环丙沙星在老年下呼吸道感染患者中的群体药代动力学分析

Population pharmacokinetics of ciprofloxacin in Chinese elderly patients with lower respiratory tract infection

目的 分析环丙沙星在老年下呼吸道感染患者中的群体药代动力学（PPK）.方法 连续入选43例2012年3月至2014年6月在北京大学第三医院呼吸重症监护室（RICU）具有铜绿假单胞菌感染危险因素者的老年下呼吸道感染患者,根据患者病情予经验给药,环丙沙星200 mg静脉输注,1次/12 h,重症感染患者予400 mg静脉输注,1次/12 h.治疗3d达到血药稳态,于第4天给药开始后7个不同时间点（1、2、3、4、6、8、12 h）中留取2个以上时间点的血清标本,同时收集临床资料.高效液相色谱（HPLC）法检测血清药物浓度.使用非线性混合效应模型（NONMEM）7.3.0软件进行群体药代动力学（PPK）分析.结果 40例患者完成研究,年龄（78±9）岁,共检测环丙沙星血清药物浓度210份.使用二室模型对环丙沙星的血药浓度数据进行群体药代动力学分析,清除率和中央室表观分布容积V1的群体典型值为17.8 L/h、49.8 L.血肌酐显著影响清除率,公式为清除率=17.8×[1-0.001 3×（血肌酐-67）]× e^ηli ×0.659^n（当剂量为200 mg时,n=1,当剂量为400 mg时,n=0.ηi为个体间随机变异）.清除率和V1在剂量为200 mg时,需要乘以系数0.659.单次给药剂量为200和400 mg时,血清峰浓度（Cmax）稳态值分别为（4.2±1.1）和（5.3±1.2）mg/L,血药谷浓度（Cmin）稳态值分别为（1.1±1.1）和（0.8±0.4） mg/L,24 h血清浓度-时间曲线下面积AUC0-24h分别为（45.5±28.1）和（47.2±11.3） mg·h· L^-1.结论 本研究中建立的环丙沙星PPK模型,可用于指导临床个体化给药.老年患者使用环丙沙星时,提高单次使用剂量为0.4g可以增加最高血药浓度,但在肾功能正常情况下,并不会引起药物潴留.

Objective To analyse population pharmacokinetic （PPK） parameter values of ciprofloxacin in Chinese elderly patients with lower respiratory tract infection.Methods Hospitalized in Respiratory Intensive Care Unit （RICU） due to severe lower respiratory tract infection and at high risks of Pseudomonas aeruginosa.43 consecutive elderly patients received an intravenous infusion of ciprofloxacin at a dose of 200/400 mg every 12/24 h empirically.Plasma samples were drawn from Day 4 and at 1,2,3,4,6,8 and 12 h after infusion.The serum concentrations of ciprofloxacin were determined by high-performance liquid chromatography （HPLC）.Ciprofloxacin population pharmacokinetic analysis was conducted by the NONMEM 7.3.0 software.Results Forty patients aged （78 ±9） years completed the study.A total of 210 serum concentrations were detected.The mean values of clearance and volume of distribution （V1） were 17.8 L/h and 49.8 L respectively.The serum creatinine level influenced ciprofloxacin according to the equation：Clearance =17.8 × [1-0.001 3 × （serum creatinine-67）] × e^ηli × 0.659^n （at a dose of 200 mg,n =1,at a dose of 400 mg,n =0;ηi for inter individual random variation）.The values of clearance and V1 were multiplied by 0.659 at a dose of 200 mg.At the doses of 200 and 400 mg,the maximum steady-state concentrations （Cmax） were （4.2 ± 1.1） and （5.3 ± 1.21） mg/L,the minimum steady-state concentrations （Cmin） （1.1 ± 1.1） and （0.8 ± 0.4） mg/L and the area under concentration-time curve measured in steady-state up to 24 h after dosing （AUC0-24 h） were （45.5 ± 28.1） and （47.2 ± 11.3） mg · h · L^-1 respectively.Conclusions The clearance of ciprofloxacin in elderly patients significantly decreases as compared with adult patients.Ciprofloxacin PPK model shows a significant influence of serum creatinine level on ciprofloxacin clearance.A single dose of 400 mg may increase serum drug concentration,but causes no in vivo drug retention.