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摘要
AimThe aim of the present study was to investigate whether increasing the bosentan dosing frequency from 2mg kg(-1) twice daily (b.i.d.) to 2mg kg(-1) three times daily (t.i.d.) in children with pulmonary arterial hypertension (PAH) (from 3months to <12years of age) would increase exposure. MethodsAn 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 2mg kg(-1) b.i.d. or t.i.d. The main pharmacokinetic endpoint was the daily exposure to bosentan over 24h corrected to the 2mg kg(-1) dose (AUC(0-24C)). The maximum plasma concentration corrected to the 2mg kg(-1) dose (C-maxC), the time to reach the maximum plasma concentration (t(max)) and safety endpoints were also assessed. ResultsThe geometric mean [95% confidence interval (CI)] for AUC(0-24C) was 8535h.ng ml(-1) (6936, 10504) and 7275h.ng ml(-1) (5468, 9679) for 2mg kg(-1) 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-maxC was 743ng ml(-1) (573, 963) and 528ng ml(-1) (386, 722) for 2mg kg(-1) b.i.d. and t.i.d., respectively [geometric mean ratio (95% CI) 0.71 (0.48, 1.05)]. The median (range) for t(max) was 3.0h (0.0-7.5) and 3.0h (1.0-8.0) for 2mg kg(-1) 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. ConclusionsThere 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 2mg kg(-1) b.i.d. remains the recommended dosing regimen for bosentan in paediatric PAH patients.
- 出版日期2017-8
