Pharmacokinetics and Pharmacodynamics of Tyrosine Kinase Inhibitors in the Treatment of Metastatic Renal Cell Carcinoma

Abstract

Tyrosine kinase inhibitors (TKIs) used in the treatment of metastatic renal cell carcinoma present high interindividual variability in clinical response and toxicity. In addition, high interindividual variability in pharmacokinetics (PK) of TKIs is observed which could explain therapeutic failure or elevated toxicity in some patients. Monitoring of plasma concentrations of TKIs and PK-guided dose adjustment could help to achieve plasma therapeutic levels in all the patients. The key step for applying PK-guided dosing is an established and stable over time exposure–response relationship. In this review, the current data about PK and PK/PD relationships of TKIs used in the treatment of metastatic renal cell carcinoma: axitinib, pazopanib, sunitinib and sorafenib are discussed with emphasis to reported factors of interindividual variability in plasma exposure (food intake, genetic background, biological and demographical variables and drug–drug interactions). In addition, this review provides recommendations about individualized dosing strategies based on exposure–response findings reported in the recent literature.