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

Abstract

Background: Although 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 findings: From 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.

Conclusions: Using 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 registration: ClinicalTrials.gov NCT01889758.

Conflict of interest statement

I have read the journal's policy and the authors of this manuscript have the following competing interests: RRA serves on the following corporate advisory committees: SangStat Medical Corporation Pharmacy Advisory Board, Biogen Pharmaceutical Corporation, Anti-CD40 Ligand Scientific Advisory Board, Protein Design Labs, Abbott Pharmaceutical Corporation, Tristar Enterprises, Inc. Clinical Trials Committee, Fujisawa Clinical Pharmacy Advisory Board, Roche Clinical Pharmacy Advisory Board, Sanofi Genzyme Advisory Board and Speakers Bureau, and Veloxis Speakers Bureau, with Research Grants with Novartis and Bristol Myers Squibb. UC reports research grants with Astellas, BioRad, Biosensors, Biotronik, HepQuant, Novartis, Roche Diagnostics, Siemens Healthcare, Thermo-Fisher, Fujirebio, Veloxis, and Waters.

Figures

Fig 1. Randomization sequence and study design.

PK, pharmacokinetics.

Fig 2

Kidney (A) and liver (B) Consolidated Standards Of Reporting Trials (CONSORT) flow diagram. (A) Individuals with a kidney transplant. (B) Individuals with a liver transplant. LFT, liver function tests; PI, principal investigator; PK, pharmacokinetics; SCr, serum creatinine; UTI, urinary tract infection.

Fig 3. Comparison of tacrolimus time concentration curves by product.

(A) Individuals with a kidney transplant. (B) Individuals with a liver transplant. Fifteen tacrolimus blood samples were collected at C0 (before the morning dose) and at 20, 40, 60 (1 hour), 80, 100, 120 (2 hours), 140, 160, and 180 (3 hours) minutes and 4, 5, 6, 8, and 12 hours to construct the tacrolimus concentration-time curves. Each tacrolimus product—Innovator, Generic Hi, and Generic Lo—was administered according to the randomly assigned treatment sequence (Fig 1) twice for 1 week before collection of steady-state pharmacokinetic profiles. Each point on the curve displays the tacrolimus mean whole blood concentrations; standard deviations are depicted by error bars. There were no statistically significant differences between any time points.