Lin Chin-Chung, Philips Lee, Xu Christine, Yeh Li-Tain
Valeant Pharmaceuticals International, 3300 Hyland Avenue, Costa Mesa, CA 92626, USA.
J Clin Pharmacol. 2004 Mar;44(3):265-75. doi: 10.1177/0091270004262974.
Ribavirin, part of the current first-line combination therapy for the treatment of chronic hepatitis C, has side effects-in particular, hemolytic anemia-that is frequently dose limiting. Based on animal studies, viramidine, a prodrug of ribavirin, is converted to ribavirin in the liver. Viramidine dosing yielded 50% higher ribavirin levels in the monkey liver but only half in plasma and red blood cells compared to ribavirin dosing. At the same dose, it also had a safer profile than ribavirin in a 28-day toxicity study in monkeys. The current study was carried out to evaluate the safety, tolerability, and pharmacokinetics of viramidine in healthy male volunteers (n = 8-18 on viramidine vs. 2 on placebo at each dose level) after oral dosing of viramidine at 200, 600, and 1200 mg. There were no serious adverse events, and most adverse events were mild. The percentages of treatment-emergent events judged to be possibly related to the study drug were 50% in the 1200-mg group, 26% in the 600-mg group, and none in the 200-mg group. Viramidine was orally absorbed and rapidly converted to ribavirin with a t(max) of 1.5 to 3.0 hours for both viramidine and ribavirin in plasma. There was dose proportionality in plasma AUC(0-168 h) and C(max) for viramidine and in plasma AUC(0-168 h) for ribavirin. Plasma AUC(0-168 h) for ribavirin was two to four times higher than plasma AUC(0-168 h) for viramidine, indicating that viramidine is extensively metabolized to ribavirin and is a prodrug of ribavirin in man. Amounts of viramidine and ribavirin excreted in the urine were small (2%-5% of dose), indicating that the main route of elimination for both viramidine and ribavirin is metabolism. Both viramidine and ribavirin were excreted into urine through the mechanism of glomerular filtration. In addition, an evaluation of the effect of a high-fat meal on the pharmacokinetics of viramidine and ribavirin after oral dosing of viramidine at 600 mg was conducted in healthy male volunteers (n = 33-34) in a crossover study design. A high-fat meal increased viramidine plasma AUC(0-168 h) by 44% and C(max) by 20%. It also increased ribavirin plasma AUC(0-168 h) by 19% and C(max) by 43%. The clinical relevance of these increases is unknown.
利巴韦林是目前治疗慢性丙型肝炎的一线联合疗法的组成部分，它具有副作用，尤其是溶血性贫血，这常常限制了用药剂量。基于动物研究，利巴韦林的前体药物维拉美啶在肝脏中转化为利巴韦林。与给予利巴韦林相比，给予维拉美啶后，猴子肝脏中的利巴韦林水平高出50%，但血浆和红细胞中的水平仅为一半。在一项为期28天的猴子毒性研究中，在相同剂量下，维拉美啶的安全性也优于利巴韦林。本研究旨在评估维拉美啶在健康男性志愿者（每个剂量水平下，服用维拉美啶的有8至18人，服用安慰剂的有2人）口服200、600和1200毫克维拉美啶后的安全性、耐受性和药代动力学。未发生严重不良事件，大多数不良事件为轻度。判定可能与研究药物有关的治疗中出现的事件百分比在1200毫克组为50%，600毫克组为26%，200毫克组为零。维拉美啶口服吸收后迅速转化为利巴韦林，血浆中维拉美啶和利巴韦林的t(max)均为1.5至3.0小时。维拉美啶的血浆AUC(0 - 168小时)和C(max)以及利巴韦林的血浆AUC(0 - 168小时)存在剂量比例关系。利巴韦林的血浆AUC(0 - 168小时)比维拉美啶的血浆AUC(0 - 168小时)高两到四倍，这表明维拉美啶在人体内广泛代谢为利巴韦林，是利巴韦林的前体药物。尿液中排泄的维拉美啶和利巴韦林量很少（占剂量的2% - 5%），这表明维拉美啶和利巴韦林的主要消除途径是代谢。维拉美啶和利巴韦林均通过肾小球滤过机制排泄到尿液中。此外，在一项交叉研究设计中，对33至34名健康男性志愿者口服600毫克维拉美啶后，高脂餐对维拉美啶和利巴韦林药代动力学的影响进行了评估。高脂餐使维拉美啶的血浆AUC(0 - 168小时)增加44%，C(max)增加20%。它还使利巴韦林的血浆AUC(0 - 168小时)增加19%，C(max)增加43%。这些增加的临床相关性尚不清楚。
