title: Phase I study of pazopanib in patients with advanced solid tumors and hepatic dysfunction: a National Cancer Institute Organ Dysfunction Working Group study.
abstract: OBJECTIVE
  Pazopanib is a potent, multitargeted receptor tyrosine kinase inhibitor; however, there is limited information regarding the effects of liver function on pazopanib metabolism and pharmacokinetics. The objective of this study was to establish the maximum-tolerated dose (MTD) and pharmacokinetic profile of pazopanib in patients with varying degrees of hepatic dysfunction.
  
  
  METHODS
  Patients with any solid tumors or lymphoma were stratified into four groups based on the degree of hepatic dysfunction according to the National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) criteria. Pazopanib was given orally once a day on a 21-day cycle. A modified 3+3 design was used.
  
  
  RESULTS
  Ninety-eight patients were enrolled. Patients in the mild group tolerated 800 mg per day. The moderate and severe groups tolerated 200 mg per day. Pharmacokinetic data in the mild group were similar to the data in the normal group. Comparison of the median Cmax and area under the curve [AUC(0-24)] in the moderate or severe groups at 200 mg per day to the values in the normal and mild groups at 800 mg per day indicated less than dose-proportional systemic exposures in patients with moderate and severe hepatic impairment. This suggests that the lower maximum-tolerated dose in the moderate and severe group is not due to a decrease in drug clearance or alteration in the proportion of metabolites.
  
  
  CONCLUSIONS
  In patients with mild liver dysfunction, pazopanib is well tolerated at the Food and Drug Administration (FDA)-approved dose of 800 mg per day. Patients with moderate and severe liver dysfunction tolerated 200 mg per day.
authors: City of Hope, Duarte, CA 91010, USA.
authors: Stephen I
authors: SI
authors: Shibata
authors: Vincent
authors: V
authors: Chung
authors: Timothy W
authors: TW
authors: Synold
authors: Jeffrey A
authors: JA
authors: Longmate
authors: A Benjamin
authors: AB
authors: Suttle
authors: Lone H
authors: LH
authors: Ottesen
authors: Heinz-Josef
authors: HJ
authors: Lenz
authors: Shivaani
authors: S
authors: Kummar
authors: R Donald
authors: RD
authors: Harvey
authors: Anne L
authors: AL
authors: Hamilton
authors: Bert H
authors: BH
authors: O'Neil
authors: John
authors: J
authors: Sarantopoulos
authors: Patricia
authors: P
authors: LoRusso
authors: Michelle A
authors: MA
authors: Rudek
authors: Afshin
authors: A
authors: Dowlati
authors: Daniel L
authors: DL
authors: Mulkerin
authors: Chandra P
authors: CP
authors: Belani
authors: Leena
authors: L
authors: Gandhi
authors: S Cecilia
authors: SC
authors: Lau
authors: S Percy
authors: SP
authors: Ivy
authors: Edward M
authors: EM
authors: Newman
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007191:Indazoles; D008107:Liver Diseases / Q000209:etiology*; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D009369:Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000473:pathology*; D011743:Pyrimidines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013449:Sulfonamides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D007191:Indazoles; D011743:Pyrimidines; D013449:Sulfonamides; C516667:pazopanib
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