Abstract
BackgroundWe demonstrated therapeutic nonequivalence of “bioequivalent” generics for meropenem, but there is no data with generics of other carbapenems.MethodsOne generic product of imipenem-cilastatin was compared with the innovator in terms of in vitro susceptibility testing, pharmaceutical equivalence, pharmacokinetic (PK) and pharmacodynamic (PD) equivalence in the neutropenic mouse thigh, lung and brain infection models. Both pharmaceutical forms were then subjected to analytical chemistry assays (LC/MS).Results and conclusionThe generic product had 30% lower concentration of cilastatin compared with the innovator of imipenem-cilastatin. Regarding the active pharmaceutical ingredient (imipenem), we found no differences in MIC, MBC, concentration or potency or AUC, confirming equivalence in terms of in vitro activity. However, the generic failed therapeutic equivalence in all three animal models. Its Emax against S. aureus in the thigh model was consistently lower, killing from 0.1 to 7.3 million less microorganisms per gram in 24 hours than the innovator (P = 0.003). Against K. pneumoniae in the lung model, the generic exhibited a conspicuous Eagle effect fitting a Gaussian equation instead of the expected sigmoid curve of the Hill model. In the brain infection model with P. aeruginosa, the generic failed when bacterial growth was >4 log10 CFU/g in 24 hours, but not if it was less than 2.5 log10 CFU/g. These large differences in the PD profile cannot be explained by the lower concentration of cilastatin, and rather suggested a failure attributable to the imipenem constituent of the generic product. Analytical chemistry assays confirmed that, besides having 30% less cilastatin, the generic imipenem was more acidic, less stable, and exhibited four different degradation masses that were absent in the innovator.
Highlights
The World Health Organization (WHO) and all Drug Regulatory Agencies (DRA) use the term “bioequivalence” to imply that a generic product has identical concentration and potency with respect to the innovator and a similar pharmacokinetic profile; from that it is assumed that both products have the same efficacy in vivo
The generic product had 30% lower concentration of cilastatin compared with the innovator of imipenem-cilastatin
Regarding the active pharmaceutical ingredient, we found no differences in MIC, MBC, concentration or potency or AUC, confirming equivalence in terms of in vitro activity
Summary
The World Health Organization (WHO) and all Drug Regulatory Agencies (DRA) use the term “bioequivalence” to imply that a generic product has identical concentration and potency with respect to the innovator (pharmaceutical equivalence) and a similar pharmacokinetic profile (pharmacokinetic equivalence); from that it is assumed that both products have the same efficacy in vivo (therapeutic equivalence). Bioequivalence does predict therapeutic equivalence of generic antimicrobials obtained by chemical synthesis like metronidazole [7], ciprofloxacin [8] and fluconazole [9], it does not for antibiotics sensu stricto (i.e., those obtain from microorganisms), like aminoglycosides [1, 5], penicillins [2, 6], and glycopeptides [3]. Research to determine the mechanisms by which a “bioequivalent” generic fails in vivo should be undertaken before the public trust in DRA is irreversibly eroded [17]. We demonstrated therapeutic nonequivalence of “bioequivalent” generics for meropenem, but there is no data with generics of other carbapenems
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