Bioequivalence between innovator and generic tacrolimus in liver and kidney transplant recipients: A randomized, crossover clinical trial

Abstract

BackgroundAlthough the generic drug approval process has a long-term successful track record, concerns remain for approval of narrow therapeutic index generic immunosuppressants, such as tacrolimus, in transplant recipients. Several professional transplant societies and publications have generated skepticism of the generic approval process. Three major areas of concern are that the pharmacokinetic properties of generic products and the innovator (that is, “brand”) product in healthy volunteers may not reflect those in transplant recipients, bioequivalence between generic and innovator may not ensure bioequivalence between generics, and high-risk patients may have specific bioequivalence concerns. Such concerns have been fueled by anecdotal observations and retrospective and uncontrolled published studies, while well-designed, controlled prospective studies testing the validity of the regulatory bioequivalence testing approach for narrow therapeutic index immunosuppressants in transplant recipients have been lacking. Thus, the present study prospectively assesses bioequivalence between innovator tacrolimus and 2 generics in individuals with a kidney or liver transplant.Methods and findingsFrom December 2013 through October 2014, a prospective, replicate dosing, partially blinded, randomized, 3-treatment, 6-period crossover bioequivalence study was conducted at the University of Cincinnati in individuals with a kidney (n = 35) or liver transplant (n = 36). Abbreviated New Drug Applications (ANDA) data that included manufacturing and healthy individual pharmacokinetic data for all generics were evaluated to select the 2 most disparate generics from innovator, and these were named Generic Hi and Generic Lo. During the 8-week study period, pharmacokinetic studies assessed the bioequivalence of Generic Hi and Generic Lo with the Innovator tacrolimus and with each other. Bioequivalence of the major tacrolimus metabolite was also assessed. All products fell within the US Food and Drug Administration (FDA) average bioequivalence (ABE) acceptance criteria of a 90% confidence interval contained within the confidence limits of 80.00% and 125.00%. Within-subject variability was similar for the area under the curve (AUC) (range 12.11–15.81) and the concentration maximum (Cmax) (range 17.96–24.72) for all products. The within-subject variability was utilized to calculate the scaled average bioequivalence (SCABE) 90% confidence interval. The calculated SCABE 90% confidence interval was 84.65%–118.13% and 80.00%–125.00% for AUC and Cmax, respectively. The more stringent SCABE acceptance criteria were met for all product comparisons for AUC and Cmax in both individuals with a kidney transplant and those with a liver transplant. European Medicines Agency (EMA) acceptance criteria for narrow therapeutic index drugs were also met, with the only exception being in the case of Brand versus Generic Lo, in which the upper limits of the 90% confidence intervals were 111.30% (kidney) and 112.12% (liver). These were only slightly above the ...

Immunosuppression with generic tacrolimus in liver and kidney transplantation—systematic review and meta‐analysis on biopsy‐proven acute rejection and bioequivalence

“…In 1 KT conversion study with a crossover design, the 90% CIs of the ratio generic/innovator for AUC 0–12 were within the EMA bioequivalence acceptance criteria and the 90% CIs of the ratio generic/innovator for C max were within the FDA bioequivalence acceptance criteria . One prospective randomized 3‐treatment 6‐period crossover pharmacokinetic study on the switch of innovator to two generic Tac formulations (Tac Sandoz and Tac Dr. Reddy) showed bioequivalence in both KT and LT recipients, except for the conversion from innovator Tac to Tac Dr. Reddy according to EMA bioequivalence criteria . No BPAR event has been reported after conversion to generic Tac in both KT and LT patients (Table ).…”

“…There were three crossover (25 patients de novo KT, 139 patients conversion LT and KT) and two parallel design studies (79 patients de novo KT), all RCTs, reporting the primary pharmacokinetic outcome of C max and AUC 0–12 (Fig. ) . Three prospective randomized pharmacokinetic studies in KT were conducted with de novo generic Tac (one study including a crossover substudy), and one after conversion .…”

“…Since publication of the most recent position statement by the Canadian Society of Transplantation in 2012, the use of generic immunosuppressants has become routine in many centers all over the world , and several high‐quality RCTs have been published together with both a considerable number of observational studies (Table ) and congress reports (Table S1). Therefore, guidelines could be updated based on the current knowledge on the safety and efficacy of generic immunosuppression after transplantation.…”

“…Among the five RCTs demonstrating comparable safety and efficacy of generic Tac and its innovator, there are two parallel design studies in KT patients and three crossover studies on bioequivalence, two after KT and one study combining a cohort of patients after LT and KT , the two latter clearly showing bioequivalence between two generic Tac themselves and their innovator. The other studies did not demonstrate bioequivalence according to EMA criteria.…”

Assessment of tacrolimus intrapatient variability in stable adherent transplant recipients: Establishing baseline values

“…41 Daily tacrolimus levels were collected during a 6-week study evaluating the bioequivalence and pharmacokinetics of generic tacrolimus formulations (NCT-01889758). 41 Daily tacrolimus levels were collected during a 6-week study evaluating the bioequivalence and pharmacokinetics of generic tacrolimus formulations (NCT-01889758).…”