Department I of Pharmacology, Clinical Pharmacology Unit, University Hospital Cologne, Cologne, Germany
MerLion Pharmaceuticals GmbH, Berlin, Germany.
Antimicrob Agents Chemother. 2018 Mar 27;62(4). doi: 10.1128/AAC.02328-17. Print 2018 Apr.
Finafloxacin is a novel fluoroquinolone with increased antibacterial activity at acidic pH and reduced susceptibility to several resistance mechanisms. A phase II study revealed a good efficacy/safety profile in patients with complicated urinary tract infections (cUTIs), while the pharmacokinetics was characterized by highly variable concentration-versus-time profiles, suggesting the need for an elaborated pharmacokinetic model. Data from three clinical trials were evaluated: 127 healthy volunteers were dosed orally ( = 77) or intravenously ( = 50), and 139 patients with cUTI received finafloxacin intravenously. Plasma (2,824 samples from volunteers and 414 samples from patients) and urine (496 samples from volunteers and 135 samples patients) concentrations were quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). NONMEM was used to build a population pharmacokinetic model, and pharmacokinetic/pharmacodynamic relationships were investigated via simulations and logistic regression. A two-compartment model with first-order elimination described the data best (central volume of distribution [] and peripheral volume of distribution [] of 47 liters [20%] and 43 liters [67%], respectively, and elimination clearance and intercompartmental clearance of 21 liters/h [54%] and 2.8 liters/h [57%], respectively [median bootstrap estimates {coefficients of variation}]). increased with body surface area, and clearance was reduced in patients (-29%). Oral absorption was described best by parallel first- and zero-order processes (bioavailability of 75%). No pharmacodynamic surrogate parameter of clinical/microbiological outcome could be identified, which depended exclusively on the MIC of the causative pathogens. Despite the interindividual variability, the present data set does not support covariate-based dose adjustments. Based on the favorable safety and efficacy data, the clinical relevance of the observed variability appears to be limited. (This study has been registered at ClinicalTrials.gov under identifier NCT01928433.).
法氟沙星是一种新型氟喹诺酮类药物，在酸性 pH 值下具有增强的抗菌活性，并且对几种耐药机制的敏感性降低。一项 II 期研究表明，该药在复杂性尿路感染（cUTI）患者中具有良好的疗效/安全性特征，而药代动力学特征为浓度-时间曲线高度可变，表明需要建立详细的药代动力学模型。对三项临床试验的数据进行了评估：127 名健康志愿者口服（n = 77）或静脉内（n = 50）给药，139 名 cUTI 患者接受法氟沙星静脉内给药。采用液相色谱-串联质谱法（LC-MS/MS）定量测定血浆（志愿者 2824 个样本和患者 414 个样本）和尿液（志愿者 496 个样本和患者 135 个样本）中的浓度。NONMEM 用于建立群体药代动力学模型，并通过模拟和逻辑回归研究药代动力学/药效学关系。一个具有一级消除的两室模型最能描述数据（中央分布容积[]和外周分布容积[]分别为 47 升[20%]和 43 升[67%]，消除清除率和两室清除率分别为 21 升/小时[54%]和 2.8 升/小时[57%]，中位数自举估计[变异系数]）。清除率与体表面积呈正相关，患者清除率降低（-29%）。口服吸收通过平行的一级和零级过程得到最佳描述（生物利用度为 75%）。无法确定临床/微生物学结果的药效替代参数，这完全取决于致病病原体的 MIC。尽管存在个体间变异性，但本数据集不支持基于协变量的剂量调整。基于有利的安全性和疗效数据，观察到的变异性的临床相关性似乎有限。（本研究已在 ClinicalTrials.gov 上注册，标识符为 NCT01928433。）
