艾司奥美拉唑在重症患者体内药代/药效学研究

Pharmacokinetics,pharmacodynamics of esomeprazole in critically ill patients

目的:探讨注射用艾司奥美拉唑在危重症患者体内的药代动力学/药效学(pharmacokinetics/pharmacodynamics,PK/PD)特征。方法:这是一项前瞻性、单中心、开放标签研究,所有患者接受艾司奥美拉唑预防应激性溃疡,给药方案为静脉输注40 mg q12h,给药天数由临床医生根据患者病情制定。共入组40名重症患者,根据采集血样的时机分为单剂组和多剂组。单剂组患者21名,在首次给药后1、3、6、8、12 h采集血样;多剂组患者34名,重复多次给药后于第5剂给药前(0 h)和开始给药后1、3、6、8、12 h采集血样,其中有15名患者同时采集首次给药和重复多次给药的血样。采用高效液相色谱-质谱联用HPLC-MS/MS测定艾司奥美拉唑血药浓度,采用非房室模型分析法计算药物PK参数。同时对禁食且保留胃管的患者在首次给药前(0 h),开始给药后1、2、4、8、12、14、16、20、24 h采集胃液测量pH值,计算pH≥4的时间百分比。记录用药期间发生的所有不良事件和严重不良事件。结果:单剂组患者平均年龄67.75岁(45~69岁),BMI(24.05±3.35)kg/m2,多剂组患者平均年龄63.35岁(24~87岁),BMI(24.08±3.29)kg/m2。首次给药后PK参数:AUC0-t(11.26±6.58)mg·h·L^(-1),C_(max)(3.08±2.06)mg/L,CL(4.13±3.68)L/h,Vd(17.12±6.13)L,t1/2(4.80±3.06)h。多次重复给药后PK参数:AUC0-t(16.70±11.20)mg·h·L^(-1),C_(max)(3.37±2.59)mg/L,CL(3.94±2.94)L/h,Vd(22.71±17.26)L,t1/2(5.23±3.34)h。给药后0~24 h内p H≥4的时间百分比为61.69%,给药后12~24 h内pH≥4的时间百分比可达100%。所有患者对艾司奥美拉唑的耐受性良好,无严重不良事件发生。结论:与健康志愿者相比,注射用艾司奥美拉唑在重症患者体内Vd增加、CL降低,药物暴露量有所增加,且重复给药后在体内存在一定蓄积。该药物在重症患者中安全性良好。

AIM:To investigate the pharmacokinetic/pharmacodynamic(PK/PD)profile of esomeprazole for injection in critically ill patients.METHODS:This was a prospective,single-center,open-label study,all patients received intravenous infused esomeprazole 40 mg q12h for stress ulcer prophylaxis,treatment duration is determined by clinicians based on patients condition.Forty critically ill patients were enrolled and were divided into single and multiple dose groups according to the timing of blood sample collection.Twenty-one patients in the single-dose group had their blood samples collected at 1,3,6,8,and 12 h after the first dose,and 34 patients in the multiple-dose group had their blood samples collected at 0 h before the fifth dose and 1,3,6,and 8,and 12 h after the fifth dose,of which 14 patients had their blood samples collected at both the first dose and the repeated doses.The concentration of esomeprazole was measured by HPLC-MS/MS,and PK parameters were analyzed using noncompartmental analysis.Gastric aspirates were collected for pH measurement in fasted patients with gastric tube before the first dose(0 h),and 1,2,4,8,12,14,16,20,24 h after the initiation of drug administration,and the percentage of time with pH≥4 was calculated.All adverse events and serious adverse events during treatment were recorded.RESULTS:Patients in the single-dose group were 67.75 years old(45-69 years)with a BMI(24.05±3.35)kg/m2,and patients in the multiple-dose group were 63.35 years old(24-87 years)with a BMI(24.08±3.29)kg/m2.PK parameters after the first dose were AUC0-t(11.26±6.58)mg·h·L^(-1),C_(max)(3.08±2.06)mg/L,CL(4.13±3.68)L/h,Vd(17.12±6.13)L,t1/2(4.80±3.06)h;PK parameters after multiple doses were AUC0-t(16.70±11.20)mg·h/L,C_(max)(3.37±2.59)mg/L,CL(3.94±2.94)L/h,Vd(22.71±17.26)L,t1/2(5.23±3.34)h.Percentage of time with pH≥4 within 0 h-24 h after administration was 61.69%,and percentage of time with pH≥4 within 12 h-24 h was up to 100%.Esomeprazole was well tolerated by all patients with no serious adverse events.CONCLUSION:Compared with healthy volunteers,injectable esomeprazole showed increased Vd,decreased CL,increased drug exposure and accumulation after repeated administration in critically ill patients.The drug had a favorable safety profile in critically ill patients.