglinide, AUC∞reduced 8%, Cmaxreduced 14%; caffeine, AUC∞increased 4%, Cmaxreduced 1%; dextromethorphan, AUC∞increased 18%, Cmaxincreased 17%; R-methadone, AUC∞reduced 10%, Cmaxincreased 3%; S-methadone, AUC∞reduced 35%, Cmaxincreased 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.
Astellas Pharma Global Development, Inc, Northbrook, IL, USA.
Takao
T
Yamazaki
Astellas Pharma Global Development, Inc, Northbrook, IL, USA.
Amit
A
Desai
PAREXEL, Baltimore, MD, USA.
Ronald
R
Goldwater
PAREXEL, Los Angeles, CA, USA.
David
D
Han
Astellas Pharma Global Development, Inc, Northbrook, IL, USA.
Corrie
C
Howieson
Astellas Pharma Global Development, Inc, Northbrook, IL, USA.
Shahzad
S
Akhtar
Astellas Pharma Global Development, Inc, Northbrook, IL, USA.
Donna
D
Kowalski
Astellas Pharma Global Development, Inc, Northbrook, IL, USA.
Christopher
C
Lademacher
Astellas Pharma Global Development, Inc, Northbrook, IL, USA.
Helene
H
Pearlman
Randstad Pharma, Deerfield, IL, USA.
Diane
D
Rammelsberg
Astellas Pharma Global Development, Inc, Northbrook, IL, USA.
Robert
R
Townsend
D000328:Adult; D019540:Area Under Curve; D016642:Bupropion / Q000008:administration & dosage*; D002110:Caffeine / Q000008:administration & dosage*; D002219:Carbamates / Q000008:administration & dosage*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003915:Dextromethorphan / Q000008:administration & dosage*; D004347:Drug Interactions; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008691:Methadone / Q000008:administration & dosage*; D008875:Middle Aged; D009570:Nitriles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010880:Piperidines / Q000008:administration & dosage*; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014230:Triazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D055815:Young Adult
D002219:Carbamates; D009570:Nitriles; D010880:Piperidines; D011725:Pyridines; D014230:Triazoles; D016642:Bupropion; D002110:Caffeine; C508735:isavuconazole; C072379:repaglinide; D003915:Dextromethorphan; D003577:Cytochrome P-450 Enzyme System; D008691:Methadone
cytochrome P450; interaction; isavuconazole; isavuconazonium; pharmacokinetics