title: Effect of Food and Esomeprazole on the Pharmacokinetics of Alectinib, a Highly Selective ALK Inhibitor, in Healthy Subjects.
abstract: Alectinib, an anaplastic lymphoma kinase (ALK) inhibitor, is approved for treatment of patients with ALK+ non-small cell lung cancer who have progressed, on or are intolerant to, crizotinib. This study assessed the effect of a high-fat meal and the proton pump inhibitor, esomeprazole, on the pharmacokinetics (PK) of alectinib. This was an open-label, 2-group study in healthy subjects. In group 1 (n = 18), subjects were randomly assigned to a 2-treatment (A, fasted conditions; B, following a high-fat meal), 2-sequence (AB or BA) crossover assessment, separated by a 10-day washout. In group 2 (n = 24), subjects were enrolled in a 2-period, fixed-sequence crossover assessment to evaluate the effect of esomeprazole. PK parameters were evaluated for alectinib, its major similarly active metabolite, M4, and the combined exposure of alectinib and M4. Administration of alectinib following a high-fat meal substantially increased the combined exposure of alectinib and M4 to 331% (90%CI, 279%-393%) and 311% (90%CI, 273%-355%) for Cmaxand AUC0-∞, respectively, versus fasted conditions. Coadministration of esomeprazole had no clinically relevant effect on the combined exposure of alectinib and M4. Alectinib should be administered under fed conditions to maximize its bioavailability, whereas no restrictions are required with antisecretory agents.
authors.affiliation: Roche Innovation Center, New York, NY, USA.
authors.forename: Peter N
authors.initials: PN
authors.lastname: Morcos
authors.affiliation: Roche Innovation Center, Basel, Switzerland.
authors.forename: Elena
authors.initials: E
authors.lastname: Guerini
authors.affiliation: Roche Innovation Center, Basel, Switzerland.
authors.forename: Neil
authors.initials: N
authors.lastname: Parrott
authors.affiliation: d3 Medicine, Parsippany, NJ, USA.
authors.forename: Georgina
authors.initials: G
authors.lastname: Dall
authors.affiliation: Roche Innovation Center, New York, NY, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Blotner
authors.affiliation: Roche Innovation Center, Basel, Switzerland.
authors.forename: Katrijn
authors.initials: K
authors.lastname: Bogman
authors.affiliation: Roche Innovation Center, Basel, Switzerland.
authors.forename: Carolina
authors.initials: C
authors.lastname: Sturm
authors.affiliation: Roche Innovation Center, Basel, Switzerland.
authors.forename: Bogdana
authors.initials: B
authors.lastname: Balas
authors.affiliation: Roche Innovation Center, Basel, Switzerland.
authors.forename: Meret
authors.initials: M
authors.lastname: Martin-Facklam
authors.affiliation: Roche Products Ltd, Welwyn, UK.
authors.forename: Alex
authors.initials: A
authors.lastname: Phipps
mesh_terms: D000328:Adult; D019540:Area Under Curve; D002227:Carbazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D059305:Diet, High-Fat; D004347:Drug Interactions; D064098:Esomeprazole / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D010880:Piperidines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011897:Random Allocation; D055815:Young Adult
chemical_list: D002227:Carbazoles; D010880:Piperidines; D047428:Protein Kinase Inhibitors; C582670:alectinib; D064098:Esomeprazole
keywords: alectinib; esomeprazole; food effect; pharmacokinetics; tyrosine kinase inhibitor