Pharmacokinetics of pazopanib: a review of the determinants, influencing factors and the clinical importance of therapeutic drug monitoring

OBJECTIVES: Pazopanib is an anti-angiogenic small molecule tyrosine kinase inhibitor approved for use in the treatment of advanced renal cell carcinoma and advanced soft tissue sarcoma. This review provides an overview of pazopanib pharmacokinetics and therapeutic drug monitoring. KEY FINDINGS: Pazopanib exhibits a multifaceted pharmacokinetic profile characterized by low and pH-dependent solubility, non-linear absorption, and time-dependent decreases in systemic exposure. Research to date has revealed numerous intrinsic and extrinsic factors significantly influencing pazopanib pharmacokinetics, including food interactions, use of gastric acid suppressants, drug-drug interactions with concomitant medications and genetic polymorphisms. Pazopanib plasma trough concentrations > 20.5 and ≥ 27 μg/ml are associated with improved efficacy in patients with renal cell carcinoma and soft tissue sarcoma, respectively, and increased pazopanib systemic exposure is associated with increased incidence of drug-related adverse events (e.g. hypertension). CONCLUSION: Pazopanib exhibits large variability in systemic exposure and consequently, achieving systemic exposures within a therapeutic range for optimal efficacy while minimizing toxicity, can be challenging when a fixed dose is used. Therefore, therapeutic drug monitoring may be a promising tool to optimize the efficacy of pazopanib while limiting drug-related toxicities, through personalized dose adjustments guided by monitoring plasma pazopanib concentrations. Further exploration into the influence of additional factors on pazopanib pharmacokinetics is essential for advancing pharmacokinetic-guided dosing strategies and improve treatment outcomes.