Clinical Use of Pediatric Bosentan in Japanese Children with Pulmonary Arterial Hypertension: Investigation of Efficacy, Pharmacokinetics, Safety, and Tolerability

DOI Web Site 13 References
  • Saji Tsutomu
    Advanced and Integrated Cardiovascular Research Course in the Young and Adolescence, Toho University
  • Nakanishi Toshio
    Pediatric Cardiology, Tokyo Women’s Medical University
  • Yamada Osamu
    Department of Pediatrics, National Cerebral and Cardiovascular Center
  • Doi Shozaburo
    Department of Pediatrics, Perinatal and Maternal Medicine, Tokyo Medical and Dental University, Graduate School
  • Ueda Hideaki
    Department of Cardiology, Kanagawa Children's Medical Center
  • Inuzuka Ryo
    Department of Pediatrics, Tokyo University
  • Somura Jyunpei
    Department of Pediatrics, Shiga University of Medical Science
  • Dingemanse Jasper
    Clinical Pharmacology, Actelion Pharmaceuticals Ltd.
  • Hatta Motonori
    Research and Development, Actelion Pharmaceuticals Japan Ltd.
  • Yokoyama Yoshinari
    Research and Development, Actelion Pharmaceuticals Japan Ltd.

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Other Title
  • 日本人小児肺動脈性肺高血圧症患者に対するボセンタン新規小児用製剤の治験成績：有効性，薬物動態，安全性，及び忍容性の検討

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Abstract

<p>Background: The efficacy, pharmacokinetics, safety, and tolerability of bosentan (Tracleer® 32 mg, new dispersible tablet for pediatric use) for pulmonary arterial hypertension (PAH) were investigated in Japanese children.</p><p>Methods: This was an open-label, multi-center, phase III, single-arm trial. Patients aged ＜15 years with PAH were administered a new pediatric formulation of bosentan (2 mg/kg twice per day). The efficacy of bosentan was evaluated during the first 12 weeks of the trial, and the subsequent period, including a post-marketing study, was evaluated by following a separate protocol. The primary outcome measure was a change in the pulmonary vascular resistance index (PVRI) from baseline to 12 weeks after starting treatment. Secondary outcome measures were changes in World Health Organization functional class (WHO-FC) every 12 weeks. Additionally, the pharmacokinetics of bosentan were evaluated by measuring blood concentrations, area under the curve (AUC), and time-to-peak blood concentrations (Tmax). To assess safety and tolerability, adverse events were evaluated, including those leading to study drug discontinuation.</p><p>Results: In total, 6 subjects with a median age of 5.5 years (range, 1–13 years; 4 males, 2 females) were enrolled. The mean change±standard deviation from baseline to Week 12 in PVRI was 4.0±258.6 dyn·sec·m2/cm5, which indicated no significant change in PVRI relative to the baseline value. WHO-FC II was unchanged in all patients. The geometric mean Cmax of bosentan and AUCtau were 494 ng/mL and 2300 ng·h/mL, respectively. Safety and tolerability were satisfactory.</p><p>Conclusion: A new pediatric formulation of bosentan was confirmed to be safe and well-tolerated in Japanese children with PAH. There was no worsening in the mean PVRI and WHO-FC.</p>

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