Date Published: November 14, 2017
Publisher: Public Library of Science
Author(s): Rita R. Alloway, Alexander A. Vinks, Tsuyoshi Fukuda, Tomoyuki Mizuno, Eileen C. King, Yuanshu Zou, Wenlei Jiang, E. Steve Woodle, Simon Tremblay, Jelena Klawitter, Jost Klawitter, Uwe Christians, Maarten W. Taal
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 upper EMA acceptance criteria limit for an AUC of 111.11%. SCABE criteria were also met for the major tacrolimus metabolite 13-O-desmethyl tacrolimus for AUC, but it failed the EMA criterion. No acute rejections, no differences in renal function in all individuals, and no differences in liver function were observed in individuals with a liver transplant using the Tukey honest significant difference (HSD) test for multiple comparisons. Fifty-two percent and 65% of all individuals with a kidney or liver transplant, respectively, reported an adverse event. The Exact McNemar test for paired categorical data with adjustments for multiple comparisons was used to compare adverse event rates among the products. No statistically significant differences among any pairs of products were found for any adverse event code or for adverse events overall. Limitations of this study include that the observations were made under strictly controlled conditions that did not allow for the impact of nonadherence or feeding on the possible pharmacokinetic differences. Generic Hi and Lo were selected based upon bioequivalence data in healthy volunteers because no pharmacokinetic data in recipients were available for all products. The safety data should be interpreted in light of the small number of participants and the short observation periods. Lastly, only the 1 mg tacrolimus strength was utilized in this study.ConclusionsUsing an innovative, controlled bioequivalence study design, we observed equivalence between tacrolimus innovator and 2 generic products as well as between 2 generic products in individuals after kidney or liver transplantation following current FDA bioequivalence metrics. These results support the position that bioequivalence for the narrow therapeutic index drug tacrolimus translates from healthy volunteers to individuals receiving a kidney or liver transplant and provides evidence that generic products that are bioequivalent with the innovator product are also bioequivalent to each other.Trial registrationClinicalTrials.gov NCT01889758.
Partial Text: Most individuals receiving a solid organ transplant require lifelong immunosuppression. Switching to generic immunosuppressants may lead to significant savings and improved adherence [1,2], which is essential for long-term graft survival . The current US Food and Drug Administration (FDA) generic drug approval process has performed well . However, concerns persist regarding whether 2-way crossover studies in healthy individuals using conventional average bioequivalence (ABE) acceptance criteria of a 90% confidence interval contained within the confidence limits of 80.00% to 125.00% are a valid approach for generic immunosuppressant approval for use after transplantation [5,6]. This debate started when cyclosporine generics were developed over 15 years ago [7,8] and was reinvigorated when tacrolimus generics were approved. Consensus documents developed by professional societies from the US, Europe, and Canada [9–12] have cautioned against generic immunosuppressant use, citing (1) the lack of data in transplant recipients, especially “high risk” transplant recipients; (2) the need to implement stricter bioequivalence standards, as tacrolimus is a narrow therapeutic index (NTI) drug for which small changes in dose or exposure can result in therapeutic failure or toxicity; and (3) the lack of bioequivalence data between generics. Molnar et al. published a systematic review and meta-analysis to compare the clinical efficacy and bioequivalence of generic immunosuppressive drugs in individuals with a transplant and concluded that high-quality data were lacking. The authors went further to state that given the serious consequences of rejection and allograft failure, well-designed studies on the bioequivalence and safety of generic immunosuppression in individuals with a transplant are needed .
Public concerns remain regarding generic tacrolimus use in individuals with a kidney or liver transplant despite the significant market penetration of generic tacrolimus in the US. Historically, concerns were generated by a lack of definitive clinical evidence with properly controlled trials in target populations . Limitations of previous studies [40–45] include retrospective evaluations, case reports, poor study design (underpowered or without appropriate controls), analysis of trough concentrations only, lack of analysis of confounders such as comedications and comorbidities, incorrect pharmacokinetic analysis, and use of nonspecific immunoassays in which metabolites may interfere with tacrolimus concentration measurements, thus leading to considerable bias and limited conclusions .