Clinical Pharmacokinetic and Pharmacodynamic Profile of Lenvatinib, an Orally Active, Small-Molecule, Multitargeted Tyrosine Kinase Inhibitor

• Published in: European journal of drug metabolism and pharmacokinetics Vol. 42; no. 6; pp. 903 - 914
• Main Authors: Hussein, Ziad, Mizuo, Hitoshi, Hayato, Seiichi, Namiki, Masayuki, Shumaker, Robert
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.12.2017
• Subjects: Administration, Oral; Biomedical and Life Sciences; Biomedicine; Drug Interactions; Human Physiology; Humans; Medical Biochemistry; Pharmaceutical Sciences/Technology; Pharmacology/Toxicology; Pharmacy; Phenylurea Compounds - pharmacokinetics; Phenylurea Compounds - pharmacology; Protein Kinase Inhibitors - pharmacokinetics; Protein Kinase Inhibitors - pharmacology; Protein-Tyrosine Kinases - antagonists & inhibitors; Quinolines - pharmacokinetics; Quinolines - pharmacology; Review Article; Vascular Endothelial Growth Factor; Everolimus; Hepatic Impairment; Stem Cell Factor; Metastatic Renal Cell Carcinoma
• ISSN: 0378-7966; 2107-0180
• DOI: 10.1007/s13318-017-0403-4

Lenvatinib is a multikinase inhibitor that targets vascular endothelial growth factor (VEGF) receptors 1–3, fibroblast growth factor receptors 1–4, platelet-derived growth factor receptor-alpha, and RET and KIT proto-oncogenes. Lenvatinib is approved for the treatment of radioiodine-refractory differentiated thyroid cancer in the United States (US), European Union (EU), Canada, Japan, and Switzerland. It is also approved in combination with everolimus for the treatment of advanced renal cell carcinoma following ≥1 VEGF-targeted treatment in the US and EU. In addition, lenvatinib is under investigation for the treatment of hepatocellular carcinoma. As lenvatinib becomes more widely available, a better understanding of its pharmacokinetic profile has become increasingly important. Following oral administration, lenvatinib is absorbed rapidly and is metabolized extensively prior to excretion. This metabolism is mediated by multiple pathways, and several metabolites of lenvatinib have been identified. The effect of food intake on lenvatinib exposure has also been studied and was found to not significantly influence overall exposure to the drug. Exposure to lenvatinib is increased in patients with severe hepatic impairment, indicating that dose reduction must be considered for those patients. The findings summarized here indicate that the clinical pharmacokinetic and pharmacodynamic profile for lenvatinib are predictable, with a dose-independent absorption and elimination profile that supports once-daily administration, and has minimal effects due to mild or moderate renal or hepatic impairment or drug interactions.