title: Impact of cytochrome P450 3A4 inducer and inhibitor on the pharmacokinetics of trabectedin in patients with advanced malignancies: open-label, multicenter studies.
abstract: OBJECTIVE
  To evaluate the pharmacokinetics, safety and survival of trabectedin, metabolized primarily by cytochrome P450 (CYP)3A4 enzyme, when coadministered with rifampin (CYP3A4 inducer) or ketoconazole (CYP3A4 inhibitor) in adult patients with advanced solid tumors.
  
  
  METHODS
  Two phase 1/2a, 2-way crossover studies were conducted. For rifampin study, 12 patients were randomized (1:1) to sequence of a cycle of trabectedin (1.3 mg/m(2), 3 h, i.v.) coadministered with rifampin (600 mg/day, 6-days), and a cycle of trabectedin monotherapy (1.3 mg/m(2), 3 h, i.v.). In ketoconazole study, eight patients were randomized (1:1) to sequence of a cycle of trabectedin (0.58 mg/m(2), 3 h, i.v.) coadministered with ketoconazole (200 mg, twice-daily, 15-doses), and a cycle of trabectedin monotherapy (1.3 mg/m(2), 3 h, i.v.).
  
  
  RESULTS
  The systemic exposure (geometric means) of trabectedin was decreased [22% (C max) and 31% (AUClast)] with rifampin coadministration and increased [22% (C max) and 66% (AUClast)] with ketoconazole coadministration. This correlated with an increased clearance with rifampin (39.6-59.8 L/h) and a decreased clearance with ketoconazole (20.3-12.0 L/h). Consistent with earlier studies, the most common (≥40%) treatment-emergent adverse events in both studies were nausea, vomiting, diarrhea, hepatic function abnormal, anemia, neutropenia, thrombocytopenia and leukopenia.
  
  
  CONCLUSIONS
  Coadministration of rifampin or ketoconazole altered the pharmacokinetics of trabectedin, but no new safety signals were observed. Coadministration of trabectedin with potent CYP3A4 inhibitors or inducers should be avoided if possible. If coadministration of trabectedin with a strong CYP3A4 inhibitor is required, close monitoring for toxicities is recommended, so that appropriate dose reductions can be instituted as warranted.
authors.affiliation: Cancer Center, Service d'oncologie médicale, Cliniques universitaires Saint-Luc, Brussels, Belgium, Jean-Pascal.Machiels@uclouvain.be.
authors.forename: Jean-Pascal
authors.initials: JP
authors.lastname: Machiels
authors.forename: Arthur
authors.initials: A
authors.lastname: Staddon
authors.forename: Catherine
authors.initials: C
authors.lastname: Herremans
authors.forename: Chi
authors.initials: C
authors.lastname: Keung
authors.forename: Apexa
authors.initials: A
authors.lastname: Bernard
authors.forename: Charles
authors.initials: C
authors.lastname: Phelps
authors.forename: Nushmia Z
authors.initials: NZ
authors.lastname: Khokhar
authors.forename: Roland
authors.initials: R
authors.lastname: Knoblauch
authors.forename: Trilok V
authors.initials: TV
authors.lastname: Parekh
authors.forename: Luc
authors.initials: L
authors.lastname: Dirix
authors.forename: Sunil
authors.initials: S
authors.lastname: Sharma
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004149:Dioxoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004336:Drug Antagonism; D016903:Drug Monitoring / Q000379:methods; D004354:Drug Screening Assays, Antitumor; D064420:Drug-Related Side Effects and Adverse Reactions / Q000209:etiology / Q000517:prevention & control; D020536:Enzyme Activators / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D007654:Ketoconazole / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D008657:Metabolic Clearance Rate; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D012293:Rifampin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000077606:Trabectedin; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D004149:Dioxoles; D020536:Enzyme Activators; D004791:Enzyme Inhibitors; D044005:Tetrahydroisoquinolines; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D000077606:Trabectedin; D007654:Ketoconazole; D012293:Rifampin