Pharmacokinetic and clinical profile of a novel formulation of bosentan in children with pulmonary arterial hypertension: the FUTURE-1 study

Autor: Xavier Jaïs, Jasper Dingemanse, Andjela Kusic-Pajic, Adele Morganti, D. Dunbar Ivy, Damien Bonnet, Sheila G. Haworth, Ingram Schulze-Neick, Rudolphus Berger, Robyn J. Barst, Alain Fraisse, Nazzareno Galiè, Maurice Beghetti, Philippe Acar
Přispěvatelé: Beghetti M, Haworth SG, Bonnet D, Barst RJ, Acar P, Fraisse A, Ivy DD, Jais X, Schulze-Neick I, Galiè N, Morganti A, Dingemanse J, Kusic-Pajic A, Berger RM., Faculteit Medische Wetenschappen/UMCG, Cardiovascular Centre (CVC), Vascular Ageing Programme (VAP)
Rok vydání: 2009
Předmět:
Zdroj: British Journal of Clinical Pharmacology, Vol. 68, No 6 (2009) pp. 948-955
British Journal of Clinical Pharmacology
British Journal of Clinical Pharmacology, 68(6), 948-955. Wiley
ISSN: 1365-2125
0306-5251
DOI: 10.1111/j.1365-2125.2009.03532.x
Popis: center dot Exposure to bosentan was lower in paediatric pulmonary arterial hypertension (PAH) patients treated with the marketed adult formulation at a dose of about 2 mg kg-1 when compared with adult PAH patients.center dot In healthy adult subjects, bosentan pharmacokinetics are less than dose-proportional at doses of >= 500 mg.WHAT THIS STUDY ADDScenter dot The pharmacokinetics of a new paediatric bosentan formulation were characterized in paediatric PAH patients.center dot The level of exposure to bosentan as observed in adult PAH patients cannot be reached in paediatric patients with b.i.d. dosing.center dot In paediatric PAH patients, nondose-proportional pharmacokinetics of bosentan occur at lower doses when compared with healthy adult subjects.AIMTo show equivalent bosentan exposure in paediatric patients with pulmonary arterial hypertension (PAH) when compared with a cohort of historical controls of adult PAH patients using a newly developed paediatric formulation.METHODSThirty-six paediatric PAH patients were enrolled in this multicentre, prospective, open-label, noncontrolled study and treated for 4 weeks with bosentan 2 mg kg-1 b.i.d. and then for 8 weeks with 4 mg kg-1 b.i.d. Blood samples were taken for pharmacokinetic purposes. Exploratory efficacy measurements included World Health Organization (WHO) functional class and parent's and clinician's Global Clinical Impression scales.RESULTSComparing children with a historical group of adults, the geometric mean ratio (90% confidence interval) of the area under the plasma concentration-time curve was 0.54 (0.37, 0.78), i.e. children had lower exposure to bosentan than adults. Bosentan concentrations following doses of 2 and 4 mg kg-1 were similar. Improvements in WHO functional class and the Global Clinical Impression scales occurred mainly in bosentan-naive patients, whereas the rare worsenings occurred in patients already on bosentan prior to study initiation. The paediatric formulation was well accepted and bosentan well tolerated in this study. No cases of elevated liver enzymes or anaemia were reported.CONCLUSIONSExposure to bosentan, as shown comparing the results from this study with those from a study in adults, was different in paediatric and adult PAH patients. Since FUTURE-1 and past studies suggest a favourable benefit-risk profile for bosentan at 2 mg kg-1 b.i.d., this dose is recommended for children with PAH. The new paediatric formulation was well tolerated.
Databáze: OpenAIRE
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