Clinical Pharmacokinetics and Pharmacodynamics of Selumetinib

• Type of Material: Article
• Authors: Olivia Campagne, St. Jude Children’s Research Hospital; Kee Kiat Yeo, Dana-Farber/Boston Children’s Cancer and Blood Disorders Center; Jason Fangusaro, Emory University; Clinton F Stewart, St. Jude Children’s Research Hospital
• Language: English
• Date: 2020-12-23
• Publisher: ADIS INT LTD
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2020, Springer Nature Switzerland AG
• Final Published Version (URL): http://dx.doi.org/10.1007/s40262-020-00967-y
• Title of Journal or Parent Work: CLINICAL PHARMACOKINETICS
• Volume: 60
• Issue: 3
• Start Page: 283
• End Page: 303
• Grant/Funding Information: The authors received no financial compensation for the preparation of this manuscript.
• Keywords: 2ND-LINE THERAPY; CELL LUNG-CANCER; POPULATION PHARMACOKINETICS; MEK 1/2 INHIBITOR; Pharmacology & Pharmacy; HEALTHY-SUBJECTS; PHASE-II TRIAL; Life Sciences & Biomedicine; Science & Technology; PLUS DOCETAXEL; INHIBITOR AZD6244 ARRY-142886; OPEN-LABEL; PROGRESSION-FREE SURVIVAL

Abstract

Selumetinib, a highly specific mitogen-activated protein kinase 1/2 inhibitor, is approved for children older than 2 years of age with neurofibromatosis 1 who have inoperable plexiform neurofibromas. By selectively binding to mitogen-activated protein kinase 1/2 proteins, selumetinib can arrest the mitogen-activated protein kinase/extracellular signal-regulated kinase signaling pathway that regulates critical cellular responses. Selumetinib has shown promising results as a single agent or in combination with conventional chemotherapy and other targeted therapies both preclinically and clinically, in multiple cancers including pediatric low-grade glioma, non-small cell lung cancer, and melanoma, among others. The pharmacokinetic profiles of selumetinib and its active metabolite N-desmethyl selumetinib have been well characterized in both adults and children. Both compounds exhibited rapid absorption and mean terminal elimination half-lives of about 7.5 h, with minimal accumulation at steady state. Three population pharmacokinetic models have been developed in adults and children, characterizing large inter- and intra-patient variabilities, and identifying significant covariates including food intake on selumetinib absorption, weight metrics, age, co-administration of cytochrome modulators, and Asian ethnicity on selumetinib apparent oral clearance. The most common side effects associated with selumetinib are dermatologic, gastrointestinal toxicities, and fatigue. Most toxicities are mild or moderate, generally tolerated and manageable. Cardiovascular and ocular toxicities remain less frequent but can be potentially more severe and require close monitoring. Overall, selumetinib exhibits a favorable safety profile and pharmacokinetic properties, with promising activity in multiple solid tumors, supporting current and further evaluation in combination with conventional chemotherapy and other targeted agents.