title: Role of P-glycoprotein on the brain penetration and brain pharmacodynamic activity of the MEK inhibitor cobimetinib.
abstract: Cobimetinib is a MEK inhibitor currently in clinical trials as an anticancer agent. The objectives of this study were to determine in vitro and in vivo if cobimetinib is a substrate of P-glycoprotein (P-gp) and/or breast cancer resistance protein (Bcrp1) and to assess the implications of efflux on cobimetinib pharmacokinetics (PK), brain penetration, and target modulation. Cell lines transfected with P-gp or Bcrp1 established that cobimetinib was a substrate of P-gp but not a substrate of Bcrp1. In vivo, after intravenous and oral administration of cobimetinib to FVB (wild-type; WT), Mdr1a/b(-/-), Bcrp1 (-/-), and Mdr1a/b(-/-)/Bcrp(-/-) knockout (KO) mice, clearance was similar in WT (35.5 ± 16.7 mL/min/kg) and KO animals (22.0 ± 3.6 to 27.6 ± 5.2 mL/min/kg); oral exposure was also similar between WT and KO animals. After an oral 10 mg/kg dose of cobimetinib, the mean total brain to plasma ratio (Kp) at 6 h postdose was 0.3 and 0.2 in WT and Bcrp1(-/-) mice, respectively. In Mdr1a/b(-/-) and Mdr1a/1b/Bcrp1(-/-) KO mice and WT mice treated with elacridar (a P-gp and BCRP inhibitor), Kp increased to 11, 6, and 7, respectively. Increased brain exposure in Mdr1a/b(-/-) and Mdr1a/1b/Bcrp1(-/-) KO and elacridar treated mice was accompanied by up to ∼65% suppression of the target (pErk) in brain tissue, compared to WT mice. By MALDI imaging, the cobimetinib signal intensity was relatively high and was dispersed throughout the brain of Mdr1a/1b/Bcrp1(-/-) KO mice compared to low/undetectable signal intensity in WT mice. The efflux of cobimetinib by P-gp may have implications for the treatment of patients with brain tumors/metastases.
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Edna F
authors.initials: EF
authors.lastname: Choo
authors.forename: Justin
authors.initials: J
authors.lastname: Ly
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Chan
authors.forename: Sheerin K
authors.initials: SK
authors.lastname: Shahidi-Latham
authors.forename: Kirsten
authors.initials: K
authors.lastname: Messick
authors.forename: Emile
authors.initials: E
authors.lastname: Plise
authors.forename: Cristine M
authors.initials: CM
authors.lastname: Quiason
authors.forename: Lulu
authors.initials: L
authors.lastname: Yang
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000502:physiology*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D000818:Animals; D001384:Azetidines / Q000493:pharmacokinetics* / Q000494:pharmacology; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002853:Chromatography, Liquid; D018432:Drug Resistance, Multiple / Q000187:drug effects; D005260:Female; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors*; D051379:Mice; D018345:Mice, Knockout; D010880:Piperidines / Q000493:pharmacokinetics* / Q000494:pharmacology; D053719:Tandem Mass Spectrometry; D014018:Tissue Distribution; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D001384:Azetidines; D048369:MAP Kinase Kinase 1; D010880:Piperidines; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C501412:Abcg2 protein, mouse; C095122:multidrug resistance protein 3; C574276:cobimetinib
keywords: P-glycoprotein; brain penetration; breast cancer resistance protein; cobimetinib