title: Absorption, distribution, metabolism and excretion (ADME) of the ALK inhibitor alectinib: results from an absolute bioavailability and mass balance study in healthy subjects.
abstract: 1. Alectinib is a highly selective, central nervous system-active small molecule anaplastic lymphoma kinase inhibitor. 2. The absolute bioavailability, metabolism, excretion and pharmacokinetics of alectinib were studied in a two-period single-sequence crossover study. A 50 μg radiolabelled intravenous microdose of alectinib was co-administered with a single 600 mg oral dose of alectinib in the first period, and a single 600 mg/67 μCi oral dose of radiolabelled alectinib was administered in the second period to six healthy male subjects. 3. The absolute bioavailability of alectinib was moderate at 36.9%. Geometric mean clearance was 34.5 L/h, volume of distribution was 475 L and the hepatic extraction ratio was low (0.14). 4. Near-complete recovery of administered radioactivity was achieved within 168 h post-dose (98.2%) with excretion predominantly in faeces (97.8%) and negligible excretion in urine (0.456%). Alectinib and its major active metabolite, M4, were the main components in plasma, accounting for 76% of total plasma radioactivity. In faeces, 84% of dose was excreted as unchanged alectinib with metabolites M4, M1a/b and M6 contributing to 5.8%, 7.2% and 0.2% of dose, respectively. 5. This novel study design characterised the full absorption, distribution, metabolism and excretion properties in each subject, providing insight into alectinib absorption and disposition in humans.
authors.affiliation: a Roche Innovation Center , New York , NY , United States.
authors.forename: Peter N
authors.initials: PN
authors.lastname: Morcos
authors.affiliation: a Roche Innovation Center , New York , NY , United States.
authors.forename: Li
authors.initials: L
authors.lastname: Yu
authors.affiliation: b Roche Innovation Center , Basel , Switzerland.
authors.forename: Katrijn
authors.initials: K
authors.lastname: Bogman
authors.affiliation: c Chugai Pharmaceuticals, Co. Ltd , Shizuoka , Japan.
authors.forename: Mika
authors.initials: M
authors.lastname: Sato
authors.affiliation: d Chugai Pharmaceutical, Co. Ltd , Tokyo , Japan.
authors.forename: Hisakazu
authors.initials: H
authors.lastname: Katsuki
authors.affiliation: c Chugai Pharmaceuticals, Co. Ltd , Shizuoka , Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Kawashima
authors.affiliation: a Roche Innovation Center , New York , NY , United States.
authors.forename: David J
authors.initials: DJ
authors.lastname: Moore
authors.affiliation: e Roche Products Ltd , Welwyn , UK , and.
authors.forename: Matt
authors.initials: M
authors.lastname: Whayman
authors.affiliation: f d3 Medicine, Parsippany , NJ , USA.
authors.forename: Keith
authors.initials: K
authors.lastname: Nieforth
authors.affiliation: b Roche Innovation Center , Basel , Switzerland.
authors.forename: Katja
authors.initials: K
authors.lastname: Heinig
authors.affiliation: b Roche Innovation Center , Basel , Switzerland.
authors.forename: Elena
authors.initials: E
authors.lastname: Guerini
authors.affiliation: b Roche Innovation Center , Basel , Switzerland.
authors.forename: Dieter
authors.initials: D
authors.lastname: Muri
authors.affiliation: b Roche Innovation Center , Basel , Switzerland.
authors.forename: Meret
authors.initials: M
authors.lastname: Martin-Facklam
authors.affiliation: e Roche Products Ltd , Welwyn , UK , and.
authors.forename: Alex
authors.initials: A
authors.lastname: Phipps
mesh_terms: D000328:Adult; D000077548:Anaplastic Lymphoma Kinase; D001682:Biological Availability; D002227:Carbazoles / Q000378:metabolism* / Q000493:pharmacokinetics; D018592:Cross-Over Studies; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D010880:Piperidines / Q000378:metabolism* / Q000493:pharmacokinetics; D047428:Protein Kinase Inhibitors / Q000378:metabolism* / Q000493:pharmacokinetics; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D014018:Tissue Distribution
chemical_list: D002227:Carbazoles; D010880:Piperidines; D047428:Protein Kinase Inhibitors; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; C582670:alectinib
keywords: Intravenous; metabolites; microtracer; pharmacokinetics; radiolabelled alectinib