title: Pharmacokinetic modulation of oral etoposide by ketoconazole in patients with advanced cancer.
abstract: OBJECTIVE
  Etoposide is a widely used cytotoxic drug that is commercially available in both intravenous and oral formulations. High interpatient pharmacokinetic variability has been associated with oral etoposide administration. Various strategies used in the past to reduce such variability have not been successful. Hence, this study was designed to evaluate if pharmacokinetic modulation of oral etoposide with ketoconazole could lead to a favorable alteration of etoposide pharmacokinetics, and to assess the feasibility and safety of this approach.
  
  
  METHODS
  Thirty-two patients were treated with ketoconazole 200 mg daily with an escalating dose of oral etoposide starting at a dose of 50 mg every other day. Pharmacokinetic samples were obtained during the first treatment cycle after the administration of an oral etoposide and ketoconazole dose. Additional baseline pharmacokinetic studies of etoposide alone were performed 4 days prior to the first treatment cycle.
  
  
  RESULTS
  Dose limiting toxicities were neutropenia and fatigue. Ketoconazole increased the area under the plasma concentration-time curve (AUC) of oral etoposide by a median of 20% (p < 0.005). Ketoconazole did not reduce the interpatient variability in etoposide pharmacokinetics. Pretreatment bilirubin levels correlated with etoposide clearance (Spearman's r = -0.48, p = 0.008). The maximum tolerated dose was etoposide administered at 50 mg daily and ketoconazole 200 mg qd for 3 of 5 weeks.
  
  
  CONCLUSIONS
  Ketoconazole reduces the apparent clearance of oral etoposide, does not alter its toxicity profile and does not reduce interpatient pharmacokinetic variability. Other methods to reduce the pharmacokinetic variability of oral etoposide are needed.
authors.affiliation: Committee on Clinical Pharmacology and Pharmacogenomics, University of Chicago, 5841 S Maryland Ave, MC2115, Chicago, IL 60637, USA.
authors.forename: Wei Peng
authors.initials: WP
authors.lastname: Yong
authors.forename: Apurva A
authors.initials: AA
authors.lastname: Desai
authors.forename: Federico
authors.initials: F
authors.lastname: Innocenti
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Ramirez
authors.forename: Dale
authors.initials: D
authors.lastname: Shepard
authors.forename: Ken
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Larry
authors.initials: L
authors.lastname: House
authors.forename: Gini F
authors.initials: GF
authors.lastname: Fleming
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Vogelzang
authors.forename: Richard L
authors.initials: RL
authors.lastname: Schilsky
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ratain
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000935:Antifungal Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001663:Bilirubin / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005047:Etoposide / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced
chemical_list: D000935:Antifungal Agents; D000972:Antineoplastic Agents, Phytogenic; D005047:Etoposide; D007654:Ketoconazole; D001663:Bilirubin