氯法拉滨注射液在白血病患者中的单剂量及多剂量临床药代动力学研究

目的: 研究氯法拉滨注射液单剂量及多剂量静脉滴注的人体药动学过程。方法: 4例白血病患者单剂量恒速静脉滴注氯法拉滨注射液 52 mg·m^-2·d^-1 ,单剂量试验结束后进入多剂量给药试验, 52 mg·m^-2·d^-1 ,连续给药 5 d。采用高效液相色谱串联质谱法测定血浆及尿液中氯法拉滨的浓度,并采用DAS药动学软件对试验数据进行处理,求算有关药动学参数。结果: 4例受试者单剂量静脉滴注氯法拉滨注射液后,主要药动学参数分别为C_max(414±205) μg/L,t_max(3.0±1.4) h,t_1/2z(4.4±2.0) h,AUC_0-t(2475±659) μg·h·L^-1,AUC_0-∞(2566±606) μg·h·L^-1,CLz(21.2±5.1) L·h^-1·m^-2,V_z(142±97) L/m²,MRT_(0-t) (6.3±2.2) h,Zeta(0.18±0.07) h^-1,24 h 平均尿液累积排泄率为(39.53±20.98)%。52 mg·m^-2·d^-1静脉滴注氯法拉滨注射液,连续给药5 d,第5日达稳态,主要药动学参数为C_max(581±126) μg/L,t_max(2.0±0.8) h,t_1/2z(6.4±3.1) h,AUC_0-t(2451±349) μg·h·L^-1,AUC_0-∞(2603±409) μg·h·L^-1,CLz(20.4±3.7) L·h^-1·m^-2,V_z(187±80) L/m,Zeta(0.13±0.05) h^-1,MRT_(0-t) (5.1±1.8) h,C_ss(102.14±14.53) μg/L,蓄积因子R(1.04±0.28),血药浓度波动度DF(576.26±226.89)%。结论: 氯法拉滨注射液静脉滴注给药 52 mg·m^-2·d^-1 ,连续给药 5 d,药物在体内无蓄积,安全性好。

Pharmacokinetics of single and multiple doses of Clofarabine for injection in patients with leukemia

AIM: To investigate the pharmacokinetics of Clofarabine for injection with a single and multiple dose administration in patients with acute leukemia.METHODS: 4 patients with acute leukemia received a single dose intravenous of 52 mg·m^-2·d^-1, and then they are repeatedly administrated with 52 mg·m^-2·d^-1 Clofarabine for 5 days.The concentrate of Clofarabine in plasma and urine were determined by HPLC-MS/MS.DAS pharmacokinetics software was used for data process and calculation of pharmacokinetic parameters.RESULTS: The main pharmacokinetic parameters of Clofarabine after single dose of 52 mg·m^-2·d^-1 Clofarabine for injection were as follows: C_max(414±205) μg/L,t_max(3.0±1.4) h, t_1/2z(4.4±2.0) h,AUC_0-t(2475±659) μg·h·L^-1, AUC_0-∞(2566±606) μg·h·L^-1, CLz(21.2±5.1) L·h^-1·m^-2, Vz(142±97) L/m, MRT_0-t(6.3±2.2) h, Zeta(0.18±0.07) h^-1, the 12 h cumulative urine excretion rate was (39.53±20.98)%, the main pharmacokinetic parameters of Clofarabine after 52 mg·m^-2·d^-1 for 5 days were as follows: C_max(581±126) μg/L, t_max(2.0±0.8) h, t_1/2z(6.4±3.1) h, AUC_0-t(2451±349) μg·h·L^-1, AUC_0-∞(2603±409) μg·h·L^-1, CLz(20.4±3.7) L·h^-1·m^-2, Vz(187±80) L/m, Zeta(0.13±0.05) h^-1, MRT_{0-24 h}(5.1±1.8) h, C_ss(102.14±14.53) μg/L,the accumulation coefficients R was (1.04±0.28), the fluctuation coefficients of plasma concentration DF was (576.26±226.89)%.CONCLUSION: No accumulation is detected when 52 mg·m^-2·d^-1 Clofarabine for injection has been administrated for 5 days, it was safe.