新型波生坦制剂在肺动脉高压儿童患者中的药代动力学和临床特征：FUTURE-1 研究。
Pharmacokinetic and clinical profile of a novel formulation of bosentan in children with pulmonary arterial hypertension: the FUTURE-1 study.
机构信息
Children's Hospital, Department of Paediatrics, University of Geneva, Geneva, Switzerland.
出版信息
Br J Clin Pharmacol. 2009 Dec;68(6):948-55. doi: 10.1111/j.1365-2125.2009.03532.x.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
- 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.
WHAT THIS STUDY ADDS
- 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.
AIM
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.
已知信息：
在接受约 2mg/kg 剂量的市场上的成人制剂治疗的儿科肺动脉高压 (PAH) 患者中，与成人 PAH 患者相比，波生坦的暴露量较低。
在健康成人受试者中，当剂量大于等于 500mg 时，波生坦的药代动力学呈剂量非比例关系。
新发现：
本研究对儿科波生坦新制剂的药代动力学进行了描述。
在接受 bid 剂量治疗的儿科 PAH 患者中，无法达到在成人 PAH 患者中观察到的波生坦暴露水平。
与健康成年受试者相比，当剂量较低时，儿科 PAH 患者的波生坦药代动力学呈非剂量比例关系。
目的：
- 展示使用新开发的儿科制剂治疗的儿科 PAH 患者与成人 PAH 患者历史队列的对照相比，波生坦的暴露量相当。
方法：
本研究为多中心、前瞻性、开放标签、非对照研究，共纳入 36 例儿科 PAH 患者，接受波生坦 2mg/kg bid 治疗 4 周，然后 4mg/kg bid 治疗 8 周。
进行药代动力学目的的血样采集。探索性疗效测量包括世界卫生组织（WHO）功能分级和父母及临床医生的总体临床印象量表。
结果：
将儿童与成人历史组进行比较，血浆浓度-时间曲线下面积的几何均数比值（90%置信区间）为 0.54（0.37，0.78），即儿童对波生坦的暴露量低于成人。
2mg/kg 和 4mg/kg 剂量的波生坦浓度相似。
在波生坦初治患者中，WHO 功能分级和总体临床印象量表主要出现改善，而在研究开始前已接受波生坦治疗的患者中，罕见恶化。
在本研究中，新制剂的接受程度良好，波生坦耐受良好。未报告肝酶升高或贫血病例。
结论：
与成人研究结果相比，儿科和成人 PAH 患者的波生坦暴露情况不同。由于 FUTURE-1 和过去的研究表明波生坦 2mg/kg bid 的获益风险比有利，因此建议将该剂量用于患有 PAH 的儿童。
新的儿科制剂耐受性良好。
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