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

Abstract

BACKGROUND: 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.METHODS: 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 = 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.RESULTS: Orally administered fumarate, benzoate, and maleate salts, in parallel-group design, resulted in mean BDQ AUC0–t of 9,267 ± SD 10,182, 19,258 ± SD 11,803, and 15,396 ± SD 9,170 ng.h/ml, respectively; and in a crossover design of 9,267 ± SD 10,182, 17,441 ± SD 24,049, and 18,087 ± SD 19,758 ng.h/ml, respectively. P values were >0.05.CONCLUSION: There was no statistically significant difference in BDQ and M2 AUC0–t following oral administration of fumarate, benzoate and maleate salts in dogs.

Bioanalysis of bedaquiline in human plasma by liquid chromatography-tandem mass spectrometry: Application to pharmacokinetic study

“…According to the available literature, several bioanalytical methods have been reported for the quantification of BDQ as a single analyte [9] , [10] , [11] , [12] , [13] , as well as in combination with metabolites or other drugs [14] , [15] , [16] , [17] , [18] , [19] , in various biological samples such as rat plasma [9] , [12] , dog plasma [10] , human serum [16] , human hair [11] , and human plasma [13] , [14] , [15] , [17] , [18] , [19] , using LC-MS/MS. Additionally, an HPLC method was reported for the estimation of BDQ along with Delamanid in human plasma, with a total run time of 7 min [20] .…”