Comparative Pharmacokinetics and Bioequivalence of 2 Formulations of Bosentan Dispersible Tablets in Healthy Chinese Volunteers Under Fasting and Fed Conditions.

Abstract

Bosentan is a dual endothelin receptor antagonist widely used in the treatment of pulmonary artery hypertension. However, there are few reports on the pharmacokinetics (PK) and bioequivalence of bosentan dispersible tablets (32 mg) in the Chinese population. This study aimed to evaluate the PK characteristics and bioequivalence of the test and reference formulations of bosentan dispersible tablets in healthy Chinese volunteers under fasting and fed conditions. A randomized, single-dose, 2-sequence, 2-period crossover study (fasting) and a 4-period replicate crossover study (fed) were conducted with 48 and 30 healthy volunteers, respectively. The bosentan plasma concentrations were measured by a validated ultra-performance liquid chromatography coupled with a tandem mass spectrometry method, and PK parameters were analyzed using noncompartmental methods. The bioequivalence statistical analysis showed that 90% confidence intervals for the geometric mean ratios of peak plasma concentration, area under the concentration-time curve (AUC) from time zero to the last measurable concentration, and AUC from time zero to infinity for the test and reference formulations were within the bioequivalence range of 80%-125% under both fasting and fed conditions. After the administration of bosentan dispersible tablets under fed conditions, the systemic exposure (based on AUC from time zero to infinity) was increased by approximately 15%-20%. These findings confirm the bioequivalence of the 2 formulations, and both formulations were well tolerated, with no safety-related adverse events reported. Given the wide therapeutic dose range of bosentan dispersible tablets for the treatment of pulmonary artery hypertension in children, the impact of food on its PK is not considered clinically significant.