title: Pharmacokinetic interaction between pazopanib and cisplatin regimen.
abstract: OBJECTIVE
  A phase I study combining daily oral pazopanib and cisplatin (given iv every 3 weeks) was performed in order to determine the maximum tolerated dose of both drugs in combination. Pharmacokinetic interactions were evaluated.
  
  
  METHODS
  Plasma pazopanib and ultrafilterable cisplatin concentrations were obtained in 32 patients treated according to four levels of dose corresponding to 200, 400 or 600 mg daily dose of pazopanib and 60 or 75 mg/m(2) of cisplatin. Two sequences of treatment were performed in order to explore any interaction of cisplatin on pazopanib pharmacokinetics and inversely. Data were analyzed using the NONMEM program.
  
  
  RESULTS
  Maximum tolerated dose was 400 mg of pazopanib and 75 mg/m(2) of cisplatin. Mean (CV % for inter-individual variability) cisplatin clearance was 10.3 L/h (33.2 %) and appeared not to be influenced by pazopanib. However, pazopanib pharmacokinetics was significantly modified by the cisplatin regimen. Mean (CV %) of oral pazopanib clearance was 0.66 L/h (55 %) at Day 0 (before cisplatin administration), 24.8 % lower at Day 1 and 32.9 % lower at Day 2. The interaction is less likely to be due to cisplatin than to a competitive inhibition of pazopanib metabolism and efflux by aprepitant, an antiemetic drug systematically administered with cisplatin. The plasma pazopanib exposures observed at Day 0 with a 400 mg dose were similar to those observed at the recommended dose of pazopanib in monochemotherapy (800 mg) during the first-in-man phase 1 study.
  
  
  CONCLUSIONS
  The observed pazopanib plasma overexposure probably contributed to the poor tolerance encountered during this phase 1 study.
authors.affiliation: Institut Claudius-Regaud, IUCT-O, Toulouse, France.|EA4553, Université Paul-Sabatier, Toulouse, France.
authors.forename: Diane-Charlotte
authors.initials: DC
authors.lastname: Imbs
authors.affiliation: Department of Medical Oncology, Institut Curie, Paris, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Diéras
authors.affiliation: Department of Medical Oncology, Centre Léon-Bérard, Lyon, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bachelot
authors.affiliation: Centre de Recherche du Cancer Nantes-Angers, UMR-INSERM U892/CNRS 6299, Institut de Cancérologie de l'Ouest, Nantes, France.
authors.forename: Mario
authors.initials: M
authors.lastname: Campone
authors.affiliation: Department of Medical Oncology, Centre Georges François-Leclerc, Dijon, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Isambert
authors.affiliation: Department of Medical Oncology, Centre François-Baclesse, Caen, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Joly
authors.affiliation: Unicancer, Paris, France. m-jimenez@unicancer.fr.
authors.forename: Marta
authors.initials: M
authors.lastname: Jimenez
authors.affiliation: Institut Claudius-Regaud, IUCT-O, Toulouse, France.|EA4553, Université Paul-Sabatier, Toulouse, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Lafont
authors.affiliation: Institut Claudius-Regaud, IUCT-O, Toulouse, France. chatelut.etienne@iuct-oncopole.fr.|EA4553, Université Paul-Sabatier, Toulouse, France. chatelut.etienne@iuct-oncopole.fr.
authors.forename: Etienne
authors.initials: E
authors.lastname: Chatelut
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D007191:Indazoles; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy / Q000473:pathology; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D007191:Indazoles; D011743:Pyrimidines; D013449:Sulfonamides; C516667:pazopanib; D040262:Receptors, Vascular Endothelial Growth Factor; D002945:Cisplatin
keywords: Platinum compounds; Population pharmacokinetics; Tyrosine kinase inhibitors