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

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 - Br J Clin Pharmacol (2009)

Bottom Line: The paediatric formulation was well accepted and bosentan well tolerated in this study.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.

View Article: PubMed Central - PubMed

Affiliation: Children's Hospital, Department of Paediatrics, University of Geneva, Geneva, Switzerland. Maurice.Beghetti@hcuge.ch

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.

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Related in: MedlinePlus

Arithmetic mean (±SD) plasma concentration vs. time profiles of bosentan in paediatric pulmonary arterial hypertension patients after multiple-dose administration of bosentan at a dose of 2 and 4 mg kg−1 b.i.d. (n= 11). 2 mg kg−1 (); 4 mg kg−1 ()
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fig03: Arithmetic mean (±SD) plasma concentration vs. time profiles of bosentan in paediatric pulmonary arterial hypertension patients after multiple-dose administration of bosentan at a dose of 2 and 4 mg kg−1 b.i.d. (n= 11). 2 mg kg−1 (); 4 mg kg−1 ()

Mentions: Figure 3 shows the plasma concentration–time profiles of bosentan following administration of doses of 2 and 4 mg kg−1 in the subgroup of patients who underwent two pharmacokinetic assessments. The two profiles overlap, yielding comparable pharmacokinetic parameters for both doses (Table 2).


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

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 - Br J Clin Pharmacol (2009)

Arithmetic mean (±SD) plasma concentration vs. time profiles of bosentan in paediatric pulmonary arterial hypertension patients after multiple-dose administration of bosentan at a dose of 2 and 4 mg kg−1 b.i.d. (n= 11). 2 mg kg−1 (); 4 mg kg−1 ()
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2805863&req=5

fig03: Arithmetic mean (±SD) plasma concentration vs. time profiles of bosentan in paediatric pulmonary arterial hypertension patients after multiple-dose administration of bosentan at a dose of 2 and 4 mg kg−1 b.i.d. (n= 11). 2 mg kg−1 (); 4 mg kg−1 ()
Mentions: Figure 3 shows the plasma concentration–time profiles of bosentan following administration of doses of 2 and 4 mg kg−1 in the subgroup of patients who underwent two pharmacokinetic assessments. The two profiles overlap, yielding comparable pharmacokinetic parameters for both doses (Table 2).

Bottom Line: The paediatric formulation was well accepted and bosentan well tolerated in this study.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.

View Article: PubMed Central - PubMed

Affiliation: Children's Hospital, Department of Paediatrics, University of Geneva, Geneva, Switzerland. Maurice.Beghetti@hcuge.ch

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.

Show MeSH
Related in: MedlinePlus