Frame B, Koup J, Miller R, Lalonde R
Department of Clinical Pharmacokinetics and Pharmacodynamics, PfizerGlobal Research and Development, Ann Arbor, Michigan 48105, USA.
Clin Pharmacokinet. 2001;40(4):307-15. doi: 10.2165/00003088-200140040-00006.
Clinafloxacin is a new fluoroquinolone antibacterial with inhibitory activity against aerobic, anaerobic and atypical bacterial pathogens. The objectives of this study are to evaluate the pharmacokinetics of clinafloxacin in healthy volunteers and patients with infections and to describe our experience with mixed-effects modelling using heterogeneous pharmacokinetic data.
Retrospective analysis of data from phase I to III trials.
204 healthy volunteers and 221 patients with infections.
Nonlinear mixed-effects modelling (MEM) was used to evaluate 3437 clinafloxacin plasma concentrations collected in 15 phase I to III trials. Models were developed separately for the healthy volunteers and patients, and then for the combined study population.
The phase I data were best described with a 2-compartment linear model with first-order absorption. The absorption lag-time and absorption rate constant were 0.24h and 1.17h(-1), respectively. The volumes of distribution were found to be nonlinear functions of body surface area. Estimated creatinine clearance was the most important covariate for systemic clearance (CL). Interoccasion variability (IOV) in CL was observed in the patients in the phase II trial. In the combined study population, the variability in CL was best described by a model including IOV and distinct variabilities for healthy volunteers and patients.
MEM was useful for evaluating data collected during different phases of drug development for this new fluoroquinolone agent.
克林沙星是一种新型氟喹诺酮类抗菌药物，对需氧菌、厌氧菌及非典型病原菌均具有抑制活性。本研究的目的是评估克林沙星在健康志愿者和感染患者中的药代动力学，并描述我们使用异质性药代动力学数据进行混合效应建模的经验。
对I期至III期试验数据进行回顾性分析。
204名健康志愿者和221名感染患者。
采用非线性混合效应建模（MEM）评估在15项I期至III期试验中收集的3437份克林沙星血药浓度。分别针对健康志愿者和患者建立模型，然后针对合并的研究人群建立模型。
I期数据用具有一级吸收的二室线性模型能得到最佳描述。吸收滞后时间和吸收速率常数分别为0.24小时和1.17小时⁻¹。分布容积是体表面积的非线性函数。估计的肌酐清除率是全身清除率（CL）最重要的协变量。在II期试验的患者中观察到CL的个体间变异性（IOV）。在合并的研究人群中，CL的变异性用一个包括IOV以及健康志愿者和患者不同变异性的模型能得到最佳描述。
MEM对于评估这种新型氟喹诺酮类药物在药物研发不同阶段收集的数据很有用。
