Paulson Susan K, Wood-Horrall Rebecca N, Hoover Randall, Quintas Megan, Lawrence Laura E, Cammarata Sue K
Pharma Start LLC, Northbrook, Illinois.
PPD Phase I Clinic, Austin, Texas.
Clin Ther. 2017 Jun;39(6):1182-1190. doi: 10.1016/j.clinthera.2017.04.009. Epub 2017 May 9.
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 AUC and C 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 AUC of 1-hydroxymidazolam, the primary metabolite of midazolam, was 105.7 (97.7-114.3); the ratio of C 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.
Steady-state dosing of delafloxacin produced no significant changes in midazolam pharmacokinetics, except for a small but not clinically relevant change in the C of 1-hydroxymidazolam. ClinicalTrials.gov identifier: NCT02505997.
德拉氟沙星是一种新型阴离子氟喹诺酮类药物，正处于治疗严重皮肤感染的III期研发阶段。本研究的目的是评估德拉氟沙星对细胞色素P450（CYP）3A底物咪达唑仑药代动力学的影响。
在多次给予德拉氟沙星达到稳态之前和之后，以咪达唑仑为探针评估CYP3A活性。在这项非随机、开放标签、单序列的I期研究中，22名健康男性和女性受试者在第1天和第8天口服单剂量5mg咪达唑仑，从第3天至第8天每12小时口服450mg德拉氟沙星。在第1天和第8天（咪达唑仑和1-羟基咪达唑仑）以及第3天和第7天（德拉氟沙星）获得完整的药代动力学曲线。
与单独使用咪达唑仑相比，与德拉氟沙星共同给药的咪达唑仑的AUC和C的几何平均比值（90%CI）分别为89.4（83.2-96.0）和93.6（83.7-104.6）。同样，咪达唑仑的主要代谢产物1-羟基咪达唑仑的AUC几何比值为105.7（97.7-114.3）；C的比值在116.1（101.7-132.4）时不等效，超出了80%至125%的CI范围。连续6天口服多剂量德拉氟沙星总体耐受性良好。
德拉氟沙星的稳态给药对咪达唑仑的药代动力学没有显著影响，除了1-羟基咪达唑仑的C有微小但无临床意义的变化。ClinicalTrials.gov标识符：NCT02505997。
