Maeda Yorinobu, Kiribayashi Yoshie, Moriya Takashi, Maruhashi Akira, Omoda Kei, Funakoshi Sachiyo, Murakami Teruo, Takano Mikihisa
Department of Pharmacy, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.
Ther Drug Monit. 2004 Feb;26(1):9-15. doi: 10.1097/00007691-200402000-00004.
The daily dose of ribavirin is currently determined based on body weight. In the present study, the authors examined factors influencing total plasma clearance (CL(total)) and the toxic level on red blood cells of ribavirin in such body weight-based dosage adjustment in Japanese chronic hepatitis C patients (13 male and 6 female). Patients received ribavirin (600 or 800 mg/d) orally, depending on their body weights, together with interferon alpha-2b (6 million units) intramuscularly. A steady-state trough plasma concentration (C(pss)) was achieved approximately 4 weeks after the initiation of treatment, but the value was scattered among patients in a range from 1100 to 4200 ng/mL. The high C(pss) of ribavirin of approximately 4000 ng/mL decreased hemoglobin concentrations to less than 8.5 g/dL. The individual CL(total), estimated by dividing dose normalized by body weight by C(pss), of ribavirin correlated significantly with the patient's creatinine clearance. In contrast, no relationship was observed with other parameters such as age, body weight, serum creatinine concentration, alanine aminotransferase (ALT) concentration, or aspartate aminotransferase (AST) concentration, though ALT and AST concentrations decreased with ribavirin treatment in most patients. These results indicate that CL(total) of ribavirin is dependent on renal function (creatinine clearance), and hemolysis is induced by high ribavirin concentrations in plasma. Dosage adjustment of ribavirin based on renal function and body weight would provide effective and safer treatment without causing hemolysis.
目前，利巴韦林的每日剂量是根据体重来确定的。在本研究中，作者调查了日本慢性丙型肝炎患者（13名男性和6名女性）在这种基于体重的剂量调整中，影响利巴韦林的总血浆清除率（CL（总））以及对红细胞毒性水平的因素。患者根据体重口服利巴韦林（600或800mg/天），同时肌肉注射α-2b干扰素（600万单位）。治疗开始约4周后达到稳态谷血浆浓度（C（稳态）），但该值在患者中分布较分散，范围为1100至4200ng/mL。利巴韦林约4000ng/mL的高C（稳态）会使血红蛋白浓度降至低于8.5g/dL。通过将体重标准化剂量除以C（稳态）估算的利巴韦林个体CL（总）与患者的肌酐清除率显著相关。相比之下，未观察到与年龄、体重、血清肌酐浓度、丙氨酸氨基转移酶（ALT）浓度或天冬氨酸氨基转移酶（AST）浓度等其他参数存在相关性，尽管大多数患者的ALT和AST浓度在利巴韦林治疗后有所下降。这些结果表明，利巴韦林的CL（总）取决于肾功能（肌酐清除率），血浆中高浓度的利巴韦林会诱导溶血。基于肾功能和体重调整利巴韦林剂量将提供有效且更安全的治疗，而不会引起溶血。
