Khakoo S, Glue P, Grellier L, Wells B, Bell A, Dash C, Murray-Lyon I, Lypnyj D, Flannery B, Walters K, Dusheiko G M
Royal Free Hospital, London, UK.
Br J Clin Pharmacol. 1998 Dec;46(6):563-70. doi: 10.1046/j.1365-2125.1998.00836.x.
The primary objective of this study was to determine whether pharmacokinetic interactions occurred between interferon alpha-2b (IFN) and ribavirin in patients with chronic hepatitis C infections. Additionally this study assessed the single and multiple-dose pharmacokinetics of ribavirin and IFN, and compared the safety, tolerability and antiviral pharmacodynamics of IFN plus ribavirin compared with either drug alone.
In this open label parallel group study, patients with chronic hepatitis C were randomized to receive IFN 3 million IU thrice weekly s.c. alone, ribavirin 600 mg twice daily p.o. alone or both drugs in combination over 6 weeks. Single and multiple dose pharmacokinetics and indices of antiviral pharmacodynamics were assessed during weeks 1 and 6, along with safety assessments during the study.
The range of mean ribavirin terminal phase half-lives after single doses was 44-49 h. Comparison of week 1 and week 6 AUC(0,12h) values showed accumulation in plasma of approximately 6-fold. The range of mean washout half-lives after week 6 was 274-298 h, reflecting release of ribavirin from deep compartment stores. The range of single and multiple dose IFN terminal phase half-lives was 5-7 h. IFN demonstrated an increase in bioavailability (approximately 2-fold) upon multiple dose administration. Ribavirin and IFN pharmacokinetic parameters for combined ribavirin and IFN were similar to those during monotherapy with either compound, although the power of this study to detect differences was low. Serum HCV-RNA titers and ALT concentrations were reduced by IFN alone, ribavirin alone reduced ALT concentrations only, and combined IFN plus ribavirin produced numerically greater falls in both measurements than either treatment alone. Serum concentrations of neopterin and activity of 2',5'-oligoadenylate synthetase (2'5'-OAS) were increased by IFN alone and in combination with ribavirin, whereas serum 2'5'-OAS activity was decreased and neopterin concentrations unaltered by ribavirin monotherapy. IFN and ribavirin monotherapy produced characteristic changes in safety laboratory tests (IFN--reductions in white cells, neutrophils and platelets; ribavirin--reduced haemoglobin) and characteristic adverse event profiles (IFN--headache, flu-like symptoms, fatigue, anorexia, nausea, myalgia, and insomnia; ribavirin--headache, fatigue, myalgia, and pruritus). There was no additive effect of combination therapy on safety laboratory tests or reported adverse events. All changes were fully reversible upon treatment cessation.
There was no evidence of pharmacokinetic interactions between IFN and ribavirin in this study. There were numerical trends indicating that the combination of IFN and ribavirin reduced titers of HCV-RNA to a greater extent than did either treatment alone, and the safety profile of combination therapy was similar to those of both monotherapy treatments.
本研究的主要目的是确定慢性丙型肝炎感染患者中，干扰素α-2b（IFN）与利巴韦林之间是否发生药代动力学相互作用。此外，本研究评估了利巴韦林和IFN的单剂量及多剂量药代动力学，并比较了IFN加利巴韦林与单独使用任一药物相比的安全性、耐受性及抗病毒药效学。
在这项开放标签平行组研究中，慢性丙型肝炎患者被随机分为三组，分别接受以下治疗，为期6周：单独皮下注射IFN 300万国际单位，每周三次；单独口服利巴韦林600毫克，每日两次；或两种药物联合使用。在第1周和第6周评估单剂量及多剂量药代动力学和抗病毒药效学指标，同时在研究期间进行安全性评估。
单剂量后利巴韦林终末相半衰期范围为44 - 49小时。第1周和第6周AUC(0,12h)值比较显示，血浆中药物蓄积约6倍。第6周后平均清除半衰期范围为274 - 298小时，反映了利巴韦林从深部隔室储存库中的释放情况。单剂量及多剂量IFN终末相半衰期范围为5 - 7小时。多次给药后IFN的生物利用度增加（约2倍）。联合使用利巴韦林和IFN时，其药代动力学参数与单独使用任一化合物进行单药治疗时相似，尽管本研究检测差异的效能较低。单独使用IFN可降低血清HCV - RNA滴度和ALT浓度，单独使用利巴韦林仅降低ALT浓度，IFN加利巴韦林联合使用在两项测量中数值上的下降幅度均大于单独使用任一治疗。单独使用IFN以及与利巴韦林联合使用均使血清新蝶呤浓度和2',5'-寡腺苷酸合成酶（2'5'-OAS）活性升高，而单独使用利巴韦林进行单药治疗时血清2'5'-OAS活性降低且新蝶呤浓度未改变。IFN和利巴韦林单药治疗在安全性实验室检查中产生特征性变化（IFN - 白细胞、中性粒细胞和血小板减少；利巴韦林 - 血红蛋白降低）以及特征性不良事件谱（IFN - 头痛、流感样症状、疲劳、厌食、恶心、肌痛和失眠；利巴韦林 - 头痛、疲劳、肌痛和瘙痒）。联合治疗在安全性实验室检查或报告的不良事件方面没有叠加效应。所有变化在停止治疗后均可完全逆转。
本研究中没有证据表明IFN与利巴韦林之间存在药代动力学相互作用。有数值趋势表明，IFN和利巴韦林联合使用比单独使用任一治疗更能降低HCV - RNA滴度，且联合治疗的安全性与两种单药治疗相似。
