注射用法罗培南钠在健康人体的耐受性及其连续给药的药代动力学

Tolerability and pharmacokinetics of multiple-dose faropenem injection in Chinese healthy volunteers

目的确定注射用法罗培南钠(碳青霉烯类抗生素)最大耐受剂量及其连续给药的药代动力学研究。方法58名健康受试者分别单次静滴注射用法罗培南钠100、200、300、450、600、800 mg及连续静滴给药每次200、300mg,每日3、2次,连续滴注7天。用HPLC法测定连续静滴注射用法罗培南钠200 mg组受试者血浆及尿中法罗培南的浓度。结果单次450 mg组和连续200、300 mg组,各1人血清ALT、AST升高外;其余受试者无任何不良反应发生。连续多剂量静滴法罗培南钠200 mg后,其药代动力学参数:tm ax为(1.00±0.00)h;Cm ax为(15.80±3.96)μg.mL-1;t1/2为(1.07±0.27)h;CL/F为(0.15±0.03)L.kg.h-1;Vd/F为(0.23±0.07)L.kg-1;Cav为(2.81±2.96)μg.mL-1;DF为(6.55±5.47);AUC0-t为(24.00±6.23)μg.h.mL-1;AUC0-∞为(23.70±6.27)μg.h.mL-1。其12 h累积尿药排泄率为40.49%。结论其最大耐受剂量为800 mg;推荐Ⅱ期临床剂量为每次200mg,每日3次。

Objective To determine the maximum tolerated dose and pharmacokinetics of faropenem sodium for consecutive injection in Chinese healthy volunteers. Methods A single dose （100, 200, 300, 450, 600 and 800 mg） and consecutive doses （200 and 300 mg） of faropenem for injection were administered to 8 groups in healthy volunteers, respectively. Faropenem were determined by HPLC method after 200 mg of faropenem were given to 8 healthy volunteers with once each 8 h, 19 consecutive times. Results Fifty-eight volunteers completed the test, the volunteers could tolerate to this mediation, expect three subjects experienced ALT and AST increased. The major pharmacokinetic parameters of faropenem were as follows ： tmax was （ 1.00 ± 0.00 ） h ; Cmax was （15.80 ±3.96） μg · mL^-1 ;t1/2 was （1.07 ±0. 27） h;CL/F was （0. 15 ±0.03） L · kg · h^-1;Va/F was （0.23 ±0.07） L · kg^-1;Cav was （2. 81 ±2. 96） μg· mL^-1 ;DF was （6.55 ±5.47） ;AUC0-t was （24. 00 ±6.23） μg· h· mL^-1;AUC0-∞ was （23.70±6.27） μg ·h · mL^-1. Accumulative urine excretion rate of 12 h was 40.49%. Conclusion Max tolerable dose of faropenem sodium for injection is 800 mg, a recommendeddose for phase Ⅱ clinical trial is 200 mg, tid.