Determination of therapeutic equivalence of generic products of gentamicin in the neutropenic mouse thigh infection model.
BACKGROUND
Drug regulatory agencies (DRA) support prescription of generic products of intravenous antibiotics assuming therapeutic equivalence from pharmaceutical equivalence. Recent reports of deaths associated with generic heparin and metoprolol have raised concerns about the efficacy and safety of DRA-approved drugs.


RESULTS
To challenge the assumption that pharmaceutical equivalence predicts therapeutic equivalence, we determined in vitro and in vivo the efficacy of the innovator product and 20 pharmaceutically equivalent generics of gentamicin. The data showed that, while only 1 generic product failed in vitro (MIC = 45.3 vs. 0.7 mg/L, P<0.05), 10 products (including gentamicin reference powder) failed in vivo against E. coli due to significantly inferior efficacy (E(max) = 4.81 to 5.32 vs. 5.99 log(10) CFU/g, P<or =0.043). Although the design lacked power to detect differences in survival after thigh infection with P. aeruginosa, dissemination to vital organs was significantly higher in animals treated with generic gentamicin despite 4 days of maximally effective treatment.


CONCLUSIONS
Pharmaceutical equivalence does not predict therapeutic equivalence of generic gentamicin. Stricter criteria based on solid experimental evidence should be required before approval for human use.
Zuluaga
Andres F
AF
Department of Pharmacology and Toxicology, University of Antioquia Medical School, Medellín, Colombia.
Agudelo
Maria
M
Cardeño
John J
JJ
Rodriguez
Carlos A
CA
Vesga
Omar
O
D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology; D001424:Bacterial Infections / Q000150:complications*; D004195:Disease Models, Animal; D016568:Drugs, Generic / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D005839:Gentamicins / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008826:Microbial Sensitivity Tests; D009503:Neutropenia / Q000150:complications / Q000188:drug therapy* / Q000382:microbiology; D009928:Organ Specificity / Q000187:drug effects; D015203:Reproducibility of Results; D016019:Survival Analysis; D013810:Therapeutic Equivalency; D013848:Thigh / Q000382:microbiology / Q000473:pathology*
D000890:Anti-Infective Agents; D016568:Drugs, Generic; D005839:Gentamicins