Population Pharmacokinetics and Use of Monte Carlo Simulation To Evaluate Currently Recommended Dosing Regimens of Ciprofloxacin in Adult Patients with Cystic Fibrosis

Pharmacodynamic data on ciprofloxacin indicate that a target area under the concentration-time curve from 0 to 24 h (AUC(0–24))/MIC ratio of ≥125 is necessary to achieve optimal bactericidal activity for the treatment of gram-negative pneumonia. The purpose of this prospective study was to (i) develop a pharmacokinetic (PK) model to be utilized for therapeutic drug monitoring (TDM) of ciprofloxacin and (ii) evaluate current ciprofloxacin dosing regimens for pneumonias in cystic fibrosis (CF) patients. Twelve adult CF patients received a single 400-mg dose of IV ciprofloxacin. Six blood samples were obtained over a 12-h interval. Serum drug concentrations were determined by high-pressure liquid chromotography and were fitted to one- and two-compartment models by using NPEM2. Ciprofloxacin MIC data for Pseudomonas aeruginosa were obtained from 1,213 CF patients enrolled in a large clinical trial. A Monte Carlo simulation was performed to estimate the fractional attainment of an AUC(0–24)/MIC ratio of ≥125. A two-compartment model best describes the serum drug concentration data. The mean fitted PK parameter values are volume of distribution in the central compartment, 0.29 liter/kg; volume of distribution at steady state, 1.1 liters/kg; total clearance, 0.34 liter/h/kg; distributional clearance, 0.89 liter/h/kg; half-life at α phase, 0.16 h; and half-life at β phase, 2.9 h. The overall fractional attainment of achieving an AUC(0–24)/MIC ratio of ≥125 against P. aeruginosa isolates with ciprofloxacin (400 mg every 12 h [q12h] and 8 qh) were 10 and 30%, respectively. A clinical breakpoint MIC of <0.5 μg/ml for susceptibility is suggested, based on an examination of the fractional attainment of the AUC(0–24)/MIC target at each MIC. The recommended doses of 400 mg q8h or q12h may be inadequate to treat an acute pulmonary exacerbation when given alone. The poor and variable AUC(0–24)/MIC ratios support the use of TDM to monitor and adjust the dosage to optimize the efficacy of ciprofloxacin therapy in these patients.

环丙沙星（ciprofloxacin）的药效动力学数据表明，若要获得最佳杀菌活性以治疗革兰阴性肺炎，需满足0至24小时浓度-时间曲线下面积（AUC(0–24)）与最低抑菌浓度（MIC）之比≥125。本前瞻性研究的目标为：(i) 建立可用于环丙沙星治疗药物监测（TDM）的药代动力学（PK）模型；(ii) 评估当前囊性纤维化（CF）患者肺炎治疗的环丙沙星给药方案。12名成年CF患者接受单次400mg静脉输注环丙沙星，在12小时内采集6份血液样本。采用高效液相色谱法测定血清药物浓度，并通过NPEM2软件将数据拟合至一室与二室模型。从一项大型临床试验纳入的1213名CF患者中获取铜绿假单胞菌（Pseudomonas aeruginosa）的环丙沙星MIC数据，通过蒙特卡洛模拟估算AUC(0–24)/MIC≥125的达标率。二室模型最能拟合血清药物浓度数据，拟合得到的平均药代动力学参数值如下：中央室分布容积0.29 L/kg；稳态分布容积1.1 L/kg；总清除率0.34 L/h/kg；分布清除率0.89 L/h/kg；α相半衰期0.16 h；β相半衰期2.9 h。针对铜绿假单胞菌菌株，采用400mg每12小时给药（q12h）与每8小时给药（q8h）方案时，AUC(0–24)/MIC≥125的总达标率分别为10%与30%。基于各MIC下AUC(0–24)/MIC靶标的达标率分析，建议将敏感性临床折点MIC设为<0.5μg/ml。单独使用400mg q8h或q12h的推荐剂量，可能不足以治疗急性肺恶化。偏低且个体差异较大的AUC(0–24)/MIC比值，提示需通过治疗药物监测（TDM）监测并调整给药剂量，以优化此类患者中环丙沙星治疗的疗效。