Martin David E, Blum Robert, Doto Judy, Galbraith Hal, Ballow Charles
Drug Development, Panacos Pharmaceuticals Inc., Gaithersburg, Maryland 20877, USA.
Clin Pharmacokinet. 2007;46(7):589-98. doi: 10.2165/00003088-200746070-00004.
Bevirimat [3-O-(3',3'-dimethylsuccinyl)-betulinic acid] is a novel inhibitor of HIV-1 maturation. This study was performed to investigate the pharmacokinetics and safety of bevirimat during repeated dosing in healthy volunteers.
The study was a 10-day, randomised, double-blind, placebo-controlled, dose escalation study. A total of 48 healthy male volunteers, aged 19-54 years, took part in the study. Treatment was administered for 10 days in six escalating dose cohorts (n = 8 in each cohort; 6 bevirimat, 2 placebo). The doses of bevirimat given in each successive cohort were 25 mg, 50 mg, 75 mg (with 150 mg loading dose), 100 mg, 150 mg and 200mg. Safety follow-up was performed 28 days after the first dose. PHARMACOKINETIC AND STATISTICAL ANALYSIS: Plasma bevirimat levels were measured from blood samples collected pre-dose on days 1-10 and then at approximately 48-hour intervals until 21 days after dosing started. On days 1 and 10, further blood samples were obtained at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours after dosing. Urine samples were collected in the morning on days 1, 5 and 11 and at the end of the study for the measurement of cortisol and 6beta-hydroxycortisol. The pharmacokinetic parameters of bevirimat were estimated using non-compartmental methods.
Dose proportionality of exposure to bevirimat, assessed by the maximum plasma concentration and the area under the plasma concentration-time curve.
The mean terminal elimination half-life of bevirimat ranged from 56.3 to 69.5 hours, and the mean clearance ranged from 173.9 to 185.8 mL/hour. Bevirimat showed approximately 4-fold greater accumulation on day 10 compared with day 1, and the degree of accumulation was similar with all doses. Maximum plasma concentrations ranged from 8 to 58 microg/mL at day 10. Testing for dose-proportionality showed that exposure to bevirimat was proportional to the dose, both after a single dose and after repeat dosing for 10 days. Measurement of the urinary 6beta-hydroxycortisol/cortisol ratio indicated that bevirimat did not affect cytochrome P450 3A activity. Repeated dosing with bevirimat for 10 days was well tolerated. There was no increase in adverse events observed for bevirimat compared with placebo, and no serious adverse events occurred. No clinically relevant changes in vital signs, physical examination or clinical laboratory evaluations were observed.
Bevirimat shows dose-proportional pharmacokinetics during repeated dosing for 10 days. Its accumulation is approximately 4-fold greater on day 10 compared with day 1. Repeated dosing with bevirimat is well tolerated. These properties make bevirimat potentially suitable for inclusion in highly active antiretroviral therapy regimens.
贝维拉马特[3 - O - (3',3'-二甲基琥珀酰基)-桦木酸]是一种新型的HIV - 1成熟抑制剂。本研究旨在调查健康志愿者重复给药期间贝维拉马特的药代动力学和安全性。
本研究为一项为期10天的随机、双盲、安慰剂对照、剂量递增研究。共有48名年龄在19 - 54岁的健康男性志愿者参与了该研究。治疗在六个递增剂量组中进行10天（每组n = 8；6组使用贝维拉马特，2组使用安慰剂）。每个连续组中贝维拉马特的剂量分别为25mg、50mg、75mg（加150mg负荷剂量）、100mg、150mg和200mg。首次给药后28天进行安全性随访。
在第1 - 10天给药前采集血样，然后每隔约48小时采集一次血样，直至给药开始后21天，以测量血浆贝维拉马特水平。在第1天和第10天，给药后0.25、0.5、0.75、1、1.5、2、3、4、6、8和12小时采集更多血样。在第1天、第5天和第11天早晨以及研究结束时收集尿样，用于测量皮质醇和6β - 羟基皮质醇。使用非房室模型方法估算贝维拉马特的药代动力学参数。
通过最大血浆浓度和血浆浓度 - 时间曲线下面积评估贝维拉马特暴露的剂量比例关系。
贝维拉马特的平均终末消除半衰期为56.3至69.5小时，平均清除率为173.9至185.8 mL/小时。与第1天相比，贝维拉马特在第10天的蓄积量约高4倍，且所有剂量的蓄积程度相似。第10天的最大血浆浓度范围为8至58μg/mL。剂量比例关系测试表明，无论是单次给药还是重复给药10天后，贝维拉马特的暴露量与剂量成正比。尿中6β - 羟基皮质醇/皮质醇比值的测量表明，贝维拉马特不影响细胞色素P450 3A活性。贝维拉马特重复给药10天耐受性良好。与安慰剂相比，未观察到贝维拉马特的不良事件增加，也未发生严重不良事件。未观察到生命体征、体格检查或临床实验室评估有临床相关变化。
贝维拉马特在重复给药10天期间表现出剂量比例性药代动力学。与第1天相比，其在第10天的蓄积量约高4倍。贝维拉马特重复给药耐受性良好。这些特性使贝维拉马特可能适合纳入高效抗逆转录病毒治疗方案。
