The Pharmacokinetics of the CYP3A Substrate Midazolam After Steady-state Dosing of Delafloxacin

Clinical Therapeutics
Susan K PaulsonSue K Cammarata

Abstract

Delafloxacin is a novel anionic fluoroquinolone in Phase III development for the treatment of serious skin infections. The objective of this study was to evaluate the effects of delafloxacin on the pharmacokinetics of midazolam, a cytochrome P450 (CYP) 3A substrate. CYP3A activity using midazolam as a probe was assessed before and after multiple doses of delafloxacin to reach steady state. In this nonrandomized, open-label, single-sequence, Phase I study, 22 healthy male and female subjects were administered a single 5-mg oral dose of midazolam on days 1 and 8, with oral delafloxacin 450 mg every 12 hours administered from days 3 to 8. Full pharmacokinetic profiles were obtained on days 1 and 8 (midazolam and 1-hydroxymidazolam) and days 3 and 7 (delafloxacin). The geometric mean ratios (90% CIs) for AUC0-∞ and Cmax of midazolam coadministered with delafloxacin versus midazolam alone were 89.4 (83.2-96.0) and 93.6 (83.7-104.6). Similarly, the geometric ratio for the AUC0-∞ of 1-hydroxymidazolam, the primary metabolite of midazolam, was 105.7 (97.7-114.3); the ratio of Cmax was not equivalent at 116.1 (101.7-132.4), which was outside the CI of 80% to 125%. Multiple doses of oral delafloxacin for 6 days were generally well tolera...Continue Reading

Citations

Oct 11, 2017·Expert Opinion on Drug Metabolism & Toxicology·Matteo BassettiFederico Pea
May 17, 2018·Future Microbiology·Matteo BassettiGlenn Tillotson
Feb 10, 2018·The Journal of Antimicrobial Chemotherapy·Bryan T MogleWesley D Kufel
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Apr 9, 2019·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·Matteo BassettiGlenn Tillotson
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Aug 5, 2021·Expert Opinion on Pharmacotherapy·Cristiana M Nascimento-Carvalho
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Jan 23, 2020·Journal of Medicinal Chemistry·William C WrightTaosheng Chen
Dec 17, 2021·Expert Review of Anti-infective Therapy·Matteo BassettiDaniele Roberto Giacobbe

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