title: Clinical Pharmacokinetics and Pharmacodynamics of Pazopanib: Towards Optimized Dosing.
abstract: Pazopanib is an inhibitor of the vascular endothelial growth factor receptor, platelet-derived growth factor receptor, fibroblast growth factor receptor and stem cell receptor c-Kit, and has been approved for the treatment of renal cell carcinoma and soft tissue sarcoma. The pharmacokinetics of pazopanib are complex and are characterized by pH-dependent solubility, large interpatient variability and low, non-linear and time-dependent bioavailability. Exposure to pazopanib is increased by both food and coadministration of ketoconazole, but drastically reduced by proton pump inhibitors. Studies have demonstrated relationships between systemic exposure to pazopanib and toxicity, such as hypertension. Furthermore, a strong relationship between pazopanib trough level ≥20 mg/L and both tumor shrinkage and progression-free survival has been established. At the currently approved daily dose of 800 mg, approximately 20% of patients do not reach this threshold and may be at risk of suboptimal treatment. As a result of this, clinical trials have explored individualized pazopanib dosing, which demonstrate the safety and feasibility of individualized pazopanib dosing based on trough levels. In summary, we provide an overview of the complex pharmacokinetic and pharmacodynamic profiles of pazopanib and, based on the available data, we propose optimized dosing strategies.
authors.affiliation: Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands. r.verheijen@nki.nl.
authors.forename: Remy B
authors.initials: RB
authors.lastname: Verheijen
authors.affiliation: Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands.|Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.affiliation: Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.|Department of Medical Oncology and Clinical Pharmacology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, The Netherlands.
authors.forename: Jan H M
authors.initials: JHM
authors.lastname: Schellens
authors.affiliation: Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands.|Department of Clinical Pharmacy, Utrecht University Medical Center, Utrecht, The Netherlands.
authors.forename: Alwin D R
authors.initials: ADR
authors.lastname: Huitema
authors.affiliation: Department of Medical Oncology and Clinical Pharmacology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, The Netherlands.
authors.forename: Neeltje
authors.initials: N
authors.lastname: Steeghs
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007191:Indazoles; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy; D011743:Pyrimidines / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D016032:Randomized Controlled Trials as Topic / Q000379:methods; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D013449:Sulfonamides / Q000008:administration & dosage* / Q000493:pharmacokinetics*
chemical_list: D020533:Angiogenesis Inhibitors; D007191:Indazoles; D011743:Pyrimidines; D017468:Receptors, Fibroblast Growth Factor; D013449:Sulfonamides; C516667:pazopanib; D017479:Receptors, Platelet-Derived Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor
keywords: Advanced Solid Tumor; Pazopanib; Renal Cell Carcinoma; Renal Cell Carcinoma Patient; Sunitinib