Comparison of pharmacokinetics and bioavailability of bedaquiline fumarate, benzoate and maleate in dogs

Abstract

B A C K G R O U N D: Bedaquiline (BDQ) as a fumarate salt is indicated as part of a regimen to treat multidrug-resistant TB (MDR-TB). BDQ benzoate and maleate have been identified as promising alternatives that will encourage generic pharmaceutical houses to manufacture this drug. Our study compared the pharmacokinetics (PK) of BDQ fumarate vs. the maleate and benzoate salts in dogs. M E T H O D S: The PK of BDQ and its active N-desmethyl metabolite M2 following intravenous administration of 1 mg/kg BDQ (as fumarate) and oral administration of 10 mg/kg BDQ as fumarate, benzoate, or maleate salts in suspension to fasted male beagle dogs was evaluated in a parallel-group and crossover study with n ¼ 4 per group. BDQ and M2 plasma concentrations were determined up to 168 h post-dose. T-tests were conducted to compare the area under the curve, AUC0–t among groups. R E S U LT S: Orally administered fumarate, benzoate, and maleate salts, in parallel-group design, resulted in mean BDQ AUC0–t of 9,267 6 SD 10,182, 19,258 6 SD 11,803, and 15,396 6 SD 9,170 ng.h/ml, respectively; and in a crossover design of 9,267 6 SD 10,182, 17,441 6 SD 24,049, and 18,087 6 SD 19,758 ng.h/ml, respectively. P values were .0.05. C O N C L U S I O N: There was no statistically significant difference in BDQ and M2 AUC0–t following oral administration of fumarate, benzoate and maleate salts in dogs.