The Effect of Generic Substitution of Tacrolimus in Liver and Kidney Transplant Recipients

Abstract

Background: In August 2009, the U.S. Food and Drug Administration (FDA) approved the first generic formulation of tacrolimus (Sandoz), an immunosuppressant used to prevent rejection in transplant recipients, after studies showed its bioequivalence to the brand name product (Prograf R -Astellas) in healthy subjects1. The current study expands on a previous report of the safety and bioequivalence of a generic product in liver and kidney transplant recipients2. Hypothesis: Generic substitution of tacrolimus in liver and kidney transplant patients will be safe, effective, and cause no significant changes in tacrolimus dose-adjusted blood concentrations. Methods: Coded data from 309 patients were obtained from the University of Pittsburgh Thomas E. Starzl Transplantation Institute. All patients were monitored for changes in liver and kidney function indices and trough blood concentrations of tacrolimus for at least two weeks before and after generic substitution. Student's paired t-test was used to evaluate the significance. Multivariate analysis was used to assess the influence of covariates on trough concentrations of tacrolimus. Results: All patients were switched to the generic product using 1:1 conversion, and doses were adjusted to maintain therapeutic blood concentrations. No significant changes were observed in any of the liver and kidney function indices. In liver transplant patients, there was no significant change in creatinine clearance after generic substitution (p>0.9). In 144 liver transplant recipients, the mean concentration/dose (C/D) ratio (±SD) was 231.8 (±293.4) ([ng/mL]/[mg/kg/day]) before substitution and 202.8 (±170.7) ([ng/mL]/[mg/kg/day]) after substitution (p>.05). In 165 kidney transplant recipients, the mean C/D ratio (±SD) was 131.4 (±109.6) ([ng/mL]/[mg/kg/day]) before substitution and 133.4 (±88.9) ([ng/mL]/[mg/kg/day]) after substitution (p>0.6). In a subset of patients with no change in dose during the observation period, the 90% CI of the ratio of tacrolimus trough concentration post-substitution to pre-substitution was (0.94, 1.03) in liver (n=95) and (1.06, 1.17) in kidney (n = 84) transplant recipients. Multivariate analysis of the same subset showed no significant effect of generic substitution on actual trough concentrations. Conclusions: Generic tacrolimus met the FDA's bioequivalence standard when trough concentrations were assessed as a surrogate for the area under the concentration versus time curve (AUC) in liver and kidney transplant patients. Substitution with generic tacrolimus did not significantly alter graft function indices and showed no signs of increased toxicity. These data suggest that, with careful blood monitoring, generic tacrolimus provides a safe alternative to the reference product.