Investigation into the interchangeability of generic formulations using immunosuppressants and a broad selection of medicines

Abstract

PurposeTo date, the interchangeability of generic drugs has only been investigated for a limited number of medicines. The objective of this study was to investigate generic-generic drug interchangeability in a large subset of generic formulations in order to cover a broad spectrum of drugs.MethodsOrally administered drugs for investigation in this study were selected using strict, predefined criteria, with the purpose to avoid bias. This selection procedure yielded atorvastatin, bicalutamide, naratriptan, olanzapine, perindopril, and venlafaxine. Further, ciclosporin, tacrolimus, and mycophenolate mofetil were investigated as test immunosuppressants. Adjusted indirect comparisons were conducted between generic drugs containing the same active substance, and the 90 % confidence interval (CI) for AUC and Cmax was calculated.ResultsIn total, 120 bioequivalence studies were identified in the Dutch medicine regulatory agency’s database, allowing 292 indirect comparisons between generic drugs. The indirect comparison results indicated that in the vast majority of cases, i.e., 80.5 %, the 90 % CIs for both AUCt and Cmax fell within the bioequivalence criteria (in 90.1 and 87.0 % for AUCt and Cmax, respectively). In 1 % of the 292 indirect comparison for AUCt and 3 % for Cmax, a wider range of 75–133 % (or 80–125 %) was exceeded.ConclusionsOverall, our study suggests that exposure-related risks associated with the exchange of different generic drugs in clinical practice are not increased to a relevant extent compared to the situation in which a generic is exchanged with the innovator.Electronic supplementary materialThe online version of this article (doi:10.1007/s00228-015-1878-z) contains supplementary material, which is available to authorized users.

Results of ASERTAA, a Randomized Prospective Crossover Pharmacogenetic Study of Immediate-Release Versus Extended-Release Tacrolimus in African American Kidney Transplant Recipients

“…ASERTAA (A Study of Extended Release Tacrolimus in African Americans) was an open-label, prospective, randomized, 2-sequence, 3-period, crossover, pharmacogenetic study conducted at the University of Pennsylvania, University of Illinois, and Washington University School of Medicine (St. Louis) between November 25, 2013, and July 30, 2015 ( Fig 1). The main study objective was to compare steady-state pharmacokinetics of once-daily LCPT tablets (dosed 15% lower than total daily IR-Tac dose) with evenly divided twice-daily IR-Tac capsules (Prograf [Astellas Pharma US, Inc] or its generic formulations [predominately Sandoz, Dr Reddy, and Accord formulations], for which the systemic exposure differs minimally compared to Prograf [35][36][37] ) in stable African American kidney recipients, according to CYP3A5 genotype. Secondary objectives were to confirm the total daily dose reduction in the LCPT group following conversion from IR-Tac and compare the safety and short-term efficacy of the 2 formulations.…”

Adjusted indirect comparisons to assess bioequivalence between generic clopidogrel products in Serbia

“…AICs have been adopted as a useful tool for assessing bioequivalence between generic products and their switchability, as well as for comparing originator products from different markets that have previously been shown to be bioequivalent with the same generic product . To our knowledge, this is the first study to compare clopidogrel generic products.…”

“…Direct comparisons between generics are not performed as there is no regulatory requirement for conducting these studies since they are not practical . Therefore, the adjusted indirect comparisons (AICs) are the most suitable method to assess bioequivalence between generics . To our knowledge, generic products of clopidogrel have not been compared between themselves, neither indirectly nor directly.…”

“…16 Therefore, the adjusted indirect comparisons (AICs) are the most suitable method to assess bioequivalence between generics. [16][17][18][19][20][21] To our knowledge, generic products of clopidogrel have not been compared between themselves, neither indirectly nor directly. Hence, the aim of our study was to investigate the bioequivalence between generic clopidogrel products of the Serbian market, whose bioequivalence data are available in the public domain, using the method of AICs.…”

Large Intra-subject Variability in Caffeine Pharmacokinetics: Randomized Cross-over Study of Single Caffeine Product

“…[26] Further, secondary analysis of 120 bioequivalence studies on 3 immunosuppressants and 6 selected drugs calculated a mean generic-generic deviation of 4.5 % for AUC T and 5.1 % for C max . [27] The data together suggest that, at a group level, most of the product-product deviations observed in typical bioequivalence studies may not be related to using 2 different products but can be observed when comparing a single drug product to itself.…”