Abstract

1. Nafithromycin is a next generation lactone ketolide antibiotic slated to enter phase III clinical development in India for the treatment of CABP as a shorter 800 mg-OD X3 day therapeutic regimen. Nafithromycin exhibits potent activity against MDR Streptococcus pneumoniae including erythromycin and telithromycin-resistant resistant strains. Older macrolides/ketolides are reported to be potent inhibitors of CYP3A4/5. To facilitate comparative assessment of drug–drug interaction potential, CYP inhibitory activities of nafithromycin was evaluated in comparison with clarithromycin, telithromycin, cethromycin and solithromycin.

2. CYP inhibitory activities were assessed against key CYP isoforms (CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and CYP3A4/5) using human liver microsomes. Additionally, time-dependent inhibition (TDI), metabolism-based inhibition (MBI) and k _inact /K _I activities were also investigated for CYP3A4/5.

3. Nafithromycin did not inhibit key CYP enzymes and was found to be a weak inhibitor of CYP3A4/5. Comparator antibiotics were found to be potent inhibitors with 2- to 50-fold leftward shifts in CYP3A4/5 IC50 values, while such shift was not noted for nafithromycin. k _inact /K _I ratio of nafithromycin was 3- to 153-fold lower than comparator drugs, further substantiating its lower affinity for CYP3A4/5.

4. In sum, weaker inhibition and lower k _inact /K _I ratio for CYP3A4/5, points towards nafithromycin’s lower propensities towards clinical drug–drug interactions as compared to other macrolides/ketolides antibiotics.

摘要

1. 纳非霉素是下一代内酯酮内酯抗生素，计划在印度进入III期临床开发阶段，以较短的800 mg-OD X3天的治疗方案来治疗CABP。纳非霉素对耐多药肺炎链球菌（包括红霉素和耐特石霉素的菌株）具有强效活性。据报道，较老的大环内酯类/酮缩酮类是CYP3A4 / 5的有效抑制剂。为了促进药物相互作用的比较评估，与克拉霉素，泰利霉素，头霉素和索洛霉素相比，评价了纳非霉素的CYP抑制活性。

2. 使用人肝微粒体评估了针对关键CYP亚型（CYP1A2、2B6、2C8、2C9、2C19、2D6和CYP3A4 / 5）的CYP抑制活性。此外，还研究了CYP3A4 / 5的时间依赖性抑制（TDI），基于代谢的抑制（MBI）和k _inact / K _I活性。

3. 纳非霉素不抑制关键的CYP酶，被发现是CYP3A4 / 5的弱抑制剂。发现比较用抗生素是强效抑制剂，其CYP3A4 / 5 IC50值向左移动2至50倍，而纳非霉素未发现这种移动。nafithromycin的k _inact / K _I比比对照药物低3至153倍，进一步证实了其对CYP3A4 / 5的较低亲和力。

4. 总之，CYP3A4 / 5的抑制作用较弱，k _inact / K _I比值较低，这表明那菲霉素与其他大环内酯类/酮缩酮类抗生素相比具有较低的临床药物相互作用倾向。