(Pre-)clinical pharmacology and activity of pazopanib, a novel multikinase angiogenesis inhibitor.
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.
Hamberg
Paul
P
Erasmus University Medical Center - Daniel den Hoed Cancer Center, Department of Medical Oncology, 3008 AE Rotterdam, The Netherlands. a.hamberg@erasmusmc.nl
Verweij
Jaap
J
Sleijfer
Stefan
S
D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D018572:Disease-Free Survival; D006801:Humans; D007191:Indazoles; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism; D011743:Pyrimidines / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D013449:Sulfonamides / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D007191:Indazoles; D011743:Pyrimidines; D013449:Sulfonamides; C516667:pazopanib; D040301:Vascular Endothelial Growth Factor Receptor-2