Relative bioavailability of a newly developed pediatric formulation of bosentan vs. the adult formulation

• Published in: International journal of clinical pharmacology and therapeutics Vol. 51; no. 6; pp. 529 - 536
• Main Authors: GUTIERREZ, Marcelo M, NICOLAS, Laurent B, DONAZZOLO, Yves, DINGEMANSE, Jasper
• Format: Journal Article
• Language: English
• Published: München Dustri 01-06-2013
• Subjects: Adult; Antihypertensive Agents - administration & dosage; Antihypertensive Agents - adverse effects; Antihypertensive Agents - blood; Antihypertensive Agents - pharmacokinetics; Biological and medical sciences; Biological Availability; Chemistry, Pharmaceutical; Cross-Over Studies; Dose-Response Relationship, Drug; Drug Design; Endothelin Receptor Antagonists; Humans; Hypertension, Pulmonary - drug therapy; Male; Medical sciences; Middle Aged; Pharmacology. Drug treatments; Pneumology; Predictive Value of Tests; Pulmonary hypertension. Acute cor pulmonale. Pulmonary embolism. Pulmonary vascular diseases; Sulfonamides - administration & dosage; Sulfonamides - adverse effects; Sulfonamides - blood; Sulfonamides - pharmacokinetics; Tablets; Human; Pediatrics; Respiratory disease; Indication; Cardiovascular disease; Infant; Bioavailability; Artery; Pulmonary hypertension; adult formulation; Bosentan; Blood vessel; Formulation; pediatric formulation; Peptidergic receptor; Adult; orphan indication; Antagonist; Circulatory system; Pharmacokinetics; Child; pulmonary arterial hypertension; Comparative study; Endothelin receptor
• ISSN: 0946-1965
• DOI: 10.5414/CP201806

Bosentan is a dual endothelin receptor antagonist approved for the treatment of pulmonary arterial hypertension (PAH). Since bosentan is frequently used to treat pediatric PAH patients, a pediatric formulation was developed.
To evaluate the pharmacokinetic properties of bosentan and its active metabolite, Ro 48-5033, of the quadrisected, dispersible pediatric vs. the adult tablet after single-dose administration to healthy subjects. Secondary objectives of the study were to compare the pharmacokinetics of two inactive metabolites and the safety of both formulations.
In this open-label, two-way crossover study, subjects (20 - 43 years) were randomized to receive single oral doses of 62.5 mg of bosentan as 1 adult tablet and 64 mg as 2 pediatric tablets of 32 mg. Blood samples were drawn over a 48-hour period to measure bosentan and its metabolites.
16 subjects were enrolled and completed the study. Following treatment with the pediatric formulation, values for Cmax and AUC0-∞ of bosentan were lower than with the adult formulation with geometric mean ratios (90% confidence interval) of 0.82 (0.65, 1.04) and 0.87 (0.78, 0.97), respectively. Similar results were obtained for the primary active metabolite Ro 48-5033. Both treatments were well tolerated.
Although the 90% confidence intervals of the geometric mean ratios of Cmax and AUC0-∞ were not entirely within the conventional bioequivalence range (0.80 - 1.25), no clinically relevant effect of formulation on the pharmacokinetics of bosentan and Ro 48-5033 was detected. Both formulations were well tolerated.