Clinical pharmacology, drug-drug interactions and safety of pazopanib: a review

ABSTRACT

Introduction: In the past decade, treatment options for metastatic renal cell carcinoma and soft-tissue sarcoma have expanded. Pazopanib was discovered during the screening of compounds that suppressed vascular endothelial growth factor receptor-2 (VEGFR-2). As other tyrosine kinase inhibitors (TKI), pazopanib is not totally specific for one target since it also inhibits stem-cell factor receptor (cKIT), platelet-derived growth factor receptors (PDGFRα, β), VEGFR-1 and −3.

Areas covered: Clinical pharmacology, drug-drug interactions and safety data published on pazopanib, between January 2006 and April 2016, are reviewed.

Expert opinion: This new therapy has been shown to improve progression-free survival compared with previous approaches, in renal cell cancer and soft-tissue sarcoma. However, some specific sub-populations, such as elderly patients, patients with brain metastases or with Eastern Cooperative Oncology Group Performance Status (ECOG PS) 2 or comorbidities, are poorly represented in pivotal pazopanib phase III studies. Pazopanib meets criteria defining therapies as candidates for therapeutic drug monitoring: large intra- and inter-patient pharmacokinetic variability, potential pharmacokinetic drug-drug interactions, pharmacokinetic/pharmacodynamic relationship and narrow therapeutic index. Knowledge of predictors that can be used to guide dosing regimens in the target population and in special populations needs to be improved.

KEYWORDS:

• Pazopanib
• toxicity
• metabolism
• drug-drug interactions
• clinical pharmacology
• targeted therapy
• renal cell carcinoma
• soft-tissue sarcoma

Article highlights

• Pazopanib has multiple targets, including VEGF receptors 1, 2, and 3; PDGFRα and β, and the stem cell factor receptor c-KIT.

• Results from in vitro studies demonstrated that pazopanib is mainly metabolized by cytochrome P450 (CYP) 3A4 and, to a lesser extent, by CYP1A2 and CYP2C8.

• The toxicities of pazopanib include hypertension, thrombosis and proteinuria, as well as hepatotoxicity, hypothyroidism, cardiac dysfunction (prolonged QT intervals and torsades de pointes), hair color changes, depigmentation phenomena, and gastrointestinal disturbances.

• Approval of pazopanib came with a black box warning about hepatotoxicity.

• Studies are needed in specific populations such as patients with brain metastases at diagnosis, ECOG PS 2, elderly people > 75 years old and/or patients with cardiac or renal comorbidities, and those with non-clear cell histology renal cell cancer or rare sarcoma subtypes. Concentration threshold of >20.5 µg.ml⁻¹ was associated with improved efficacy (PFS, P<0.004; tumor shrinkage, P<0.001).

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Declaration of interest

Pascaline Boudou-Rouquette had travel/accommodations expenses covered by Novartis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This manuscript was not funded.