title: A bosentan pharmacokinetic study to investigate dosing regimens in paediatric patients with pulmonary arterial hypertension: FUTURE-3.
abstract: The aim of the present study was to investigate whether increasing the bosentan dosing frequency from 2 mg kg-1twice daily (b.i.d.) to 2 mg kg-1three 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-1b.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-1dose (AUC0-24C). The maximum plasma concentration corrected to the 2 mg kg-1dose (CmaxC), the time to reach the maximum plasma concentration (tmax) and safety endpoints were also assessed.
  
  
  
  The geometric mean [95% confidence interval (CI)] for AUC0-24Cwas 8535 h.ng ml-1(6936, 10 504) and 7275 h.ng ml-1(5468, 9679) for 2 mg kg-1b.i.d. and t.i.d., respectively [geometric mean ratio (95% CI) 0.85 (0.61, 1.20)]. The geometric mean (95% CI) for CmaxCwas 743 ng ml-1(573, 963) and 528 ng ml-1(386, 722) for 2 mg kg-1b.i.d. and t.i.d., respectively [geometric mean ratio (95% CI) 0.71 (0.48, 1.05)]. The median (range) for tmaxwas 3.0 h (0.0-7.5) and 3.0 h (1.0-8.0) for 2 mg kg-1b.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-1b.i.d. remains the recommended dosing regimen for bosentan in paediatric PAH patients.
authors.affiliation: Centre for Congenital Heart Diseases, Department of Paediatric Cardiology, Beatrix Children's Hospital, University Medical Centre, University of Groningen, Groningen, The Netherlands.
authors.forename: Rolf M F
authors.initials: RMF
authors.lastname: Berger
authors.affiliation: Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors.forename: Martine
authors.initials: M
authors.lastname: Gehin
authors.affiliation: Children's Hospital, Paediatric Cardiology Unit, University of Geneva, Geneva, and Centre Universitaire Romand de Cardiologie et Chirurgie Cardiaque Pédiatriques, Geneva and Lausanne, Switzerland.
authors.forename: Maurice
authors.initials: M
authors.lastname: Beghetti
authors.affiliation: Children's Hospital Colorado, Department of Pediatric Cardiology, Denver, CO, USA.
authors.forename: Dunbar
authors.initials: D
authors.lastname: Ivy
authors.affiliation: Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors.forename: Andjela
authors.initials: A
authors.lastname: Kusic-Pajic
authors.affiliation: Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors.forename: Peter
authors.initials: P
authors.lastname: Cornelisse
authors.affiliation: Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors.forename: Simon
authors.initials: S
authors.lastname: Grill
authors.affiliation: M3C-Hospital Necker Enfants Malades, Department of Paediatric Cardiology, Université Paris Descartes, Paris, France.
authors.forename: Damien
authors.initials: D
authors.lastname: Bonnet
mesh_terms: D000284:Administration, Oral; D000959:Antihypertensive Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D000077300:Bosentan; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D065128:Endothelin Receptor Antagonists / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy*; D007223:Infant; D008297:Male; D011446:Prospective Studies; D013449:Sulfonamides / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D013449:Sulfonamides; D000077300:Bosentan
keywords: paediatrics; pharmacokinetics; vascular disease