他克莫司缓释胶囊对肝移植术后稳定期受者安全性和临床疗效评估

Extended release formulation of tacrolimus: efficacy and safety in stable liver transplant recipients

目的通过他克莫司缓释胶囊(MR4)的Ⅲ期临床试验(MR4LTxCN02)评价MR4在肝移植术后稳定期受者中的安全性和临床疗效。方法受试者随机分配入MR4或他克莫司(FK506)组,MR4组药物剂量按1∶1进行药物转换,每日口服1次;FK506组维持每12h服药1次至试验结束。在为期3个月的临床试验阶段,随访了受试者生命体征、不良事件、血常规、尿常规、肝功能、血糖、血脂及FK506的谷值浓度。随访结果采用SAS8.0统计软件进行了Fisher精确卡方检验及t检验分析。结果MR4组按1∶1药物转换后与FK506组具有同等的安全性和临床疗效。与FK506组比较,MR4组具有感冒、上呼吸道感染症状减少倾向,没有增加不良事件或不良反应的发生率。转换药物后的剂量和血药浓度与换药前未发生显著变化;药代动力学检测结果表明,MR4具备缓释剂型的药代动力学特征,并与FK506具有良好的生物等效性。结论MR4与FK506具有同等的安全性和临床疗效,同时简化了服药次数,在提高受者长期依从性以及术后生活质量方面具有较大的优势。

Objective To investigate the efficacy, safety and pharmacokinetics of a once-daily extended release formulation of tacrolimus （MR4） in liver transplant recipients. Methods In an openlabel study, stable liver transplant recipients （ n = 26） were randomly divided into MR4 or tacrolimus （TAC） group. MR4 group were converted from twice-a-day TAC to once-daily MR4 on a 1：1 （mg： mg） basis for their total daily dose in the morning and were maintained for 3 months post-conversion, using the same therapeutic monitoring and patient care techniques employed with TAC. During the experimental period, patients＇ vital signs, adverse events, liver biochemistry, blood glucose and lipid, and tacrolimus trough concentration were under evaluation. All statistics were carried out by SAS 8.0 software. Results The efficacy and safety profile of MR4 was consistent with that previously reported for TAC. MR4 group had a tendency to have less flu or upper respiratory tract infection and the incidence of adverse events and side effects was comparable in both groups. Based on pharmacokinetic profiles obtained on study day 1 （ TAC ） and day 86 （ MR4 ）, steady state exposure （ AUC0.24 ） was equivalent between MR4 and TAC; the mean MR4/TAC ratio was 96.4% ; MR4 obtained extended release pharmacy characteristics. Conclusions These results support that the safety profile of MR4 was consistent with that previously reported for TAC. Liver transplant recipients can be converted from twice-a-day TAC to once-daily MR4 with neither special efficacy nor safety concerns. Compliance in transplant recipients might be improved with MR4-based regimens owing to its less frequent dosing.