PowerPoint Slides for: Bioavailability, Efficacy and Safety of Generic Immunosuppressive Drugs for Kidney Transplantation: A Systematic Review and Meta-Analysis

<i>Background:</i> Concerns exist over the extrapolation of bioavailability studies of generic immunosuppressive drugs in healthy volunteers, regarding their efficacy and safety in kidney transplant recipients. We conducted a meta-analysis of trials examining the bioavailability of generic (test) immunosuppressive drugs relative to their brand (reference) counterparts in healthy volunteers, based on the US Food and Drug Administration requirements for approval of generics, and their efficacy and safety in kidney transplant recipients. <i>Methods:</i> Eligible studies were identified in PubMed, Cochrane Central Register of Controlled Trials, Scopus, ClinicalTrials.gov, and conference abstracts. <i>Results:</i> Twenty crossover trials of healthy volunteers (n = 641) and 6 parallel-arm randomized controlled trials of kidney transplant recipients (n = 594) were identified. The 90% CI of the pooled test-to-reference drug ratio for maximum or peak plasma concentration (Cmax) and area under the plasma concentration time-curve from time 0 to time of last determinable concentration (AUC(0-t)) fell within the required range (0.80-1.25) for cyclosporine (Cmax 0.91; 90% CI 0.86-0.95; and AUC(0-t) 0.97; 90% CI 0.94-1.00), tacrolimus (Cmax 1.17; 90% CI 1.09-1.24; and AUC(0-t) 1.00; 90% CI 0.97-1.03) and mycophenolate mofetil (Cmax 0.98; 90% CI 0.96-1.01; and AUC(0-t) 1.00; 90% CI 0.99-1.01). In subgroup analyses, some generic cyclosporine formulations did not meet criteria for bioequivalence. No significant differences were observed in the time to maximum plasma concentration and terminal plasma half-life between generic and brand drugs. In parallel-arm trials, generic cyclosporine was non-inferior to brand counterpart in terms of acute allograft rejection, infections, and death. <i>Conclusions:</i> Not all generic immunosuppressive drugs have similar relative bioavailability to their brand name counterparts. Evidence on their efficacy and safety is inconclusive. Tighter regulatory requirement for approval of generic drugs with narrow therapeutic index is needed.

<i>研究背景：</i> 目前针对健康受试者开展的仿制药免疫抑制剂生物利用度研究外推至肾移植受者的有效性与安全性尚存争议。本研究基于美国食品药品监督管理局（US Food and Drug Administration）的仿制药审批要求，开展一项荟萃分析，评估健康受试者中仿制药（试验组）相较于原研药（参比组）免疫抑制剂的生物利用度，同时分析此类仿制药在肾移植受者中的有效性与安全性。
<i>研究方法：</i> 通过PubMed、Cochrane对照试验中心注册库、Scopus、ClinicalTrials.gov及会议摘要检索符合纳入标准的研究。
<i>研究结果：</i> 最终纳入641名健康受试者的交叉试验共20项，以及594名肾移植受者的平行组随机对照试验共6项。环孢素、他克莫司及吗替麦考酚酯的合并试验组与参比组药物比值的90%置信区间（CI）均落在规定范围（0.80~1.25）内：其中环孢素的峰浓度（maximum plasma concentration, Cmax）比值为0.91，90% CI为0.86~0.95；血浆浓度-时间曲线下面积（从0时至最后可测浓度时点，area under the plasma concentration-time curve from time 0 to last determinable concentration, AUC(0-t)）比值为0.97，90% CI为0.94~1.00。他克莫司的Cmax比值为1.17，90% CI为1.09~1.24；AUC(0-t)比值为1.00，90% CI为0.97~1.03。吗替麦考酚酯的Cmax比值为0.98，90% CI为0.96~1.01；AUC(0-t)比值为1.00，90% CI为0.99~1.01。亚组分析显示，部分环孢素仿制药制剂未达到生物等效性标准。仿制药与原研药在达峰时间及终末血浆半衰期方面无显著差异。平行组试验结果表明，仿制药环孢素在急性移植物排斥反应、感染及死亡结局上均不劣于原研药。
<i>研究结论：</i> 并非所有仿制药免疫抑制剂均与原研药具有相当的相对生物利用度。此类仿制药的有效性与安全性相关证据仍不明确。需针对治疗指数狭窄的仿制药制定更为严格的审批监管要求。