Identification, structural elucidation and nonclinical characterisation of oxMET...

연구 요약

Identification, structural elucidation and nonclinical characterisation of oxMET1: a further major metabolite of xevinapant?

Xenobiotica; the fate of foreign compounds in biological systems 학술지에 발표된 이 연구는 Lang B, Schieferstein H, Scheible H 외 연구팀이 수행하였습니다.

이 연구는 'Identification, structural elucidation and nonclinical characterisation of oxMET1: a further major metabolite of xevinapant?'에 대한 과학적 분석을 제공합니다.

핵심 내용

Xevinapant, an oral IAP (inhibitor of apoptosis protein) inhibitor, was clinically investigated for the treatment of various cancers. A novel metabolite of xevinapant, oxidated D-1143-MET1 (oxMET1), was identified in the human mass balance study, which had not been detected in previous non- and clinical studies but represented almost 10% of the total drug exposure after single-dose administration and was therefore pinpointed for its structural and initial nonclinical characterization.Using high-resolution mass spectrometry (HRMS) and nuclear magnetic resonance (NMR) spectroscopy after a semi-preparative isolation of oxMET1 it was possible to determine its definitive structure.OxMET1 exhibited only negligible inhibitory activity on cIAP1 in vitro, and thus, taking the low unbound fraction in human plasma into account, contribution to in vivo efficacy was considered low.In addition, coverage of human exposure could be shown in plasma samples from toxicity studies performed with preclinical species, so oxMET1, although likely major, was not a disproportionate circulating metabolite in humans. Based on these findings, this metabolite did not raise safety concerns according to the MIST guidelines, however it warrants further characterisation of its drug-drug interaction (DDI) potential. The integrated workflow presented here highlights the importance of metabolite characterization in drug development.

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의사/약사의 전문적 판단을 대체하지 않습니다 (PMID: 41697154)