br Conclusion In vivo pharmacokinetic
Conclusion In vivo pharmacokinetic studies showed that dasatinib monohydrate pretreatment significantly decreased the blood level of CsA in rats, which was most probably due to the induction of CYP3A2 isoenzymes. The nilotinib pre-treatment had no significant effects on cyclosporine pharmacokinetics in rats.
Role of the funding source
Conflict of interest
Introduction Awareness of potential drug–drug interactions is important in drug development, notably with antibiotics because they are often concomitantly administered with other drugs such as pressors, other antibiotics for empiric therapy, and, in the case of fluoroquinolones, antacids and other multivalent cation-containing drugs. These interactions may increase or decrease the action of either drug and change the rate and extent of Deferasirox and plasma protein binding displacement; microbiologically, they may alter the ability of cell membranes or receptor sites to bind to either drug. Drug–drug interactions can be either pharmacokinetic or pharmacodynamic in nature, which could lead to a change in efficacy and/or toxicity. Fluoroquinolones are widely used in both inpatient and outpatient settings; thus, clinicians ought to be aware of any drug–drug interactions. Apart from the aforementioned antacids, which reduce the oral absorption of many fluoroquinolones, other interactions have been described in the literature for fluoroquinolones with xanthines, including theophylline and caffeine, warfarin, probenecid, phenytoin, and digoxin.2, 3, 4 Delafloxacin, a novel anionic fluoroquinolone for the treatment of gram-positive and gram-negative infections (including atypicals and anaerobes), is undergoing clinical development for acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia.5, 6, 7 The US Food and Drug Administration’s Draft Guidance on Drug Interaction Studies recommends that pharmacokinetic interactions be defined during drug development as part of the drug’s safety and effectiveness. Delafloxacin has been studied in in vitro metabolic studies and is not an inhibitor of cytochrome P450 (CYP) 1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4/5, nor is it an inducer of CYP1A2 or CYP2B6. However, delafloxacin is a mild in vitro inducer of CYP3A in cultures of human hepatocytes (data on file, Melinta Therapeutics, Lincolnshire, IL). Midazolam, a benzodiazepine sedative-hypnotic agent, is metabolized by CYP3A and has been adopted as a metabolic probe of CYP3A in humans.9, 10 We therefore studied the in vivo impact of delafloxacin on midazolam pharmacokinetics in healthy subjects to assess any potential for clinical drug–drug interactions. This study also study evaluated the pharmacokinetics of multiple doses of oral delafloxacin.
Subjects and Methods
Discussion Fluoroquinolones, in particular ciprofloxacin, levofloxacin, grepafloxacin, norfloxacin, and clinafloxacin, have been associated with inhibition of CYP1A2.4, 11, 12 In vitro studies conducted with human liver microsomes showed that delafloxacin is not an inhibitor of CYP1A2 nor any of the other isozymes (CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4/5). However, delafloxacin was a mild inducer of CYP3A in cultures of human hepatocytes. Because delafloxacin may be coadministered with drugs that are substrates of CYP3A, such as midazolam, we evaluated the effect of multiple doses of oral delafloxacin on the pharmacokinetic profile of a single oral dose of midazolam. Midazolam systemic exposures as measured by AUC0–∞ and Cmax were equivalent when oral midazolam was administered after 5 days of oral delafloxacin BID. The 90% CIs for the ratio of mean midazolam AUC0–∞ and Cmax were contained within 80% and 125%, satisfying the criterion for lack of effect. Analysis of delafloxacin trough levels showed that delafloxacin was generally at steady state after 4 days (day 7 of the study), which is adequate to assess the interaction. Furthermore, the dose-corrected midazolam AUC0–∞ and Cmax values calculated in our study are similar to values found in the literature.13, 14, 15, 16, 17 The geometric ratio of Cmax for 1-hydroxymidazolam at 116.1 (101.7–132.4) was not equivalent, as it was just outside the CI of 80% to 125%; however, total exposures (AUC) were equivalent, which suggests that, overall, delafloxacin did not increase metabolism to 1-hydroxymidazolam. In addition, the mean terminal phase kinetics were unchanged when midazolam was coadministered with delafloxacin. Interestingly, the mean t½ of 1-hydroxymidazolam, the primary metabolite of midazolam, decreased by ~46% (2.68 versus 4.95 hours) when midazolam was coadministered with delafloxacin. The reason for the difference is not completely understood but may be a result of a number of samples below the lower limit of quantitation (0.1 ng/mL).