对轻度或中度肝功能损害或肝功能正常的参与者进行索替列司他药代动力学和安全性的 1 期研究。

IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pharmacology Research & Perspectives Pub Date : 2024-08-01 DOI:10.1002/prp2.1213
Wei Yin, Pranab Mitra, Veronique Copalu, Thomas C Marbury, Juan Carlos Rondon, Eric J Lawitz, Valerie Lloyd, Mike Baratta, Mahnaz Asgharnejad, Tom Hui, Yasir Khan
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引用次数: 0

摘要

这项1期、开放标签、三臂研究(NCT05098054)比较了肝功能受损患者服用索替列司他(TAK-935)的药代动力学和安全性。与健康匹配的参与者相比,中度肝功能损害者的药代动力学比约高115%,轻度肝功能损害者的药代动力学比约高216%,中度肝功能损害者的药代动力学比约高199%,轻度肝功能损害者的药代动力学比约高45%,轻度肝功能损害者的药代动力学比约高35%,轻度肝功能损害者的药代动力学比约高30%。中度肝功能损害会降低肝脏将索替司他代谢为 M-I 的能力;葡萄糖醛酸化为 M3 的能力也会受到影响。轻度肝功能损害导致血浆 M-I 总暴露量降低,但葡萄糖醛酸化不受影响。各研究臂的 TEAEs 相似且轻微,未观察到新的安全性发现。中度而非轻度肝功能损害患者需要减少索替司他的剂量。
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Phase 1 pharmacokinetic and safety study of soticlestat in participants with mild or moderate hepatic impairment or normal hepatic function.

This phase 1, open-label, three-arm study (NCT05098054) compared the pharmacokinetics and safety of soticlestat (TAK-935) in participants with hepatic impairment. Participants aged ≥18 to <75 years had moderate (Child-Pugh B) or mild (Child-Pugh A) hepatic impairment or normal hepatic function (matched to hepatic-impaired participants by sex, age, and body mass index). Soticlestat was administered as a single oral 300 mg dose. Pharmacokinetic parameters of soticlestat and its metabolites TAK-935-G (M3) and M-I were assessed and compared by group. The incidence of treatment-emergent adverse events (TEAEs) and other safety parameters were also monitored. The pharmacokinetic analyses comprised 35 participants. Participants with moderate hepatic impairment had lower proportions of bound and higher proportions of unbound soticlestat than participants with mild hepatic impairment and normal hepatic function. Total plasma soticlestat pharmacokinetic parameters (maximum observed concentration [Cmax], area under the concentration-time curve from time 0 to time of last quantifiable concentration [AUClast], and AUC from time 0 to infinity [AUC]) were approximately 115%, 216%, and 199% higher with moderate and approximately 45%, 35%, and 30% higher with mild hepatic impairment, respectively, than healthy matched participants. Moderate hepatic impairment decreased the liver's ability to metabolize soticlestat to M-I; glucuronidation to M3 was also affected. Mild hepatic impairment resulted in a lower total plasma M-I exposure, but glucuronidation was unaffected. TEAEs were similar across study arms, mild, and no new safety findings were observed. A soticlestat dose reduction is required for individuals with moderate but not mild hepatic impairment.

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来源期刊
Pharmacology Research & Perspectives
Pharmacology Research & Perspectives Pharmacology, Toxicology and Pharmaceutics-General Pharmacology, Toxicology and Pharmaceutics
CiteScore
5.30
自引率
3.80%
发文量
120
审稿时长
20 weeks
期刊介绍: PR&P is jointly published by the American Society for Pharmacology and Experimental Therapeutics (ASPET), the British Pharmacological Society (BPS), and Wiley. PR&P is a bi-monthly open access journal that publishes a range of article types, including: target validation (preclinical papers that show a hypothesis is incorrect or papers on drugs that have failed in early clinical development); drug discovery reviews (strategy, hypotheses, and data resulting in a successful therapeutic drug); frontiers in translational medicine (drug and target validation for an unmet therapeutic need); pharmacological hypotheses (reviews that are oriented to inform a novel hypothesis); and replication studies (work that refutes key findings [failed replication] and work that validates key findings). PR&P publishes papers submitted directly to the journal and those referred from the journals of ASPET and the BPS
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