Limits...
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.

Show MeSH

Related in: MedlinePlus

Individual AUCt values of bosentan in paediatric (dose = 4 mg kg−1 b.i.d.; n = 35) and adult pulmonary arterial hypertension (dose ≈ 1.8 mg kg−1 b.i.d.; n= 11) patients by age
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2805863&req=5

fig02: Individual AUCt values of bosentan in paediatric (dose = 4 mg kg−1 b.i.d.; n = 35) and adult pulmonary arterial hypertension (dose ≈ 1.8 mg kg−1 b.i.d.; n= 11) patients by age

Mentions: The pharmacokinetic profile of bosentan was characterized by a median tmax of 3 h followed by rapid disposition. Descriptive statistics of pharmacokinetic parameters of bosentan and its metabolites Ro 48-5033 and Ro 64-1056 after administration of a dose of 4 mg kg−1 are summarized in Table 2. No pharmacokinetic analysis could be performed for the metabolite Ro 47-8634 because in most plasma samples the concentration of this metabolite was below the limit of quantification. The ratio of the geometric means for AUCt between paediatric and adult patients was 0.54 (95% CL 0.37, 0.78), indicating (i) that exposure to bosentan in children in the current study was half the exposure found in adult patients, and (ii) that the ratio was not within the predefined equivalence limits of 0.66–1.50. When comparing bosentan-naive patients at study start with those already on bosentan, it was noted that the AUCt of bosentan was similar in both subgroups (4298 ng h−1 ml−1, 95% CL 3497, 5282; and 4514 ng h−1 ml−1, 95% CL 2594, 7855, respectively). Exposure to the metabolites Ro 48-5033 and Ro 64-1056 was low compared with that of bosentan, with Ro 48-5033 having the highest exposure of these two metabolites. WHO FC and the dichotomous covariates sex, i.v. epoprostenol treatment, and bosentan treatment at baseline did not affect the pharmacokinetics of bosentan (data not shown). In addition, analysis for the continuous variables age (Figure 2) and body weight did not show a trend for an effect on pharmacokinetics.


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)

Individual AUCt values of bosentan in paediatric (dose = 4 mg kg−1 b.i.d.; n = 35) and adult pulmonary arterial hypertension (dose ≈ 1.8 mg kg−1 b.i.d.; n= 11) patients by age
© Copyright Policy
Related In: Results  -  Collection

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

fig02: Individual AUCt values of bosentan in paediatric (dose = 4 mg kg−1 b.i.d.; n = 35) and adult pulmonary arterial hypertension (dose ≈ 1.8 mg kg−1 b.i.d.; n= 11) patients by age
Mentions: The pharmacokinetic profile of bosentan was characterized by a median tmax of 3 h followed by rapid disposition. Descriptive statistics of pharmacokinetic parameters of bosentan and its metabolites Ro 48-5033 and Ro 64-1056 after administration of a dose of 4 mg kg−1 are summarized in Table 2. No pharmacokinetic analysis could be performed for the metabolite Ro 47-8634 because in most plasma samples the concentration of this metabolite was below the limit of quantification. The ratio of the geometric means for AUCt between paediatric and adult patients was 0.54 (95% CL 0.37, 0.78), indicating (i) that exposure to bosentan in children in the current study was half the exposure found in adult patients, and (ii) that the ratio was not within the predefined equivalence limits of 0.66–1.50. When comparing bosentan-naive patients at study start with those already on bosentan, it was noted that the AUCt of bosentan was similar in both subgroups (4298 ng h−1 ml−1, 95% CL 3497, 5282; and 4514 ng h−1 ml−1, 95% CL 2594, 7855, respectively). Exposure to the metabolites Ro 48-5033 and Ro 64-1056 was low compared with that of bosentan, with Ro 48-5033 having the highest exposure of these two metabolites. WHO FC and the dichotomous covariates sex, i.v. epoprostenol treatment, and bosentan treatment at baseline did not affect the pharmacokinetics of bosentan (data not shown). In addition, analysis for the continuous variables age (Figure 2) and body weight did not show a trend for an effect on pharmacokinetics.

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