Christians Uwe, Klawitter Jelena, Clavijo Claudia F
Clinical Research and Development, Department of Anesthesiology, University of Colorado Denver, Aurora, Colorado 80045-7503, USA.
Kidney Int Suppl. 2010 Mar(115):S1-7. doi: 10.1038/ki.2009.504.
Immunosuppressants are considered critical dose/narrow therapeutic index drugs and there is the lingering suspicion among physicians and patients that generic versions may differ in quality and therapeutic efficacy from the brand name drug. The innovator's and the generic active drug molecule are exactly the same and are produced following exactly the same tight rules of good manufacturing practice. Upon oral administration, the drug molecule separates from the formulation and passes the membranes of gut mucosa cells; from this point on, the formulation has no influence on the kinetics of a drug and its biological effects. As formulations may differ, bioequivalence testing in healthy volunteer studies establishes equal relative oral bioavailability. Due to the number of patients required to achieve sufficient statistical power, to test the therapeutic equivalence of two formulations of the same drug with the same bioavailability is an unrealistic goal. An often overlooked fact is that the approval by drug regulatory agencies of several post-approval versions of the innovators' immunosuppressants is based on the identical guidelines used for approval of generics. The FDA has issued specific guidelines describing the requirements for approval of generic versions of tacrolimus, sirolimus, and mycophenolic acid. The standard average bioequivalence approach is recommended and in the cases of tacrolimus and sirolimus, the effect of food should also be tested. No studies in the patient population are requested. Immunosuppressants are not regarded as drugs that require a special status to establish bioequivalence between generic and the innovator's versions.
免疫抑制剂被视为关键剂量/治疗指数狭窄的药物，医生和患者一直怀疑仿制药在质量和治疗效果上可能与品牌药有所不同。创新药和仿制药的活性药物分子完全相同，并且都是按照严格的药品生产质量管理规范生产的。口服给药后，药物分子从制剂中分离出来并穿过肠黏膜细胞的膜；从这一点开始，制剂对药物的动力学及其生物学效应没有影响。由于制剂可能不同，健康志愿者研究中的生物等效性测试确定了相对口服生物利用度相等。由于需要足够数量的患者才能获得足够的统计效力，因此测试具有相同生物利用度的同一药物的两种制剂的治疗等效性是一个不切实际的目标。一个经常被忽视的事实是，药品监管机构批准创新免疫抑制剂的多个批准后版本所依据的指南与批准仿制药所使用的指南相同。美国食品药品监督管理局（FDA）已经发布了具体指南，描述了他克莫司、西罗莫司和霉酚酸仿制药批准的要求。推荐采用标准平均生物等效性方法，对于他克莫司和西罗莫司，还应测试食物的影响。不需要在患者群体中进行研究。免疫抑制剂不被视为需要特殊地位来确定仿制药和创新药版本之间生物等效性的药物。
