Amantea M A, Bowden R A, Forrest A, Working P K, Newman M S, Mamelok R D
SEQUUS Pharmaceuticals, Inc., Menlo Park, California 94025, USA.
Antimicrob Agents Chemother. 1995 Sep;39(9):2042-7. doi: 10.1128/AAC.39.9.2042.
The purpose of this study was to evaluate the pharmacokinetics of amphotericin B colloidal dispersion and its effect on creatinine clearance in bone marrow transplant patients with systemic fungal infections. Seventy-five patients (42 females and 33 males) with a median age of 34.5 years and a median weight of 70.0 kg were enrolled in the study. Patients received 1 of 15 dose levels (range, 0.5 to 8.0 mg/kg of body weight) daily for a mean duration of 28 days and a mean cumulative dose amount of 8 g. Plasma samples for amphotericin B determination (median number, 4; range, 2 to 30) and daily serum creatinine values were obtained for each patient. Iterative two-stage analysis, one of several approaches to population pharmacokinetic and pharmacodynamic modelling, was employed for the pharmacokinetic analysis. The plasma data were available for 51 of 75 patients and were best described by a two-compartment model. Both plasma clearance and volume of distribution increased with escalating doses; the overall average terminal elimination half-life was 29 h. Of the covariates studied, only body weight and dose size were significant. Serum creatinine values over the duration of therapy were available for 59 of 75 patients. Overall, there was no net change in renal function over the duration of therapy; 12 patients had > 30% increases in creatinine clearance, whereas 13 had > 30% decreases. No measure of amphotericin B colloidal dispersion exposure, demographic values, or concomitant treatment with other medications was related to changes in the creatinine clearance.
本研究的目的是评估两性霉素B胶体分散体的药代动力学及其对全身真菌感染的骨髓移植患者肌酐清除率的影响。75名患者（42名女性和33名男性）入组本研究，年龄中位数为34.5岁，体重中位数为70.0 kg。患者每天接受15个剂量水平（范围为0.5至8.0 mg/kg体重）中的1个剂量，平均疗程为28天，平均累积剂量为8 g。为每位患者采集用于测定两性霉素B的血浆样本（中位数为4；范围为2至30）和每日血清肌酐值。药代动力学分析采用迭代两阶段分析法，这是群体药代动力学和药效学建模的几种方法之一。75名患者中有51名患者的血浆数据可用，这些数据用二室模型描述最佳。血浆清除率和分布容积均随剂量增加而增加；总体平均末端消除半衰期为29小时。在所研究的协变量中，只有体重和剂量大小具有显著性。75名患者中有59名患者在治疗期间有血清肌酐值。总体而言，在治疗期间肾功能没有净变化；12名患者的肌酐清除率增加> 30%，而13名患者的肌酐清除率降低> 30%。两性霉素B胶体分散体暴露量、人口统计学值或与其他药物的联合治疗均与肌酐清除率的变化无关。
