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新規TRH類縁体であるロバチレリンの体内動態に関する研究

小林 薫 北里大学

2021.07.20

概要

脊髄小脳変性症(SCD)は、小脳や脊髄の神経や伝導路に病変の主座を持ち、進行性の小脳性運動失調を主徴とする神経変性疾患の1つであり、神経難病として特定疾患に指定されている。SCD患者は日本国内で3万人を超えると推定され、SCDは希少疾患の範疇に入る。SCDの根治療法は未だになく、現状では諸症状に対する対症療法が行われている。SCDに伴う運動失調は、患者の日常生活動作と生活の質を著しく低下させるだけでなく、患者家族の介護負担を増大させることから、SCDの治療において運動失調を改善させる意義は極めて大きい。

これまでに甲状腺刺激ホルモン放出ホルモン(TRH)がSCD治療に有効であることが臨床において示されており、国内においてはプロチレリン酒石酸塩水和物(合成TRH)及びタルチレリン水和物(TRH類縁体)のみ保険適用が認められ、SCD患者に処方されている。プロチレリンは、血中半減期が短いこと(4~5分)、中枢移行性が低いこと及びバイオアベイラビリティが低いこと(2.0%)から、静脈内又は筋肉内注射で投与される。これらの欠点を改善したタルチレリンでは、Smg錠を1日2回投与する経口剤として処方されている。SCDの運動失調に対してこれら両薬剤以外には有効性を示す治療薬はなく、両薬剤よりも中枢作用や効果持続性が改善された経口投与可能な治療薬の早期開発が切望されている。

ロバチレリンは既存薬よりも良好な経口吸収性、中枢移行性及び代謝安定性を有するSCD治療薬を目指して創製された新規TRHT類縁体であり、その有効性及び安全性を確認する非臨床及び臨床試験が実施され、研究開発が進められている。

本研究では、ロバチレリンの体内動態を明らかにすることを目的とし、第1章ではラット及びイスを用いて非臨床における吸収、分布、代謝及び排泄を評価した。また、既存薬であるタルチレリンの体内動態との比較からロバチレリンの新規経日SCD治療薬としての可能性を考察した。第2章では、健康成人男性における単回経口投与後のロバチレリンの吸収、代謝及び排泄を評価した。また、invitro試験によりヒトにおけるロバチレリンの主要代謝物生成酵素を特定した。第3章では、第2章の結果からシトクロムP450(CYP)3A4/S阻害薬との併用による薬物相互作用(DDI)が懸念されたため、臨床DDI試験を実施し、ロバチレリンの体内動態に及ぼすイトラコナゾール(CYP3A4/S及びP-sp阻害薬)の影響について評価した。さらに、invitro試験においてロバチレリンの排出トランスポーター(P-sp及びBCRP)に対する基質性を評価し、イトラコナゾールによるDDIの発生機序について考察した。

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