title: Evaluation of pharmacokinetic interaction between PA-824 and midazolam in healthy adult subjects.
abstract: This study assessed the safety, tolerability, and pharmacokinetic interaction between PA-824, a novel antitubercular nitroimidazo-oxazine, and midazolam, a CYP3A4 substrate, in 14 healthy adult male and female subjects. The study followed up on observations in vitro that PA-824 caused weak and time-dependent inhibition of CYP3A4. Subjects received a single oral dose of midazolam (2 mg), followed by a 2-day washout. After the washout, all subjects received PA-824 (400 mg) once daily for 14 consecutive days. On day 14, all subjects received the final PA-824 dose coadministered with a 2-mg oral dose of midazolam. The pharmacokinetic endpoints AUC0-t, AUC(0-∞), and C(max) for midazolam and 1-hydroxy midazolam were compared between midazolam administered alone versus midazolam coadministered with PA-824. Statistical analysis demonstrated that the mean midazolam values of C(max), AUC(0-t), and AUC(0-∞) parameters were reduced by ca. 16, 15, and 15%, respectively, when PA-824 was coadministered with midazolam. The total exposure (AUC) of 1-hydroxy midazolam was 13 to 14% greater when coadministered with PA-824 compared to midazolam administered alone. The Cmax of 1-hydroxy midazolam was similar between treatments. Based on these results, PA-824 does not inhibit or induce CYP3A4 to a clinically meaningful extent and is not likely to markedly affect the pharmacokinetics of CYP3A4 metabolized drugs.
authors.affiliation: School of Pharmacy, University of Otago, Dunedin, New Zealand.
authors.forename: Helen
authors.initials: H
authors.lastname: Winter
authors.forename: Erica
authors.initials: E
authors.lastname: Egizi
authors.forename: Ngozi
authors.initials: N
authors.lastname: Erondu
authors.forename: Ann
authors.initials: A
authors.lastname: Ginsberg
authors.forename: Doris J
authors.initials: DJ
authors.lastname: Rouse
authors.forename: Diana
authors.initials: D
authors.lastname: Severynse-Stevens
authors.forename: Elliott
authors.initials: E
authors.lastname: Pauli
authors.forename: Daniel
authors.initials: D
authors.lastname: Everitt
mesh_terms: D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D008875:Middle Aged; D009593:Nitroimidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D013997:Time Factors; D055815:Young Adult
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D009593:Nitroimidazoles; C410767:pretomanid; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008874:Midazolam