title: Pharmacokinetic study of the phase III, randomized, double-blind, multicenter trial (TRIBUTE) of paclitaxel and carboplatin combined with erlotinib or placebo in patients with advanced Non-small Cell Lung Cancer (NSCLC).
abstract: OBJECTIVE
  To assess the pharmacokinetics and evaluate potential drug-drug interactions between erlotinib, paclitaxel and carboplatin.
  
  
  METHODS
  1,079 previously untreated patients with advanced NSCLC were enrolled and randomized in a phase III trial (TRIBUTE) to receive either erlotinib or placebo in combination with paclitaxel 200 mg/m2 IV over 3 h and carboplatin at a calculated dose to achieve an AUC 6 mg∙min/mL. To determine possible drug-drug interaction with this combination, a subset of 24 (12 erlotinib, 12 placebo) patients were enrolled onto an intensive pharmacokinetic (IPK) substudy group at a single site. All IPK patients received either erlotinib 150 mg/day or placebo-controlled tablets. Analyses were completed using validated analytical methodologies. Non-compartmental modeling was utilized to estimate PK parameters.
  
  
  RESULTS
  Complete blood sampling for pharmacokinetic analysis was obtained in 21 of 24 patients. Mean AUC(0-τ) for erlotinib and the OSI-420 metabolite were 29,997 ng∙h/mL and 3,020 ng∙h/mL, respectively. Mean (SD) paclitaxel clearances (L/h/M(2)) were 11.7 (3.4) and 12.7 (6.7) in the placebo and erlotinib treatment groups, respectively. The resultant paclitaxel AUC(0-∞) (ng∙h/mL) was 18,400 (5,300) for the placebo group and 17,800 (5,500) for the erlotinib group. For carboplatin, the mean (SD) clearances (L/h) were 16.8 (3.9) and 16.1 (4.4) for the placebo and erlotinib groups, respectively. The resultant carboplatin AUC(0-∞) (ng/mL∙h) were 49,900 (9,700) for the placebo group and 48,400 (11,900) for the erlotinib group. No significant differences were observed in these paclitaxel or carboplatin pharmacokinetic group comparisons.
  
  
  CONCLUSIONS
  The addition of erlotinib to a standard chemotherapy regimen for NSCLC did not alter the systemic exposures (AUC(0-∞)) of paclitaxel (p = 0.80) and carboplatin (p = 0.756) when erlotinib-treated patients were compared to placebo-treated patients. The pharmacokinetics of erlotinib and its metabolite OSI-420 did not appear to be altered by the concomitant administration of paclitaxel and carboplatin.
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 432, Houston, TX 77030, USA. htran@mdanderson.org
authors.forename: Hai T
authors.initials: HT
authors.lastname: Tran
authors.forename: Ralph G
authors.initials: RG
authors.lastname: Zinner
authors.forename: George R
authors.initials: GR
authors.lastname: Blumenschein
authors.forename: Yun W
authors.initials: YW
authors.lastname: Oh
authors.forename: Vassiliki A
authors.initials: VA
authors.lastname: Papadimitrakopoulou
authors.forename: Edward S
authors.initials: ES
authors.lastname: Kim
authors.forename: Charles
authors.initials: C
authors.lastname: Lu
authors.forename: Mubashira
authors.initials: M
authors.lastname: Malik
authors.forename: Bert L
authors.initials: BL
authors.lastname: Lum
authors.forename: Roy S
authors.initials: RS
authors.lastname: Herbst
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D004311:Double-Blind Method; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D010919:Placebos; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D010919:Placebos; D011799:Quinazolines; D016190:Carboplatin; D000069347:Erlotinib Hydrochloride; D017239:Paclitaxel