title: Phase I and pharmacokinetic study of erlotinib for solid tumors in patients with hepatic or renal dysfunction: CALGB 60101.
abstract: OBJECTIVE
  We investigated dose and pharmacokinetics of erlotinib in patients with hepatic dysfunction or renal dysfunction.
  
  
  METHODS
  Patients were assigned to one of three cohorts: cohort 1, AST > or = 3x upper limit of normal; cohort 2, direct bilirubin of 1 to 7 mg/dL; and cohort 3, creatinine of 1.6 to 5.0 mg/dL. Cohort 1a was amended for albumin less than 2.5 g/dL. Erlotinib was administered orally daily to groups of at least three assessable patients in escalating doses of 50, 75, 100, and 150 mg, starting with 50 mg in hepatic dysfunction patients and 75 mg in renal dysfunction patients.
  
  
  RESULTS
  Between December 2001 and May 2005, 55 patients were accrued. The distribution of assessable patients was: two of three in cohort 1, three of three in cohort 1a, 16 of 30 in cohort 2, and 18 of 18 in cohort 3. Dose-limiting toxicity (DLT) consisted of elevation of both total and direct bilirubin 1.5x baseline in three patients (cohort 1: one of five patients at 50 mg; cohort 2: two of six patients at 100 mg). In cohort 2, one of seven patients had DLT at 75 mg. No DLT was encountered in cohort 3 with 12 patients at 150 mg. Apparent oral clearance (mean +/- standard deviation) was cohort dependent as follows: 1.9 +/- 0.2 L/h in cohort 1; 3.7 +/- 4.7 L/h in cohort 1a; 2.4 +/- 1.1 L/h in cohort 2; and 4.5 +/- 2.7 L/h in cohort 3 (Kruskal-Wallis, P < .017).
  
  
  CONCLUSIONS
  Patients with renal dysfunction tolerate 150 mg of erlotinib daily and seem to have an erlotinib clearance similar to patients without organ dysfunction. Patients with hepatic dysfunction should be treated at a reduced dose (ie, 75 mg daily) consistent with their reduced clearance.
authors.affiliation: Wake Forest University School of Medicine, Winston-Salem, NC 27157-1082, USA. aamiller@wfubmc.edu
authors.forename: Antonius A
authors.initials: AA
authors.lastname: Miller
authors.forename: Daryl J
authors.initials: DJ
authors.lastname: Murry
authors.forename: Kouros
authors.initials: K
authors.lastname: Owzar
authors.forename: Donna R
authors.initials: DR
authors.lastname: Hollis
authors.forename: Lionel D
authors.initials: LD
authors.lastname: Lewis
authors.forename: Hedy L
authors.initials: HL
authors.lastname: Kindler
authors.forename: John L
authors.initials: JL
authors.lastname: Marshall
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Villalona-Calero
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Edelman
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Hohl
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Lichtman
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ratain
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D000069347:Erlotinib Hydrochloride; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007674:Kidney Diseases / Q000150:complications* / Q000175:diagnosis / Q000378:metabolism; D007677:Kidney Function Tests; D008107:Liver Diseases / Q000150:complications* / Q000175:diagnosis / Q000378:metabolism; D008111:Liver Function Tests; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000401:mortality* / Q000473:pathology; D011336:Probability; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D018570:Risk Assessment; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D011799:Quinazolines; D000069347:Erlotinib Hydrochloride