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

Abstract

WHAT IS KNOWN:

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.

AIM:

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.

MATERIALS AND METHODS:

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.

RESULTS:

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.

WHAT IS NEW AND CONCLUSION:

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.

• Authors: Marcelo M Gutierrez, Laurent B Nicolas, Yves Donazzolo, Jasper Dingemanse
• Journal: International journal of clinical pharmacology and therapeutics (Int J Clin Pharmacol Ther) Vol. 51 Issue 6 Pg. 529-36 (Jun 2013) ISSN: 0946-1965 [Print] Germany
• PMID: 23611572 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Antihypertensive Agents
• Endothelin Receptor Antagonists
• Sulfonamides
• Tablets
• Bosentan

Topics

• Adult
• Antihypertensive Agents (administration & dosage, adverse effects, blood, pharmacokinetics)
• Biological Availability
• Bosentan
• Chemistry, Pharmaceutical
• Cross-Over Studies
• Dose-Response Relationship, Drug
• Drug Design
• Endothelin Receptor Antagonists
• Humans
• Hypertension, Pulmonary (drug therapy)
• Male
• Middle Aged
• Predictive Value of Tests
• Sulfonamides (administration & dosage, adverse effects, blood, pharmacokinetics)
• Tablets