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.

• Intravenous
• metabolites
• microtracer
• pharmacokinetics
• radiolabelled alectinib

Acknowledgments

The authors would like to thank the investigators and subjects for their contribution to this clinical study. Third-party medical writing assistance, under the direction of the authors, was provided by Rhiannon Owen and Louise Clarke of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd. The authors would like to thank Chugai colleagues Kenji Takanashi and Dr. Toshito Nakagawa for the preclinical characterisation of alectinib pharmacokinetics and metabolism. Additionally, the authors thank Dr. Stephen Fowler, Dr. Masaki Ishigai and Kazuhiro Nishimiya for review and valuable inputs into the manuscript.

Declaration of interest

P.N. Morcos, L. Yu, K Bogman, D Moore, M Whayman, K Heinig, E Guerini, D Muri, M Martin-Facklam and A Phipps are employees of Roche. M Sato, H Katsuki and K Kawashima are employees of Chugai Pharmaceutical. K Nieforth is an employee of d³ medicine.

This work was supported by F. Hoffmann-La Roche (study number NP28989).

Previous presentations

Morcos PN, Yu L, Nieforth K, et al. (2016d). Absorption, distribution, metabolism and excretion (ADME) of the ALK inhibitor alectinib: results from an absolute bioavailability/mass balance study in healthy subjects. Clin Pharmacol Ther; 99. Abstract PI-118.