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.
RCT Entities:
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: Catherine C Bell; Anita C A Dankers; Volker M Lauschke; Rowena Sison-Young; Roz Jenkins; Cliff Rowe; Chris E Goldring; Kevin Park; Sophie L Regan; Tracy Walker; Chris Schofield; Audrey Baze; Alison J Foster; Dominic P Williams; Amy W M van de Ven; Frank Jacobs; Jos van Houdt; Tuula Lähteenmäki; Jan Snoeys; Satu Juhila; Lysiane Richert; Magnus Ingelman-Sundberg Journal: Toxicol Sci Date: 2018-04-01 Impact factor: 4.849
Authors: Catherine C Bell; Delilah F G Hendriks; Sabrina M L Moro; Ewa Ellis; Joanne Walsh; Anna Renblom; Lisa Fredriksson Puigvert; Anita C A Dankers; Frank Jacobs; Jan Snoeys; Rowena L Sison-Young; Rosalind E Jenkins; Åsa Nordling; Souren Mkrtchian; B Kevin Park; Neil R Kitteringham; Christopher E P Goldring; Volker M Lauschke; Magnus Ingelman-Sundberg Journal: Sci Rep Date: 2016-05-04 Impact factor: 4.379
Authors: Rowena L Sison-Young; Volker M Lauschke; Esther Johann; Eliane Alexandre; Sébastien Antherieu; Hélène Aerts; Helga H J Gerets; Gilles Labbe; Delphine Hoët; Martina Dorau; Christopher A Schofield; Cerys A Lovatt; Julie C Holder; Simone H Stahl; Lysiane Richert; Neil R Kitteringham; Robert P Jones; Mohamed Elmasry; Richard J Weaver; Philip G Hewitt; Magnus Ingelman-Sundberg; Chris E Goldring; B Kevin Park Journal: Arch Toxicol Date: 2016-06-25 Impact factor: 5.153