Absorption, distribution, metabolism and excretion (ADME) of the ALK inhibitor alectinib: results from an absolute bioavailability and mass balance study in healthy subjects

• Published in: Xenobiotica 2017-03, Vol.47 (3), p.217-229
• Main Authors: Morcos, Peter N., Yu, Li, Bogman, Katrijn, Sato, Mika, Katsuki, Hisakazu, Kawashima, Kosuke, Moore, David J, Whayman, Matt, Nieforth, Keith, Heinig, Katja, Guerini, Elena, Muri, Dieter, Martin-Facklam, Meret, Phipps, Alex
• Format: Article
• Language: English
• Subjects: Adult; Biological Availability; Carbazoles - metabolism; Carbazoles - pharmacokinetics; Cross-Over Studies; Healthy Volunteers; Humans; Intravenous; Male; metabolites; microtracer; Middle Aged; pharmacokinetics; Piperidines - metabolism; Piperidines - pharmacokinetics; Protein Kinase Inhibitors - metabolism; Protein Kinase Inhibitors - pharmacokinetics; radiolabelled alectinib; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors; Tissue Distribution
• ISSN: 0049-8254; 1366-5928
• DOI: 10.1080/00498254.2016.1179821

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.