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Abstract：
This study aimed to explore the pharmacokinetics (PK) and safety of oral (PO) and intravenous (IV) lefamulin in healthy Chinese subjects and to evaluate the efficacy of the intravenous administration regimen using pharmacokinetic/pharmacodynamic (PK/PD) analysis. This study was a randomized, open-label, single- and multiple-dose, intravenous and oral administration study. PK parameters were calculated, and the probability of target attainment (PTA) and the cumulative fraction of response (CFR) after IV administration of lefamulin 150 mg 1 h q12 h were analyzed with Monte Carlo simulations. Lefamulin exhibited extensive distribution. The mean steady-state AUC0-24 h of 150 mg lefamulin IV and 600 mg lefamulin PO were 10.03 and 13.96 μg·h/mL, respectively. For Streptococcus pneumoniae and Staphylococcus aureus, based on the free-drug AUC over MIC ratio (fAUC/MIC) target of 1-log10 cfu reduction, the PK/PD breakpoints were 0.25 and 0.125 mg/L, respectively. The CFR was over 90% for both types of strains with 95% protein binding rate, suggesting that the regimen was microbiologically effective. Lefamulin was safe and well-tolerated. The PK of lefamulin in healthy Chinese subjects were consistent with that in foreign countries. Lefamulin demonstrated the microbiological effectiveness against Streptococcus pneumoniae and Staphylococcus aureus.
摘要：
本研究旨在探讨健康中国受试者口服（PO）和静脉（IV）lefamulin的药代动力学（PK）和安全性，并使用药代动力学/药效学（PK/PD）分析评估静脉给药方案的有效性。这项研究是随机的，开放标签，单剂量和多剂量，静脉和口服给药研究。计算PK参数，用蒙特卡洛模拟分析了静脉给药lefamulin150mg1hq12h后达到目标的概率（PTA）和累积反应分数（CFR）。Lefamulin表现出广泛的分布。150mglefamulinIV和600mglefamulinPO的平均稳态AUC0-24h分别为10.03和13.96μg·h/mL，分别。对于肺炎链球菌和金黄色葡萄球菌，基于1-log10cfu降低的游离药物AUC超过MIC比率（fAUC/MIC）目标，PK/PD断点分别为0.25和0.125mg/L，分别。两种类型的菌株的CFR均超过90％，蛋白质结合率为95％，表明该方案在微生物学上是有效的。Lefamulin安全且耐受性良好。健康中国受试者的lefamulinPK与国外一致。Lefamulin证明了对肺炎链球菌和金黄色葡萄球菌的微生物有效性。
