Absorption, distribution, metabolism and excretion (ADME) of the ALK inhibitor alectinib: results from an absolute bioavailability and mass balance study in healthy subjects. (4th March 2017)

• Record Type: Journal Article
• 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
• Is Part Of: Xenobiotica. Volume 47:Number 3(2017)
• Page Start: 217
• Page End: 229
• Publication Date: 2017-03-04
• Subjects: Intravenous -- metabolites -- microtracer -- pharmacokinetics -- radiolabelled alectinib; Metabolism -- Periodicals; Drugs -- Physiological effect -- Periodicals; Food additives -- Periodicals; Chemicals -- Physiological effect -- Periodicals; Biochemistry -- Periodicals; Pharmaceutical Preparations -- metabolism -- Periodicals; Metabolism -- Periodicals; 574.133
• DOI: 10.1080/00498254.2016.1179821
• Languages: English
• ISSNs: 0049-8254

Abstract

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.