title: Pazopanib exposure decreases as a result of an ifosfamide-dependent drug-drug interaction: results of a phase I study.
abstract: BACKGROUND
  The vascular endothelial growth factor receptor (VEGFR) pathway plays a pivotal role in solid malignancies and is probably involved in chemotherapy resistance. Pazopanib, inhibitor of, among other receptors, VEGFR1-3, has activity as single agent and is attractive to enhance anti-tumour activity of chemotherapy. We conducted a dose-finding and pharmacokinetic (PK)/pharmacodynamics study of pazopanib combined with two different schedules of ifosfamide.
  
  
  METHODS
  In a 3+3+3 design, patients with advanced solid tumours received escalating doses of oral pazopanib combined with ifosfamide either given 3 days continuously or given 3-h bolus infusion daily for 3 days (9 g m(-2) per cycle, every 3 weeks). Pharmacokinetic data of ifosfamide and pazopanib were obtained. Plasma levels of placental-derived growth factor (PlGF), vascular endothelial growth factor-A (VEGF-A), soluble VEGFR2 (sVEGFR2) and circulating endothelial cells were monitored as biomarkers.
  
  
  RESULTS
  Sixty-one patients were included. Pazopanib with continuous ifosfamide infusion appeared to be safe up to 1000 mg per day, while combination with bolus infusion ifosfamide turned out to be too toxic based on a variety of adverse events. Ifosfamide-dependent decline in pazopanib exposure was observed. Increases in PlGF and VEGF-A with concurrent decline in sVEGFR2 levels, consistent with pazopanib-mediated VEGFR2 inhibition, were observed after addition of ifosfamide.
  
  
  CONCLUSIONS
  Continuous as opposed to bolus infusion ifosfamide can safely be combined with pazopanib. Ifosfamide co-administration results in lower exposure to pazopanib, not hindering biological effects of pazopanib. Recommended dose of pazopanib for further studies combined with 3 days continuous ifosfamide (9 g m(-2) per cycle, every 3 weeks) is 800 mg daily.
authors.affiliation: Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, Daniel den Hoed Cancer Center, Rotterdam, The Netherlands.
authors.forename: P
authors.initials: P
authors.lastname: Hamberg
authors.affiliation: Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors.forename: M J
authors.initials: MJ
authors.lastname: Boers-Sonderen
authors.affiliation: Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors.forename: W T A
authors.initials: WT
authors.lastname: van der Graaf
authors.affiliation: Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, Daniel den Hoed Cancer Center, Rotterdam, The Netherlands.
authors.forename: P
authors.initials: P
authors.lastname: de Bruijn
authors.affiliation: GlaxoSmithKline, Clinical Pharmacology Modeling and simulation, Research Triangle Park, NC, USA.
authors.forename: A B
authors.initials: AB
authors.lastname: Suttle
authors.affiliation: Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, Daniel den Hoed Cancer Center, Rotterdam, The Netherlands.
authors.forename: F A L M
authors.initials: FA
authors.lastname: Eskens
authors.affiliation: Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, Daniel den Hoed Cancer Center, Rotterdam, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Verweij
authors.affiliation: Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors.forename: C M L
authors.initials: CM
authors.lastname: van Herpen
authors.affiliation: Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, Daniel den Hoed Cancer Center, Rotterdam, The Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: Sleijfer
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D042783:Endothelial Cells / Q000166:cytology; D005260:Female; D006801:Humans; D007069:Ifosfamide / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007191:Indazoles; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000097:blood; D011743:Pyrimidines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013449:Sulfonamides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000097:blood; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000097:blood; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000037:antagonists & inhibitors; D055815:Young Adult
chemical_list: D007191:Indazoles; C000608036:PGF protein, human; D011257:Pregnancy Proteins; D011743:Pyrimidines; D013449:Sulfonamides; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000072483:Placenta Growth Factor; C516667:pazopanib; C581309:FLT4 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3; D007069:Ifosfamide