Susan K Paulson1, Rebecca N Wood-Horrall2, Randall Hoover3, Megan Quintas4, Laura E Lawrence4, Sue K Cammarata5. 1. Pharma Start LLC, Northbrook, Illinois. 2. PPD Phase I Clinic, Austin, Texas. 3. Pharmacology Consultant, Bel Air, Maryland. 4. Melinta Therapeutics, Inc, Lincolnshire, Illinois. 5. Melinta Therapeutics, Inc, Lincolnshire, Illinois. Electronic address: scammarata@melinta.com.
Abstract
PURPOSE: 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. METHODS: 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). FINDINGS: 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 tolerated. IMPLICATIONS: Steady-state dosing of delafloxacin produced no significant changes in midazolam pharmacokinetics, except for a small but not clinically relevant change in the Cmax of 1-hydroxymidazolam. ClinicalTrials.gov identifier: NCT02505997.
PURPOSE: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. METHODS: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). FINDINGS: 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 tolerated. IMPLICATIONS: Steady-state dosing of delafloxacin produced no significant changes in midazolam pharmacokinetics, except for a small but not clinically relevant change in the Cmax of 1-hydroxymidazolam. ClinicalTrials.gov identifier: NCT02505997.
Authors: William C Wright; Jude Chenge; Jingheng Wang; Hazel M Girvan; Lei Yang; Sergio C Chai; Andrew D Huber; Jing Wu; Peter O Oladimeji; Andrew W Munro; Taosheng Chen Journal: J Med Chem Date: 2020-01-22 Impact factor: 7.446
Authors: William O'Riordan; Alison McManus; Juri Teras; Ivan Poromanski; Maria Cruz-Saldariagga; Megan Quintas; Laura Lawrence; ShuJui Liang; Sue Cammarata Journal: Clin Infect Dis Date: 2018-08-16 Impact factor: 9.079
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