Pharmacokinetics and pharmacogenetics of the MEK1/2 inhibitor, selumetinib, in Asian and Western healthy subjects: a pooled analysis.

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Dymond AW, Elks C, Martin P, Carlile DJ, Mariani G, Lovick S, Huang Y, Lorch U, Brown H, So K

Pharmacokinetics and pharmacogenetics of the MEK1/2 inhibitor, selumetinib, in Asian and Western healthy subjects: a pooled analysis.

Eur J Clin Pharmacol. 2017 Jun;73(6):717-726. doi: 10.1007/s00228-017-2217-3. Epub 2017 Mar 10.

PubMed ID

28283692 [ View in PubMed

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Abstract

PURPOSE: Emerging data on selumetinib, a MEK1/2 inhibitor in clinical development, suggest a possible difference in pharmacokinetics (PK) between Japanese and Western patients. This pooled analysis sought to assess the effect of ethnicity on selumetinib exposure in healthy Western and Asian subjects, and to identify any association between genetic variants in the UGT1A1, CYP2C19 and ABCG2 genes and observed differences in selumetinib PK. METHODS: A pooled analysis of data from ten Phase I studies, one in Asian subjects (encompassing Japanese, non-Japanese Asian and Indian Asian subjects) and nine in Western subjects, was conducted. Key findings were derived from the collective exposure data across doses of 25, 35, 50 and 75 mg selumetinib; primary variables were dose-normalized AUC and Cmax. RESULTS: PK data from 308 subjects (10 studies) were available for the pooled analysis; genetic data from 87 subjects (3 studies) were available for the pharmacogenetic analysis. Dose-normalized AUC and Cmax were 35% (95% CI: 25-47%) and 39% (95% CI: 24-56%) higher in the pooled Asian group, respectively, compared with Western subjects. PK exposure parameters were similar between the Japanese, non-Japanese Asian and Indian groups. There was no evidence that the polymorphisms assessed in the genes UGT1A1, CYP2C19 and ABCG2 account for observed PK differences. CONCLUSIONS: Selumetinib exposure was higher in healthy Asian subjects compared with Western subjects, and these data provide valuable insight for clinicians to consider when treating patients of Asian ethnicity with selumetinib.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Selumetinib	Cytochrome P450 2C19	Protein	Humans	No	Substrate	Details
Selumetinib	UDP-glucuronosyltransferase 1-1	Protein	Humans	No	Substrate	Details

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Selumetinib	ATP-binding cassette sub-family G member 2	Protein	Humans	Unknown	Substrate	Details