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

Abstract：

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT:* 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. * In healthy adult subjects, bosentan pharmacokinetics are less than dose-proportional at doses of >or=500 mg. WHAT THIS STUDY ADDS:* The pharmacokinetics of a new paediatric bosentan formulation were characterized in paediatric PAH patients. * The level of exposure to bosentan as observed in adult PAH patients cannot be reached in paediatric patients with b.i.d. dosing. * In paediatric PAH patients, nondose-proportional pharmacokinetics of bosentan occur at lower doses when compared with healthy adult subjects. AIM:To 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. METHODS:Thirty-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. RESULTS:Comparing 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. CONCLUSIONS:Exposure 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.

journal_name

Br J Clin Pharmacol

journal_title

British journal of clinical pharmacology

authors

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

doi

10.1111/j.1365-2125.2009.03532.x

subject

Has Abstract

pub_date

2009-12-01 00:00:00

pages

948-55

issue

eissn

0306-5251

issn

1365-2125

pii

BCP3532

journal_volume

pub_type

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