Research Article: Nontherapeutic equivalence of a generic product of imipenem-cilastatin is caused more by chemical instability of the active pharmaceutical ingredient (imipenem) than by its substandard amount of cilastatin

Date Published: February 6, 2019

Publisher: Public Library of Science

Author(s): Maria Agudelo, Carlos A. Rodriguez, Andres F. Zuluaga, Omar Vesga, Vijai Gupta.


We demonstrated therapeutic nonequivalence of “bioequivalent” generics for meropenem, but there is no data with generics of other carbapenems.

One 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).

The 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.

Partial Text

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). However, there is substantial experimental evidence that the bioequivalence assumption is wrong [1–10]. Although 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].

The data demonstrate that this generic of imipenem-cilastatin and the innovator have the same concentration of the API (i.e., imipenem), but the generic product failed pharmaceutical equivalence due to a substandard amount of the DHP-I inhibitor cilastatin (30% less than announced). However, the generic fulfilled DRA criteria for PK equivalence because its imipenem component reach the same concentration of the innovator in blood, which suggests that imipenem was protected from DHP-1 hydrolysis with only 70% of the required amount of cilastatin [4]. In addition to failing pharmaceutical equivalence, the generic also failed therapeutic equivalence in most (but not all) of our animal models, indicating that there must be other reasons to explain nonequivalence of this product.




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