A bosentan pharmacokinetic study to investigate dosing regimens in paediatric patients with pulmonary arterial hypertension: FUTURE-3.

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Serval ID
serval:BIB_91482515D4DF
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
A bosentan pharmacokinetic study to investigate dosing regimens in paediatric patients with pulmonary arterial hypertension: FUTURE-3.
Journal
British journal of clinical pharmacology
Author(s)
Berger RMF, Gehin M., Beghetti M., Ivy D., Kusic-Pajic A., Cornelisse P., Grill S., Bonnet D.
Working group(s)
FUTURE-3 investigators
ISSN
1365-2125 (Electronic)
ISSN-L
0306-5251
Publication state
Published
Issued date
08/2017
Peer-reviewed
Oui
Volume
83
Number
8
Pages
1734-1744
Language
english
Notes
Publication types: Clinical Trial, Phase III ; Journal Article ; Multicenter Study ; Randomized Controlled Trial
Publication Status: ppublish
Abstract
The aim of the present study was to investigate whether increasing the bosentan dosing frequency from 2 mg kg <sup>-1</sup> twice daily (b.i.d.) to 2 mg kg <sup>-1</sup> three times daily (t.i.d.) in children with pulmonary arterial hypertension (PAH) (from ≥3 months to <12 years of age) would increase exposure.
An open-label, prospective, randomized, multicentre, multiple-dose, phase III study was conducted. Patients (n = 64) were randomized 1:1 to receive oral doses of bosentan of 2 mg kg <sup>-1</sup> b.i.d. or t.i.d. The main pharmacokinetic endpoint was the daily exposure to bosentan over 24 h corrected to the 2 mg kg <sup>-1</sup> dose (AUC <sub>0-24C</sub> ). The maximum plasma concentration corrected to the 2 mg kg <sup>-1</sup> dose (C <sub>maxC</sub> ), the time to reach the maximum plasma concentration (t <sub>max</sub> ) and safety endpoints were also assessed.
The geometric mean [95% confidence interval (CI)] for AUC <sub>0-24C</sub> was 8535 h.ng ml <sup>-1</sup> (6936, 10 504) and 7275 h.ng ml <sup>-1</sup> (5468, 9679) for 2 mg kg <sup>-1</sup> b.i.d. and t.i.d., respectively [geometric mean ratio (95% CI) 0.85 (0.61, 1.20)]. The geometric mean (95% CI) for C <sub>maxC</sub> was 743 ng ml <sup>-1</sup> (573, 963) and 528 ng ml <sup>-1</sup> (386, 722) for 2 mg kg <sup>-1</sup> b.i.d. and t.i.d., respectively [geometric mean ratio (95% CI) 0.71 (0.48, 1.05)]. The median (range) for t <sub>max</sub> was 3.0 h (0.0-7.5) and 3.0 h (1.0-8.0) for 2 mg kg <sup>-1</sup> b.i.d. and t.i.d., respectively. The proportions of patients who experienced ≥1 adverse event were similar in the b.i.d. (66.7%) and t.i.d. (67.7%) groups.
There appeared to be no clinically relevant difference in exposure to bosentan, or in safety, when increasing the frequency of bosentan dosing from b.i.d. to t.i.d. Therefore, the present study provides no indication that the dosing recommendation should be changed, and 2 mg kg <sup>-1</sup> b.i.d. remains the recommended dosing regimen for bosentan in paediatric PAH patients.

Keywords
Administration, Oral, Antihypertensive Agents/pharmacokinetics, Antihypertensive Agents/therapeutic use, Area Under Curve, Child, Child, Preschool, Dose-Response Relationship, Drug, Drug Administration Schedule, Endothelin Receptor Antagonists/pharmacokinetics, Endothelin Receptor Antagonists/therapeutic use, Female, Humans, Hypertension, Pulmonary/drug therapy, Infant, Male, Prospective Studies, Sulfonamides/pharmacokinetics, Sulfonamides/therapeutic use, paediatrics, pharmacokinetics, vascular disease
Pubmed
Web of science
Open Access
Yes
Create date
28/02/2017 19:16
Last modification date
20/08/2019 14:54
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