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

Abstract

Background: 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.

Methods: Eligible studies were identified in PubMed, Cochrane Central Register of Controlled Trials, Scopus, ClinicalTrials.gov, and conference abstracts.

Results: 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.

Conclusions: 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.

Fig. 1.

Study selection flow diagram.

Fig. 2.

Forest plot displaying the pooled weighted ratio of the T/R immunosuppressive drug for the mean C_max with the corresponding 90% CI. ‘Test’ refers to the generic immunosuppressive drug, and ‘reference’ to its brand counterpart.

Fig. 3.

Forest plot displaying the pooled weighted ratio of the T/R immunosuppressive drug for the mean AUC_(0–t)> with the corresponding 90% CI. ‘Test’ refers to the generic immunosuppressive drug, and ‘reference’ to its brand counterpart.

Fig. 4.

Forest plot displaying the pooled weighted mean difference of the brand versus generic immunosuppressive drug for the mean T_max, with the corresponding 95% CI. ‘Test’ refers to the generic immunosuppressive drug, and ‘reference’ to its brand counterpart.

Fig. 5.

Forest plot displaying the pooled weighted mean difference of the brand versus generic immunosuppressive drug for the mean T_1/2, with the corresponding 95% CI. ‘Test’ refers to the generic immunosuppressive drug, and ‘reference’ to its brand counterpart.