Abstract
Lenvatinib is a tyrosine kinase inhibitor of the vascular endothelial growth factor receptor used against nonoperative thyroid cancer; however, hypertension is a major dose-limiting side effect. In this study, hypertension caused by lenvatinib was described through a novel population pharmacodynamic model using postmarketing surveillance data obtained in Japan. The model consists of two maximum effect model components based on the (1) concentration of lenvatinib in plasma and (2) cumulative area under the curve of lenvatinib. In addition, antihypertensive drug of either an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker or calcium channel blocker accounted for by lowering effect on diastolic blood pressure. Based on virtual simulations, the combination of antihypertensive drug and dose adjustment of lenvatinib showed a reduction in the probability of grade greater than or equal to 3 hypertension. The present model provides useful guidance in managing hypertension during treatment with lenvatinib in the real-world setting.
© 2021 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.
MeSH terms
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Aged
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Angiotensin Receptor Antagonists / pharmacology
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Angiotensin-Converting Enzyme Inhibitors / pharmacology
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Antihypertensive Agents / pharmacology
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Area Under Curve
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Blood Pressure / drug effects
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Calcium Channel Blockers / pharmacology
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Dose-Response Relationship, Drug
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Drug-Related Side Effects and Adverse Reactions
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Female
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Humans
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Hypertension / chemically induced*
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Hypertension / drug therapy
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Japan / epidemiology
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Male
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Middle Aged
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Phenylurea Compounds / administration & dosage
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Phenylurea Compounds / adverse effects
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Phenylurea Compounds / pharmacokinetics*
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Phenylurea Compounds / pharmacology
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Product Surveillance, Postmarketing / methods*
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Product Surveillance, Postmarketing / statistics & numerical data
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Protein Kinase Inhibitors / administration & dosage
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Protein Kinase Inhibitors / adverse effects
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Protein Kinase Inhibitors / pharmacokinetics*
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Protein Kinase Inhibitors / pharmacology
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Quinolines / administration & dosage
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Quinolines / adverse effects
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Quinolines / pharmacokinetics*
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Quinolines / pharmacology
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Thyroid Neoplasms / drug therapy*
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Vascular Endothelial Growth Factor A
Substances
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Angiotensin Receptor Antagonists
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Angiotensin-Converting Enzyme Inhibitors
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Antihypertensive Agents
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Calcium Channel Blockers
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Phenylurea Compounds
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Protein Kinase Inhibitors
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Quinolines
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Vascular Endothelial Growth Factor A
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lenvatinib