Expert opinion on drug metabolism & toxicology · 2024
Evaluating the drug-drug interactions of SHR4640 on repaglinide and midazolam in healthy subjects.
СтатьяРандомизированное исследованиеНазвание и аннотация: Перевод пока не подготовлен
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Cheng Yuanzhi, Hu Xiaotong, Pei Zejun, Zhang Zhe, Lin Hongda, Feng Sheng, Gao Zhenyan, Ma Yanlin, Cao Zhihai, Zhang Qian, Zheng Liang, Zhang Wei, Shen Kai, Hu Wei
Аннотация
BACKGROUND: SHR4640, a highly selective URAT1 inhibitor, was evaluated to investigate its inhibitory effects on CYP2C8 and CYP3A4 in vivo clinical trial. This study assessed the pharmacokinetic (PK) impact of SHR4640 when co-administered with the CYP2C8 probe substrate repaglinide and the CYP3A4 probe substrate midazolam.
RESEARCH DESIGN AND METHODS: In this single-center, randomized, double-blind, placebo-controlled study, participants were randomly allocated in a 1:1:1 ratio to SHR4640 Group A, SHR4640 Group B, and placebo group and received oral repaglinide, midazolam, SHR4640 or placebo at specific times. The primary endpoints included the main PK parameters of repaglinide and midazolam, both alone and in combination with SHR4640 (AUC0-inf, AUC0-t, and Cmax).
RESULTS: The increase in the area under the concentration-time curve (AUC) for repaglinide, when co-administered with SHR4640, was less than 1.25-fold, while the AUC for midazolam exhibited a slight increase of 46%.
CONCLUSIONS: SHR4640 exerts a weak inhibitory effect on the AUC of CYP enzyme probe substrates and has minimal potential for drug-drug interactions and presents a favorable safety profile.
CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov identifier is NCT06196580 (Name: PK Effects of SHR4640 on Repaglinide and Midazolam, and the Impact of SHR4640 on QT Interval).
RESEARCH DESIGN AND METHODS: In this single-center, randomized, double-blind, placebo-controlled study, participants were randomly allocated in a 1:1:1 ratio to SHR4640 Group A, SHR4640 Group B, and placebo group and received oral repaglinide, midazolam, SHR4640 or placebo at specific times. The primary endpoints included the main PK parameters of repaglinide and midazolam, both alone and in combination with SHR4640 (AUC0-inf, AUC0-t, and Cmax).
RESULTS: The increase in the area under the concentration-time curve (AUC) for repaglinide, when co-administered with SHR4640, was less than 1.25-fold, while the AUC for midazolam exhibited a slight increase of 46%.
CONCLUSIONS: SHR4640 exerts a weak inhibitory effect on the AUC of CYP enzyme probe substrates and has minimal potential for drug-drug interactions and presents a favorable safety profile.
CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov identifier is NCT06196580 (Name: PK Effects of SHR4640 on Repaglinide and Midazolam, and the Impact of SHR4640 on QT Interval).
Предметные рубрики MeSH
HumansMidazolamDrug InteractionsCarbamatesPiperidinesMaleAdultDouble-Blind MethodYoung AdultCytochrome P-450 CYP3AHealthy VolunteersArea Under CurveFemaleCytochrome P-450 CYP2C8 InhibitorsHypoglycemic AgentsCytochrome P-450 CYP2C8Administration, OralMiddle AgedCytochrome P-450 CYP3A InhibitorsCyclobutanesPyrrolesQuinolinesSulfones