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

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.