title: Pharmacokinetics, safety, and efficacy of bosentan in pediatric patients with pulmonary arterial hypertension.
abstract: BACKGROUND
  Bosentan, a dual endothelin-receptor antagonist, is registered for the treatment of pulmonary arterial hypertension. Little is known about the effects of bosentan in children. This study was conducted to investigate the pharmacokinetics, safety, and efficacy of bosentan in pediatric patients with pulmonary arterial hypertension.
  
  
  METHODS
  In this 2-center, open-label study, 19 pediatric patients with pulmonary arterial hypertension were enrolled and stratified for body weight and epoprostenol use. Patients weighing between 10 and 20 kg, between 20 and 40 kg, or greater than 40 kg received a single dose of 31.25, 62.5, or 125 mg, respectively, on day 1, followed by 4 weeks of treatment with the initial dose. The dose was then up-titrated to the target dose (31.25, 62.5, or 125 mg twice daily). Pharmacokinetic and hemodynamic parameters were obtained at baseline and after 12 weeks of treatment. Six-minute walk distance and cardiopulmonary exercise testing results were measured at baseline and at week 12 in children aged 8 years or older.
  
  
  RESULTS
  The variability in exposure among the 3 groups was less than 2-fold after single- and multiple-dose administration. The exposure to bosentan decreased over time in all groups. The covariates body weight, gender, age, and the use of epoprostenol had no significant effect on the pharmacokinetics of bosentan. Bosentan produced hemodynamic improvement and was well tolerated. The mean change from baseline in mean pulmonary artery pressure was -8.0 mm Hg (95% confidence interval, -12.2 to -3.7 mm Hg), and that in pulmonary vascular resistance index was -300 dyne x s x m(2)/cm(5) (95% confidence interval, -576 to -24 dyne x s x m(2)/cm(5)).
  
  
  CONCLUSIONS
  The pharmacokinetics of bosentan in pediatric patients with pulmonary arterial hypertension and healthy adults are similar, and treatment with bosentan resulted in hemodynamic improvement. These results suggest that the applied dosing regimens may be appropriate to treat pediatric patients.
authors.affiliation: Actelion Pharmaceuticals Ltd, Department of Clinical Pharmacology, Gewerbestrasse, Allscwil, Switzerland. paul.cangiersbergen@actelion.com
authors.forename: Robyn J
authors.initials: RJ
authors.lastname: Barst
authors.forename: Dunbar
authors.initials: D
authors.lastname: Ivy
authors.forename: Jasper
authors.initials: J
authors.lastname: Dingemanse
authors.forename: Allison
authors.initials: A
authors.lastname: Widlitz
authors.forename: Kelly
authors.initials: K
authors.lastname: Schmitt
authors.forename: Aimee
authors.initials: A
authors.lastname: Doran
authors.forename: Deborah
authors.initials: D
authors.lastname: Bingaman
authors.forename: Ngoc
authors.initials: N
authors.lastname: Nguyen
authors.forename: Michael
authors.initials: M
authors.lastname: Gaitonde
authors.forename: Paul L M
authors.initials: PL
authors.lastname: van Giersbergen
mesh_terms: D000293:Adolescent; D000704:Analysis of Variance; D000959:Antihypertensive Agents / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001835:Body Weight; D000077300:Bosentan; D002648:Child; D002675:Child, Preschool; D004334:Drug Administration Schedule; D005260:Female; D006207:Half-Life; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy*; D008297:Male; D013449:Sulfonamides / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D000959:Antihypertensive Agents; D013449:Sulfonamides; D000077300:Bosentan