(Pre-)clinical pharmacology and activity of pazopanib, a novel multikinase angiogenesis inhibitor

Abstract

Pazopanib is a recently approved, novel tyrosine kinase inhibitor specifically designed to impair angiogenesis by abrogating vascular endothelial growth factor receptor 2 (VEGFR-2) to exert its function. Pazopanib inhibits VEGF-induced endothelial cell proliferation in vitro and angiogenesis in vivo and demonstrates antitumor activity in mouse models. Furthermore, the pazopanib concentration resulting in maximal inhibition of VEGFR-2 phosphorylation in vivo was in line with the steady-state concentration required to inhibit growth of tumor xenografts, suggesting that pazopanib's mechanism of action is indeed through VEGFR-2 inhibition. In a phase I trial, a generally well-tolerated dose was identified at which the majority of patients achieved pazopanib plasma concentrations above the concentration required for maximal in vivo inhibition of VEGFR-2 phosphorylation in preclinical models. Administered as monotherapy, evidence of antitumor activity was observed in phase II studies in several tumor types, including soft tissue sarcoma, renal cell cancer (RCC), ovarian cancer, and non-small cell lung cancer. Recently, the U.S. Food and Drug Administration granted approval for treatment with pazopanib in patients with RCC based on the longer progression-free survival time observed with this agent in a placebo-controlled, randomized trial. This review summarizes the preclinical and clinical pharmacokinetics and pharmacodynamics of pazopanib, as well as data on clinical activity, that ultimately resulted in its recent approval.

Figure 1.

VEGFR-2 downstream pathway. By binding to the intracellular domain of VEGFR-2, pazopanib abrogates this pathway. Abbreviations: BAD, Bcl-2-associated death promoter; Casp-9, caspase 9; cPLA₂, cytosolic phospholipases A2; DAG, diacyl glycerol; eNOS, endothelial nitric oxide synthase; Erk, extracellular signal–related kinase; FAK, focal adhesion kinase; FKHR, forkhead box O1; Grb2, growth factor receptor-bound protein 2; IP₃, inositol 1,4,5-trisphosphate; MEK, mitogen-activated protein kinase/extracellular signal–related kinase kinase; mTOR, mammalian target of rapamycin; PG, prostaglandin; PIP₂, phosphatidylinositol-bisphosphate; PI3K, phosphoinositide 3-kinase; PKC, protein kinase C; PLC-γ, phospholipase Cγ; SOS, son of sevenless; VEGFR, vascular endothelial growth factor receptor.

Figure 2.

Steady-state exposure to pazopanib in the individual patients in the phase I study. Reprinted from Hurwitz HI, Dowlati A, Saini S et al. Phase I trial of pazopanib in patients with advanced cancer. Clin Cancer Res 2009;15:4220–4227, with permission of the American Association for Cancer Research.