title: Preclinical evaluation of the potential for cytochrome P450 inhibition and induction of the selective ALK inhibitor, alectinib.
abstract: 1. A novel selective anaplastic lymphoma kinase (ALK) inhibitor, alectinib, has shown remarkable efficacy and safety in patients with ALK-positive non-small-cell lung cancer (NSCLC). The purpose of this study was to evaluate in vitro the potential to inhibit and induce cytochrome P450 (CYP) isoforms for alectinib and its major metabolite M4. 2. Alectinib and M4 did not show the meaningful direct inhibition of six major CYP isoforms (CYP1A2, 2B6, 2C9, 2C19, 2D6 and 3A4) in human liver microsomes (HLM). Alectinib, but not M4, competitively inhibited CYP2C8, by which few marketed drugs are exclusively metabolized, with an inhibition constant of 1.98 μM. 3. Out of the seven CYP isoforms in HLM, alectinib and M4 showed time-dependent inhibition (TDI) of only CYP3A4, which suggests low TDI potential due to low inactivation efficiency. 4. Alectinib exhibited quite smaller induction of mRNA expression of CYP1A2, 2B6 and 3A4 genes in human hepatocytes compared to the respective positive controls, suggesting a low potential of enzyme induction. 5. In summary, the risk of alectinib causing drug-drug interactions with coadministered drugs is expected to be low due to the weak potential of CYP inhibition and induction estimated in the preclinical studies.
authors.affiliation: a Research Division , Chugai Pharmaceutical Co., Ltd. , Shizuoka , Japan.
authors.forename: Nobuo
authors.initials: N
authors.lastname: Sekiguchi
authors.affiliation: a Research Division , Chugai Pharmaceutical Co., Ltd. , Shizuoka , Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Nagao
authors.affiliation: a Research Division , Chugai Pharmaceutical Co., Ltd. , Shizuoka , Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Takanashi
authors.affiliation: a Research Division , Chugai Pharmaceutical Co., Ltd. , Shizuoka , Japan.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Kato
authors.affiliation: a Research Division , Chugai Pharmaceutical Co., Ltd. , Shizuoka , Japan.
authors.forename: Akihisa
authors.initials: A
authors.lastname: Kaneko
authors.affiliation: a Research Division , Chugai Pharmaceutical Co., Ltd. , Shizuoka , Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Morita
authors.affiliation: a Research Division , Chugai Pharmaceutical Co., Ltd. , Shizuoka , Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Shindoh
authors.affiliation: a Research Division , Chugai Pharmaceutical Co., Ltd. , Shizuoka , Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Ishigai
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D002227:Carbazoles / Q000494:pharmacology*; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism
chemical_list: D002227:Carbazoles; D065607:Cytochrome P-450 Enzyme Inhibitors; D010880:Piperidines; D003577:Cytochrome P-450 Enzyme System; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; C582670:alectinib
keywords: CYP2C8; CYP3A4; drug–drug interaction; in vitro; irreversibility; time-dependent inhibition