Generic vancomycin products fail in vivo despite being pharmaceutical equivalents of the innovator

Abstract

Generic versions of intravenous antibiotics are not required to demonstrate therapeutic equivalence with the innovator because therapeutic equivalence is assumed from pharmaceutical equivalence. To test such assumptions, we studied three generic versions of vancomycin in simultaneous experiments with the innovator and determined the concentration and potency of the active pharmaceutical ingredient by microbiological assay, single-dose pharmacokinetics in infected mice, antibacterial effect by broth microdilution and time-kill curves (TKC), and pharmacodynamics against two wild-type strains of Staphylococcus aureus by using the neutropenic mouse thigh infection model. The main outcome measure was the comparison of magnitudes and patterns of in vivo efficacy between generic products and the innovator. Except for one product exhibiting slightly greater concentration, vancomycin generics were undistinguishable from the innovator based on concentration and potency, protein binding, in vitro antibacterial effect determined by minimal inhibitory or bactericidal concentrations and TKC, and serum pharmacokinetics. Despite such similarities, all generic products failed in vivo to kill S. aureus, while the innovator displayed the expected bactericidal efficacy: maximum antibacterial effect (Emax) (95% confidence interval [CI]) was 2.04 (1.89 to 2.19), 2.59 (2.21 to 2.98), and 3.48 (2.92 to 4.04) versus 5.65 (5.52 to 5.78) log10 CFU/g for three generics and the innovator product, respectively (P<0.0001, any comparison). Nonlinear regression analysis suggests that generic versions of vancomycin contain inhibitory and stimulatory principles within their formulations that cause agonistic-antagonistic actions responsible for in vivo failure. In conclusion, pharmaceutical equivalence does not imply therapeutic equivalence for vancomycin.

FIG. 1.

In vivo efficacy against S. aureus GRP-0057 (years 2002 and 2003) at a low inoculum (4.30 ± 0.05 log₁₀ CFU per thigh when subcutaneous treatment q1h started). Vancomycin generic products are compared with the innovator (VAN-Lilly) in dose-effect experiments (2.34 to 1,200 mg/kg per day) using the neutropenic mouse thigh infection model (each data point represents the mean CFU/g of both thighs from a single mouse). (A) Pharmacodynamic patterns of VAN-Abbott US and VAN-Lilly fitted to the Hill model. Despite containing a significantly greater concentration of API (125%), VAN-Abbott US was completely ineffective in vivo. VAN-Abbott US is shown in a separate graph because of its greater AUC/MIC ratio than that of VAN-Lilly (123%; their dosing regimens were identical). (B) VAN-APP and VAN-Proclin were both pharmaceutically equivalent to VAN-Lilly, but neither was therapeutically equivalent due to their marked Eagle effect. The curve for VAN-APP ends at 300 mg/kg (fAUC/MIC, 267 h) because this product was discontinued and the remaining amount was insufficient for the highest doses.

FIG. 2.

In vivo efficacy against S. aureus GRP-0057 (year 2004) at a high inoculum (6.74 log₁₀ CFU per thigh when intravenous treatment q8h started). VAN-Abbott US was compared with the innovator (VAN-Lilly) after intravenous administration (75 to 1,200 mg/kg per day) but with 2.5-log increases in the inoculum size. The greater bacterial load required four times more vancomycin to reach maximum effect (600 mg/kg; fAUC/MIC, 534.1 h) and caused the Eagle effect in both products, but the efficacy of VAN-Abbott US was significantly inferior to that of VAN-Lilly (E_max, 3.82 ± 0.33 versus 5.35 ± 0.13, respectively; P < 0.0001). Note that despite the use of identical dosing regimens, the AUC/MIC ratio of VAN-Abbott US is 124% of that of VAN-Lilly due to pharmaceutical nonequivalence.

FIG. 3.

In vivo efficacy against S. aureus ATCC 29213 (year 2005) at a low inoculum (4.13 log₁₀ CFU per thigh when subcutaneous treatment q1h started), after some makers of generics acquired manufacturing secrets from Eli Lilly. Vancomycin generic products were compared with the innovator (VAN-Lilly) in dose-effect experiments (18.75 to 300 mg/kg per day) using the neutropenic mouse thigh infection model (each data point represents the mean CFU/g of both thighs from a single mouse). VAN-Abbott France, VAN-Baxter, and VAN-Lilly fitted to the Hill model and were indistinguishable (P = 0.7681). VAN-Proclin, on the other hand, displayed again the Eagle effect, fitting the Gaussian instead of the Hill model, as happened before 2005.

FIG. 4.

In vivo efficacy of vancomycin products available in Colombia during 2008 against S. aureus GRP-0057 at low (A) and very high (B) inocula (4.07 and 8.34 log₁₀ CFU per thigh when subcutaneous treatment q1h started, respectively). After VAN-Lilly was discontinued, VAN-Baxter replaced it as the innovator product; both panels show its dose-effect relationship compared with those of the newest version of VAN-Abbott (commercialized under the brand name Hospira) and VAN-Proclin. At a low inoculum, VAN-Hospira was indistinguishable from VAN-Baxter while VAN-Proclin was again ineffective; the very high inoculum had a marked impact on vancomycin pharmacodynamics, but VAN-Proclin remained inferior despite losing its Eagle effect.