Therapeutic Equivalence (TE) of 5 Generic Products (GP) of Cefotaxime (TAX) Compared with the Original Compound (OC) in the Neutropenic Mouse Thigh Infection Model (NMTIM)

Abstract

ABSTRACT: Background: Contrary to accepted dogma, recent animal model data with GP demonstrated that pharmaceutical equivalence (PE) does not predi ct TE for penicillin G, ampicillin, oxacillin, amikacin, and lincomycin. Here, we report PE and TE of 5 GP of TAX legally marketed in Colombia.Methods: PE was determined by microbiologic assays using Antibiotic Medium 1 as seeding agar and S. aureus ATCC 6538p as testing organism, comparingtheir standard curves against the OC by curve fitting analysis (CFA). MIC / MBC by broth microdilution against E. coli SIG-1 and P. aeruginosa ATCC 27853 were compared by Kruskal-Wallis test. For the NMTIM, we used 6 week-old, 25±2 g MPF female mice of the strain Udea:ICR(CD-1) infected with E. coli SIG-1. Primary pharmacodynamic parameters (PDP) Emax, ED50, and Hill’s slope were calculated by least squares nonlinear regression (NLR) applied to the sigmoid dose-response model andused to compute secondary PDP bacteriostatic dose (BD) and the doses needed to kill 1 (1LKD) and 2 logs of bacteria (2LKD). TE was determined comparing each PDPas well as whole NLR curves.Results: 3 GP available for testing failed PE; 2 had greater concentration than the OC (up to 146-149%, P≤0.0375) and 1 had different potency. Despite of this,MIC / MBC of all 5 GP were not different compared with the OC (P=0.1437). Mice had 107.3-7.6 CFU/g before treatment during 24h with TAX 0.586-150 mg/kg/day dividedq1h. At the end of therapy, untreated controls had 109.2-9.4 CFU/g (24h growth=1.8-1.9 log10 CFU/g). Even though all 3 tested GP failed PE, in vivo efficacy of 5 GP was nodifferent compared with the OC: Emax = 4.25-5.09 vs 4.65 log10 CFU/g; BD = 0.9-1.9 vs 1.67 mg/kg; 1LKD=2.1-4.8 vs 4.0 mg/kg (P>0.1018).Conclusion: In vivo efficacy of TAX GP was no different from the OC. However, GP were not “ equivalent” because they had significantly g reater concentrationof active principle or different potency respect to the OC.