Metabolites of alectinib in human: their identification and pharmacological activity

Abstract

Two metabolites (M4 and M1b) in plasma and four metabolites (M4, M6, M1a and M1b) in faeces were detected through the human ADME study following a single oral administration of [14C]alectinib, a small-molecule anaplastic lymphoma kinase inhibitor, to healthy subjects. In the present study, M1a and M1b, which chemical structures had not been identified prior to the human ADME study, were identified as isomers of a carboxylate metabolite oxidatively cleaved at the morpholine ring. In faeces, M4 and M1b were the main metabolites, which shows that the biotransformation to M4 and M1b represents two main metabolic pathways for alectinib. In plasma, M4 was a major metabolite and M1b was a minor metabolite. The contribution to in vivo pharmacological activity of these circulating metabolites was assessed from their in vitro pharmacological activity and plasma protein binding. M4 had a similar cancer cell growth inhibitory activity and plasma protein binding to that of alectinib, suggesting its contribution to the antitumor activity of alectinib, whereas the pharmacological activity of M1b was insignificant.

Effect of Hepatic Impairment on the Pharmacokinetics of Alectinib

“…Both alectinib and M4 show high protein binding in vitro (≥99%) and therefore, consistent with recommendations in guidance documents, the fu% was estimated for both analytes. Alectinib and M4 fu% values did not appear substantially different between hepatic impairment and respective matched healthy subjects.…”

“…Both alectinib and M4 display high binding to plasma proteins in vitro; therefore, clinical samples were collected to investigate the effect of hepatic impairment on fu% for both analytes. Figure illustrates box plots of individual mean fu% for alectinib and M4, respectively, by hepatic function.…”

“…As both alectinib and M4 inhibit ALK with similar potency in vitro the effect of hepatic impairment on the combined exposure of alectinib and M4, adjusted for molecular weight, was determined in this study. This approach has been explored for other alectinib clinical pharmacology investigations and for other small‐molecule kinase inhibitors with active metabolites .…”

“…Given that both alectinib and M4 are pharmacologically active, with similar activity and potency against ALK , statistical analyses for C max and AUC 0‐∞ were performed on the molecularly weight adjusted combined exposure of alectinib and M4. Analyses were conducted on total and unbound PK parameters for the respective analytes.…”

Exposure–response analysis of alectinib in crizotinib-resistant ALK-positive non-small cell lung cancer

“…Patient samples were excluded if they were taken after drug administration or collected within 8 days of a documented dose deviation during the study. Both alectinib and its major metabolite, M4, have demonstrated similar in vitro potency and activity against the target ALK kinase and similar protein binding supporting that both analytes contribute to overall alectinib efficacy and safety [21]. Therefore, the combined exposure of alectinib and M4 (alectinib + M4) steady-state trough concentration adjusted for the individual molecular weights was utilized as the overall alectinib exposure measure (herein C trough,ss ) in the exposure–response analyses.…”