Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
School of Pharmacy, University of Waterloo, Kitchener, Ontario, Canada.
CPT Pharmacometrics Syst Pharmacol. 2017 Dec;6(12):814-822. doi: 10.1002/psp4.12252. Epub 2017 Oct 25.
Solithromycin is a fluoroketolide antibiotic under investigation for community-acquired bacterial pneumonia (CABP). We developed a whole-body physiologically based pharmacokinetic (PBPK) model for solithromycin in adults using PK-Sim and MoBi version 6.2, which incorporated time-dependent CYP3A4 auto-inhibition. The model was developed and evaluated using plasma and epithelial lining fluid (ELF) concentration data from 100 healthy subjects and 22 patients with CABP (1,966 plasma, 30 ELF samples). We performed population simulations and calculated the number of observations falling outside the 90% prediction interval. For the oral regimen (800 mg on day 1 and 400 mg daily on days 2-5) that was evaluated in phase III studies, 11% and 23% of observations from healthy adults fell outside the 90% prediction interval for plasma and ELF, respectively. This regimen should be effective because ≥97% of simulated adults achieved area under the concentration vs. time curve (AUC) to minimum inhibitory concentration ratios associated with a log colony forming unit reduction in ELF.
索利霉素是一种氟酮内酯类抗生素，正在研究用于治疗社区获得性细菌性肺炎（CABP）。我们使用 PK-Sim 和 MoBi 版本 6.2 为成人开发了索利霉素的全身生理基于药代动力学（PBPK）模型，该模型纳入了时间依赖性 CYP3A4 自动抑制。该模型是使用 100 名健康受试者和 22 名社区获得性细菌性肺炎患者（1966 个血浆，30 个上皮衬里液样本）的血浆和上皮衬里液浓度数据开发和评估的。我们进行了群体模拟并计算了落在 90%预测区间之外的观察次数。在 III 期研究中评估的口服方案（第 1 天 800mg，第 2-5 天每天 400mg），分别有 11%和 23%的健康成年人的血浆和上皮衬里液观察结果落在 90%预测区间之外。由于模拟的成年人中≥97%的人达到了与上皮衬里液中最小抑菌浓度相关的浓度-时间曲线下面积（AUC）与单位形成菌落数减少对数相关的 AUC：最小抑菌浓度比值，该方案应该是有效的。
