Allergan plc, Madison, NJ, USA.
qPharmetra LLC, Cary, NC, USA.
Clin Pharmacol Drug Dev. 2020 Jan;9(1):21-31. doi: 10.1002/cpdd.695. Epub 2019 May 14.
Dalbavancin is indicated for the treatment of acute bacterial skin and skin structure infections caused by susceptible gram-positive microorganisms. This analysis represents the update of the population pharmacokinetics (popPK) modeling and target attainment simulations performed with data from the single-dose safety and efficacy study and an unrelated but substantial revision of the preclinical pharmacokinetic/pharmacodynamic target (fAUC/MIC, free area under concentration-time curve/minimum inhibitory concentration ratio). A 3-compartment distribution model with first-order elimination provided an appropriate fit, with typical dalbavancin clearance of 0.05 L/h and total volume of distribution of ∼15 L. Impact of intrinsic factors was modest, although statistically significant (P < .05) relationships with total clearance were found for the following covariates: creatinine clearance, weight, and albumin - dose adjustment was only indicated for severe renal impairment. Under the new nonclinical target, simulations of the popPK model projected that >99% of subjects would achieve the nonclinical target at MIC values up to and including 2 mg/L.
达巴万星适用于治疗由敏感革兰阳性微生物引起的急性细菌性皮肤和皮肤结构感染。这一分析代表了对单次剂量安全性和疗效研究数据进行的群体药代动力学（popPK）建模和目标达成模拟的更新，以及对非相关但大量的临床前药代动力学/药效学目标（fAUC/MIC，游离浓度时间曲线下面积/最小抑菌浓度比值）的实质性修订。具有一级消除的 3 室分布模型提供了适当的拟合，典型的达巴万星清除率为 0.05 L/h，总分布容积约为 15 L。内在因素的影响较小，但与总清除率有统计学意义（P<.05）的关系，以下协变量与总清除率有关：肌酐清除率、体重和白蛋白 - 仅对严重肾功能损害需要调整剂量。根据新的非临床目标，popPK 模型的模拟预测，在 MIC 值高达 2mg/L 及以下时，超过 99%的受试者将达到非临床目标。
