Unique Metabolic Pathway of [¹⁴C]Lenvatinib after Oral Administration to Male Cynomolgus Monkey

Abstract

ABSTRACT:Lenvatinib, a potent inhibitor of multiple tyrosine kinases, including vascular endothelial growth factor receptors 2 and 3, generated unique metabolites after oral administration of [ 14 C]lenvatinib (30 mg/kg) to a male cynomolgus monkey. Lenvatinib was found to be transformed to a GSH conjugate, through displacement of an O-aryl moiety, at the quinoline part of the molecule in the liver and kidneys. The GSH conjugate underwent further hydrolysis by ␥-glutamyltranspeptidase and dipeptidases, followed by intramolecular rearrangement, to form N-cysteinyl quinoline derivatives, which were dimerized to form disulfide dimers and also formed an N,S-cysteinyl diquinoline derivative. In urine, a thioacetic acid conjugate of the quinoline was also observed as one of the major metabolites of lenvatinib. Lenvatinib is a 4-O-aryl quinoline derivative, and such compounds have been known to undergo conjugation with GSH, accompanied by release of the O-aryl moiety. Because of intramolecular rearrangement in the case of lenvatinib, hydrolysis of the GSH conjugate yielded N-cysteinylglycine and N-cysteine conjugates instead of the corresponding S-conjugates. Because the N-substituted derivatives possess free sulfhydryl groups, dimerization through disulfide bonds and another nucleophilic substitution reaction with lenvatinib resulted in the formation of disulfanyl dimers and an N,S-cysteinyl diquinoline derivative, respectively. Characteristic product ions at m/z 235 and m/z 244, which were associated with thioquinoline and N-ethylquinoline derivatives, respectively, were used to differentiate S-and N-derivatives in this study. On the basis of accurate mass and NMR measurements, a unique metabolic pathway for lenvatinib in monkey and the proposed formation mechanism have been elucidated.

Safety and Pharmacokinetics of Lenvatinib in Patients with Advanced Hepatocellular Carcinoma

“…Recently, Schlumberger and colleagues in a phase III, double-blind, placebo-controlled trial in patients with radioiodine-refractory differentiated thyroid cancer (SELECT) demonstrated improved progression-free survival and manageable safety profiles with lenvatinib 24 mg once daily (21). However, since lenvatinib is metabolized in the liver (22) through a cytochrome P450 3A (CYP3A)-based mechanism (23), the impaired hepatic function in patients with HCC may affect lenvatinib exposure, and drug doses used in other tumor types may not be appropriate in this patient group (24,25). Therefore, dose-finding studies have been recommended in patients with HCC stratified by Child-Pugh (CP) classes A and B (26).…”

Effect of Rifampicin on the Pharmacokinetics of Lenvatinib in Healthy Adults

“…In vitro and in vivo studies have demonstrated that lenvatinib is metabolized in both liver and kidney, and it is primarily excreted directly in bile [8, 9]. In a radiolabelled human mass balance study examining total lenvatinib (parent + metabolites), ~64 % of the radioactivity was recovered in the faeces and ~25 % in urine, with only 2.5 % of the administered lenvatinib dose recovered intact [8].…”

Drug Therapy for Advanced-Stage Liver Cancer

“…While still quite a few phase-III trials in the first-line setting for HCC are ongoing, testing drugs like Lenvatinib (www.clinicaltrials.gov; NCT01761266), a multikinase TKI inhibiting VEGFR2 and 3 [26], drug treatment for advanced stage HCC beyond sorafenib does not seem to be an easy target for drug development. Currently, a major search for informative biomarkers is taking place that should allow a more targeted approach in subgroups of patients with specific molecular profiles.…”