376P - Pharmacokinetics (PK) and pharmacogenetics (PG) of the MEK1/2 inhibitor, selumetinib, in Asian and Western healthy subjects: a pooled analysis

Date 10 October 2016
Event ESMO 2016 Congress
Session Poster display
Topics Clinical research
Basic Scientific Principles
Presenter Angela Dymond
Citation Annals of Oncology (2016) 27 (6): 114-135. 10.1093/annonc/mdw368
Authors A. Dymond1, C. Elks2, P. Martin3, D. Carlile4, G. Mariani5, S. Lovick6, Y. Huang7, U. Lorch8, H. Brown2, K. So5
  • 1Quantitative Clinical Pharmacology, AstraZeneca, SK10 4TF - Macclesfield/GB
  • 2Personalised Healthcare & Biomarkers, AstraZeneca, Cambridge/GB
  • 3Imed, AstraZeneca, Macclesfield/GB
  • 4Quantitative Clinical Pharmacology, AstraZeneca, Cambridge/GB
  • 5Global Medicines Development, AstraZeneca, Cambridge/GB
  • 6Biometrics And Information Sciences, AstraZeneca, Macclesfield/GB
  • 7Global Medicines Development, Biometrics & Information Sciences, AstraZeneca, Gaithersburg/US
  • 8St. George's University Of London, Richmond Pharmacology, London/GB

Abstract

Background

Selumetinib (AZD6244, ARRY-142886) is an oral, potent and highly selective, allosteric MEK1/2 inhibitor with a short half-life. PK of selumetinib may be influenced by ethnicity and genetic differences in metabolising enzymes and transporter proteins.

Methods

Pooled PK data from ten Phase I, single-dose studies of selumetinib (25, 35, 50 and 75 mg) in healthy Asian subjects (Japanese [JPN], non-Japanese Asian [NJA], or Indian [IND]) and Western subjects (white or black) were analysed. PK parameters were derived using non compartmental methods and statistical comparisons performed by ANOVA stepwise model fitting. Variants in the cytochrome P450 enzyme CYP2C19 and the transporters UGT1A1 and ABCG2 were assessed across ethnic groups: white (n = 24), black (n = 21) and Asian (n = 42), using PG data from three of these studies and standard genotyping methods. Associations with PK were analysed using linear regression.

Results

Compared with Western subjects, dose-normalised AUC and Cmax were 35% and 39% higher respectively in Asian subjects, adjusting for baseline bodyweight (Table 1). Exposure was similar among Western subjects. Geomeans for dose-normalised AUC and Cmax ranged from 2% to 18% greater for NJA and IND compared with JPN, indicating exposures are similar across Asian populations. Genetic analysis showed that allele frequencies of variants in CYP2C19, UGT1A1 and ABCG2 varied between ethnic groups. The genetic variants CYP2C19*2, CYP2C19*3, CYP2C19*17, UGT1A1*6, UGT1A1*26, and ABCG2 421C > A, did not show any clear associations with selumetinib exposure after correction for multiple testing.

Parameter Dose-normalised
AUC* Cmax
Geometric least squares mean Difference 95% CI Geometric least squares mean Difference 95% CI
All Asian (n = 72) vs. Western (n = 236) 4.284 vs. 3.982 1.353 1.246, 1.469 3.205 vs. 2.877 1.388 1.235, 1.560
Black (n = 87) vs. white (n = 149) 3.989 vs. 3.975 1.014 0.951, 1.081 2.847 vs. 2.907 0.942 0.860, 1.032
JPN (n = 27) vs. white (n = 149) 4.384 vs. 3.975 1.505 1.354, 1.673 3.280 vs. 2.907 1.453 1.251, 1.687
NJA (n = 36) vs. white (n = 149) 4.292 vs. 3.975 1.373 1.244, 1.516 3.088 vs. 2.907 1.198 1.042, 1.377
IND (n = 9) vs. white (n = 149) 4.177 vs. 3.975 1.223 1.034, 1.447 3.247 vs. 2.907 1.405 1.108, 1.781

*Western, n = 235; white, n = 148; Point estimate: adjusted ratio of geometric means; for each comparison, a value above one implies an increase in exposure vs. the comparator. Data derived from the following studies: NCT01635023, NCT01974349, NCT02056392, NCT02322749, NCT02238782, NCT02063204, NCT02063230, NCT02093728, NCT02046850, NCT01960374.

Conclusions

Selumetinib exposure was greater in Asian than Western subjects. Although allele frequencies differed between populations, there did not appear to be any associations between the genetic variants analysed and selumetinib exposure. Data provide valuable insight for the use of selumetinib in Asian populations.

Clinical trial identification

NCT01635023, NCT01974349, NCT02056392, NCT02322749, NCT02238782, NCT02063204, NCT02063230, NCT02093728, NCT02046850, NCT01960374

Legal entity responsible for the study

AstraZeneca

Funding

AstraZeneca

Disclosure

A. Dymond, S. Lovick, H. Brown: Employee of and shareholder in AstraZeneca. C. Elks, D. Carlile, G. Mariani, Y. Huang, K. So: Employee of AstraZeneca. P. Martin: Previous employee of, and current shareholder in, AstraZeneca. U. Lorch: Employee of Richmond Pharmacology, which was paid to perform trial EudraCT 2013-0003203-19 on behalf of AstraZeneca.