title: Effects of ketoconazole and esomeprazole on the pharmacokinetics of pazopanib in patients with solid tumors.
abstract: OBJECTIVE
  The metabolism of pazopanib is primarily mediated by CYP3A4. The solubility of pazopanib is pH-dependent, and an elevated gastric pH may decrease its bioavailability. This study evaluated the effect of a potent CYP3A4 inhibitor, ketoconazole, and the proton pump inhibitor esomeprazole on the pharmacokinetics and safety of pazopanib and its metabolites.
  
  
  METHODS
  In Arm A, patients received pazopanib 400 mg alone once daily for 7 days followed by pazopanib 400 mg plus ketoconazole 400 mg once daily for 5 days. In Arm B, patients received pazopanib 800 mg once daily for 7 days, followed by pazopanib 800 mg plus esomeprazole 40 mg once daily for 5 days, and then pazopanib alone on the last day.
  
  
  RESULTS
  Arm A enrolled 21 patients. In the presence of ketoconazole, mean area under the plasma concentration-time curve 24 h post-dose (AUC(0-24)) and mean maximum observed concentration (C max) of pazopanib increased by 66 and 45 %, respectively; mean AUC(0-24) and C max for pazopanib metabolites were lower or remained unchanged. Arm B enrolled 13 patients. In the presence of esomeprazole, mean pazopanib AUC(0-24) and C max decreased by 40 and 42 %, respectively; mean values of those parameters for metabolites of pazopanib also decreased.
  
  
  CONCLUSIONS
  Concomitant use of pazopanib with a strong CYP3A4 inhibitor should be avoided. If coadministration is necessary, pazopanib should be reduced to 400 mg. Concomitant use of pazopanib and proton pump inhibitors should also be avoided. Alternative dosing regimens that do not increase gastric pH at the time of pazopanib dosing should be considered.
authors: The Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA. tanan@umdnj.edu
authors: Antoinette R
authors: AR
authors: Tan
authors: Darlene G
authors: DG
authors: Gibbon
authors: Mark N
authors: MN
authors: Stein
authors: Diana
authors: D
authors: Lindquist
authors: Jeffery W
authors: JW
authors: Edenfield
authors: Julie C
authors: JC
authors: Martin
authors: Charles
authors: C
authors: Gregory
authors: A Benjamin
authors: AB
authors: Suttle
authors: Hiroomi
authors: H
authors: Tada
authors: Jeffrey
authors: J
authors: Botbyl
authors: Joseph J
authors: JJ
authors: Stephenson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D064098:Esomeprazole / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007191:Indazoles; D007654:Ketoconazole / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D054328:Proton Pump Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D020533:Angiogenesis Inhibitors; D065692:Cytochrome P-450 CYP3A Inhibitors; D007191:Indazoles; D054328:Proton Pump Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; C516667:pazopanib; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D064098:Esomeprazole; D007654:Ketoconazole