title: Individualized Pazopanib Dosing: A Prospective Feasibility Study in Cancer Patients.
abstract: OBJECTIVE
  Pazopanib is a tyrosine kinase inhibitor approved for the treatment of renal cell carcinoma and soft tissue sarcoma. Retrospective analyses have shown that an increased median progression-free survival and tumor shrinkage appear in patients with higher plasma trough levels (Cmin). Therefore, patients with low Cminmight benefit from pharmacokinetically guided individualized dosing.
  
  
  METHODS
  We conducted a prospective multicenter trial in 30 patients with advanced solid tumors. Pazopanib Cminwas measured weekly by LC-MS/MS. At weeks 3, 5, and 7, the pazopanib dose was increased if the measured Cminwas <20 mg/L and toxicity was <grade 3.
  
  
  RESULTS
  In total, 17 patients had at least one Cmin<20 mg/L at weeks 3, 5, and 7. Of these, 10 were successfully treated with a pharmacokinetically guided dose escalation, leading to daily dosages ranging from 1,000 to 1,800 mg. Cminin these patients increased significantly from 13.2 (38.0%) mg/L [mean (CV%)] to 22.9 mg/L (44.9%). Thirteen patients had all Cminlevels ≥20.0 mg/L. Of these, 9 patients with a high Cminof 51.3 mg/L (45.1%) experienced ≥grade 3 toxicity and subsequently required a dose reduction to 600 or 400 mg daily, yet in these patients, Cminremained above the threshold at 28.2 mg/L (25.3%).
  
  
  CONCLUSIONS
  A pharmacokinetically guided individualized dosing algorithm was successfully applied and evaluated. The dosing algorithm led to patients being treated at dosages ranging from 400 to 1,800 mg daily. Further studies are needed to show a benefit of individualized dosing on clinical outcomes, such as progression-free survival. Clin Cancer Res; 22(23); 5738-46. ©2016 AACRSee related commentary by Ornstein and Rini, p. 5626.
authors.affiliation: Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek, Amsterdam, the Netherlands. r.verheijen@nki.nl.
authors.forename: Remy B
authors.initials: RB
authors.lastname: Verheijen
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
authors.forename: Sander
authors.initials: S
authors.lastname: Bins
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
authors.forename: Ron H J
authors.initials: RH
authors.lastname: Mathijssen
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.|Department of Medical Oncology, UMC Utrecht Cancer Center, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Martijn P
authors.initials: MP
authors.lastname: Lolkema
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
authors.forename: Leni
authors.initials: L
authors.lastname: van Doorn
authors.affiliation: Department of Medical Oncology and Clinical Pharmacology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek, Amsterdam, the Netherlands.|Department of Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands.
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
authors.affiliation: Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek, 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 Medical Oncology, UMC Utrecht Cancer Center, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Marlies H G
authors.initials: MH
authors.lastname: Langenberg
authors.affiliation: Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek, Amsterdam, the Netherlands.
authors.forename: Alwin D R
authors.initials: AD
authors.lastname: Huitema
authors.affiliation: Department of Medical Oncology, UMC Utrecht Cancer Center, University Medical Center Utrecht, Utrecht, the Netherlands.|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: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D018572:Disease-Free Survival; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D007191:Indazoles; D007680:Kidney Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011743:Pyrimidines / Q000008:administration & dosage*; D012509:Sarcoma / Q000188:drug therapy*; D013449:Sulfonamides / Q000008:administration & dosage*
chemical_list: D020533:Angiogenesis Inhibitors; D007191:Indazoles; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; C516667:pazopanib