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

Tsutomu Saji; 佐地勉; Toshio Nakanishi; 中西敏雄; Osamu Yamada; 山田修; Shozaburo Doi; 土井庄三郎; Hideaki Ueda; 上田秀明; Ryo Inuzuka; 犬塚亮; Jyunpei Somura; 宗村純平; Jasper Dingemanse; JasperDingemanse; Motonori Hatta; 八田基稔; Yoshinari Yokoyama; 横山由斉

doi:10.9794/jspccs.34.22

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

佐地勉¹^,†，中西敏雄²，山田修³，土井庄三郎⁴，上田秀明⁵，犬塚亮⁶，宗村純平⁷，Jasper Dingemanse⁸，八田基稔⁹，横山由斉⁹Tsutomu Saji¹^,†, Toshio Nakanishi², Osamu Yamada³, Shozaburo Doi⁴, Hideaki Ueda⁵, Ryo Inuzuka⁶, Jyunpei Somura⁷, Jasper Dingemanse⁸, Motonori Hatta⁹, Yoshinari Yokoyama⁹

¹ 東邦大学医学部心血管病研究先端統合講座Advanced and Integrated Cardiovascular Research Course in the Young and Adolescence, Toho University ◇ Tokyo, Japan

² 東京女子医科大学成人先天性心疾患病態学寄附研究部門Pediatric Cardiology, Tokyo Women’s Medical University ◇ Tokyo, Japan

³ 国立循環器病研究センター小児循環器科Department of Pediatrics, National Cerebral and Cardiovascular Center ◇ Osaka, Japan

⁴ 東京医科歯科大学大学院医歯学総合研究科小児・周産期地域医療学講座（小児）Department of Pediatrics, Perinatal and Maternal Medicine, Tokyo Medical and Dental University, Graduate School ◇ Tokyo, Japan

⁵ 神奈川県立こども医療センター循環器内科Department of Cardiology, Kanagawa Children's Medical Center ◇ Kanagawa, Japan

⁶ 東京大学小児科Department of Pediatrics, Tokyo University ◇ Tokyo, Japan

⁷ 滋賀医科大学小児科Department of Pediatrics, Shiga University of Medical Science ◇ Shiga, Japan

⁸ Actelion Pharmaceuticals Ltd.Clinical Pharmacology, Actelion Pharmaceuticals Ltd. ◇ Actelion Pharmaceuticals Ltd., Allschwil, Switzerland

⁹ アクテリオンファーマシューティカルズジャパン株式会社研究開発本部Research and Development, Actelion Pharmaceuticals Japan Ltd. ◇ Tokyo, Japan

^†2017年5月22日逝去．Deceased 22 May 2017.

受付日：2017年2月10日Received: February 10, 2017

受理日：2018年1月12日Accepted: January 12, 2018

発行日：2018年1月1日Published: January 1, 2018

背景：日本人小児PAH患者に対するボセンタン（BOS）新規小児用製剤の有効性，薬物動態，安全性，及び忍容性を検討する目的で治験を実施した．

方法：本研究は非盲検，単群，多施設共同，第3相試験として実施した．投与対象は15歳未満のPAH患者とし，BOS新規小児用製剤を2 mg/kg，1日2回（4 mg/kg/日）投与した．治験期間は12週までの有効性評価期間，その後の継続期間及び製造販売後臨床試験期間の2プロトコルで実施した．主要評価項目はベースライン値から12週後の右心カテーテル検査で肺血管抵抗係数（PVRI）の変化とし，副次評価項目は，投薬終了まで12週毎のWHO機能分類（WHO-FC）の変化等とした．さらに，薬物動態として血中濃度，曝露量，最高濃度到達時間を評価し，安全性及び忍容性では有害事象，投与中止に至った有害事象等を評価した．

結果：患者数は6例，中央値5.5歳（1～13歳），男：女は4 : 2であった．投与後のPVRIは平均4.0±258.6 dyn·sec·m²/cm⁵低下したが統計学的な有意差は認めなかった．WHO-FCは，全例IIで不変であり，BOSの血漿中薬物濃度の幾何平均値は，最高血漿中濃度が494 ng/mL，1投与間隔の薬物血漿中濃度–時間曲線下面積が2300 ng·h/mLであった．安全性及び忍容性は良好であった．

結論：日本人小児PAH患者に対するBOS新規小児用製剤の安全性と忍容性が確認された．有効性評価項目である平均PVRI及びWHO-FCの悪化はなかった．

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.

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 (T_max). To assess safety and tolerability, adverse events were evaluated, including those leading to study drug discontinuation.

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 C_max of bosentan and AUC_tau were 494 ng/mL and 2300 ng·h/mL, respectively. Safety and tolerability were satisfactory.

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.

Key words: Bosentan; children; endothelin receptor antagonist; new formulation; pulmonary arterial hypertension

日本小児循環器学会雑誌 Pediatric Cardiology and Cardiac Surgery

原著Original