Transplant Recipients

harmacokinetic 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
Bioequivalence
after kidney or liver
between innovator and generic

tacrolimus in liver and kidney
transplant recipients: A
randomized, crossover clinical
trial
Rita R Alloway 1, Alexander A Vinks 2 3, Tsuyoshi Fukuda 2 3, Tomoyuki Mizuno 2 3, Eileen
C King 3 4, Yuanshu Zou 3 4, Wenlei Jiang 5, E Steve Woodle 6, Simon Tremblay 1, Jelena
Klawitter 7, Jost Klawitter 7, Uwe Christians 7
Affiliations Expand
 PMID: 29135993
 PMCID: PMC5685573
 DOI: 10.1371/journal.pmed.1002428
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, pFig 1.
Randomization sequence and study design.
Fig 2
Kidney (A) and liver (B)…
Fig 3. Comparison of tacrolimus time concentration…

Transplant Recipients

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harmacokinetic studies assessed the bioequivalence of Generic Hi and

Generic Lo with the Innovator tacrolimus and with each other.

Conclusions: Using an innovative, controlled bioequivalence study

between innovator and generic

Methods and findings: From December 2013 through October

Kidney (A) and liver (B)…

Fig 3. Comparison of tacrolimus time concentration…

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