Even Apparently Insignificant Chemical Deviations among Bioequivalent Generic Antibiotics Can Lead to Therapeutic Nonequivalence: the Case of Meropenem

Abstract

e Several studies with animal models have demonstrated that bioequivalence of generic products of antibiotics like vancomycin, as currently defined, do not guarantee therapeutic equivalence. However, the amounts and characteristics of impurities and degradation products in these formulations do not violate the requirements of the U.S. Pharmacopeia (USP). Here, we provide experimental data with three generic products of meropenem that help in understanding how these apparently insignificant chemical differences affect the in vivo efficacy. Meropenem generics were compared with the innovator in vitro by microbiological assay, susceptibility testing, and liquid chromatography/mass spectrometry (LC/MS) analysis and in vivo with the neutropenic guinea pig soleus infection model (Pseudomonas aeruginosa) and the neutropenic mouse thigh (P. aeruginosa), brain (P. aeruginosa), and lung (Klebisella pneumoniae) infection models, adding the dihydropeptidase I (DHP-I) inhibitor cilastatin in different proportions to the carbapenem. We found that the concentration and potency of the active pharmaceutical ingredient, in vitro susceptibility testing, and mouse pharmacokinetics were identical for all products; however, two generics differed significantly from the innovator in the guinea pig and mouse models, while the third generic was therapeutically equivalent under all conditions. Trisodium adducts in a bioequivalent generic made it more susceptible to DHP-I hydrolysis and less stable at room temperature, explaining its therapeutic nonequivalence. We conclude that the therapeutic nonequivalence of generic products of meropenem is due to greater susceptibility to DHP-I hydrolysis. These failing generics are compliant with USP requirements and would remain undetectable under current regulations.

Relevance of various animal models of human infections to establish therapeutic equivalence of a generic product of piperacillin/tazobactam

“…Combining all these studies, 61.7% of the generic products failed therapeutic equivalence despite enjoying approval for human use by the Colombian DRA, which guaranteed the public that these generics had pharmaceutical equivalence and, by default, bioequivalence. What these data demonstrate is that neither of these tests is useful to predict in vivo efficacy [2,[4][5][6][7][8][9]14,15,[25][26][27][28][29][30][31][32][33][34][35][36][37][38][39].…”

“…Five to seven total doses of each TZP product, spanning from no effect to maximal effect, and administered to subgroups of two mice in the sepsis model and three mice in the pneumonia and meningoencephalitis models, produced the dose-response curves necessary for pharmacodynamic (PD) analysis by non-linear regression (NLR). These animal models were uniformly lethal 20-48 h after inoculation, and death occurred as a consequence of an active infection in which the inoculum grew ≥2 log from hour 0 to hour 24 in untreated controls [2,21]. We emphasise this point because the scientific validation of any animal model of human infection comes exclusively from experimental facts (i.e.…”

“…However, recent experimental evidence demonstrates that pharmaceutical equivalence and bioequivalence do not predict therapeutic equivalence of generic antimicrobials [2][3][4][5][6][7][8]. Interestingly, these data suggest that chemically synthesised or semisynthetic drugs such as quinolones tend to be easier to imitate than fermentation products such as early ␤-lactams, glycopeptides or aminoglycosides [9].…”

“…Interestingly, these data suggest that chemically synthesised or semisynthetic drugs such as quinolones tend to be easier to imitate than fermentation products such as early ␤-lactams, glycopeptides or aminoglycosides [9]. For instance, there are studies in animal models demonstrating in vivo inferiority of all generics of oxacillin [5] and vancomycin [7], one-half of 20 generics of gentamicin [8], and 2 of the 3 generics of meropenem [2]. At least one large clinical trial demonstrated inferiority of a generic cefuroxime to prevent surgical site infections in coronary bypass patients [3], and there is a well-documented case of therapeutic failure of generic vancomycin in a liver transplant patient with a severe infection caused http://dx.doi.org/10.1016/j.ijantimicag.2014.…”

In silico Evaluation of Impurities Found in Some Generic Drugs of Piperacillin/ Tazobactam

“…Problems with generic products of meropenem have also been pointed out. Agudelo et al reported the therapeutic nonequivalence of generic products with the original drug in animal models of infection [3]. In addition, since the grain size of bulk powder of all generic meropenem products was larger than that of the brand drug, the dissolution time in physiological saline was three times longer compared to the brand drug [4].…”