title: Pharmacokinetic and clinical profile of a novel formulation of bosentan in children with pulmonary arterial hypertension: the FUTURE-1 study.
abstract: BACKGROUND
  * 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.
  
  
  CONCLUSIONS
  * 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.
  
  
  OBJECTIVE
  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.
authors.affiliation: Children's Hospital, Department of Paediatrics, University of Geneva, Geneva, Switzerland. Maurice.Beghetti@hcuge.ch
authors.forename: Maurice
authors.initials: M
authors.lastname: Beghetti
authors.forename: Sheila G
authors.initials: SG
authors.lastname: Haworth
authors.forename: Damien
authors.initials: D
authors.lastname: Bonnet
authors.forename: Robyn J
authors.initials: RJ
authors.lastname: Barst
authors.forename: Philippe
authors.initials: P
authors.lastname: Acar
authors.forename: Alain
authors.initials: A
authors.lastname: Fraisse
authors.forename: Dunbar D
authors.initials: DD
authors.lastname: Ivy
authors.forename: Xavier
authors.initials: X
authors.lastname: Jais
authors.forename: Ingram
authors.initials: I
authors.lastname: Schulze-Neick
authors.forename: Nazzareno
authors.initials: N
authors.lastname: Galiè
authors.forename: Adele
authors.initials: A
authors.lastname: Morganti
authors.forename: Jasper
authors.initials: J
authors.lastname: Dingemanse
authors.forename: Andjela
authors.initials: A
authors.lastname: Kusic-Pajic
authors.forename: Rolf M F
authors.initials: RM
authors.lastname: Berger
mesh_terms: D000328:Adult; D000959:Antihypertensive Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D000077300:Bosentan; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy*; D008297:Male; D013449:Sulfonamides / Q000493:pharmacokinetics*
chemical_list: D000959:Antihypertensive Agents; D013449:Sulfonamides; D000077300:Bosentan