Background: The previous formulation of epoetin alfa in Japan was a citrate-buffered protein solution containing gelatin hydrolysate as the protein protective agent. To eliminate pain at injection sites, and the risks of anaphylactic shock and unknown infections by gelatin we have developed a new formulation of phosphate-buffered epoetin alfa, which does not contain gelatin hydrolysate.
Aim: To compare the bioequivalence of two formulations of epoetin alfa administered by the subcutaneous route.
Methods: Four separate studies were performed to assess the bioequivalence of two epoetin alfa formulations using different strength and doses, i.e. 750 IU per 0.5 ml x 0.5 ml (= 750 IU per subject), 750 IU per 0.5 ml x 4 ml (= 6000 IU per subject), 6000 IU per 0.5 ml x 0.5 ml (= 6000 IU per subject) and 24,000 IU per 0.5 ml x 0.125 ml (= 6000 IU per subject). Each study was a single-centre, open-label, randomized, two-treatment, two-period, crossover study for which healthy volunteers were enrolled. Bioequivalence was assessed using the confidence interval (CI) of the ratios for the log-transformed, baseline-corrected Cmax and AUC(0,t). Baseline-corrected AUC(0,t) was calculated using the following equation: AUC(0,t) = AUC(0,t), uncorrected -- predose level x observation period.
Results: The ratios (gelatin-free/gelatin-containing) for the log-transformed Cmax and AUC(0,t) after 6000 IU per subject injection of three different concentrations of epoetin alfa were well within the usual range for bioequivalence (90% CI 0.8, 1.25). The 90% CI of the ratio for Cmax after 750 IU per subject injection was 0.906, 1.24, which was within the bioequivalence range. However, the ratio for AUC(0,t) was not determined in this lowest dose because of negative AUC(0,t) values obtained in 12/60 cases. The overall safety data were consistent with those expected for a healthy study population, and did not present any concerns suggestive of adverse effects due to either formulation.
Conclusions: The point estimates and 90% CIs of the ratios of Cmax and AUC(0,t) for the gelatin-free/gelatin-containing formulations indicated that the two formulations are bioequivalent.