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)

Purpose To assess the pharmacokinetics and evaluate potential drug-drug interactions between erlotinib, paclitaxel and carboplatin. Experimental Design 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 \( {\hbox{AU}}{{\hbox{C}}_{0 - \tau }} \) 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/M²) were 11.7 (3.4) and 12.7 (6.7) in the placebo and erlotinib treatment groups, respectively. The resultant paclitaxel \( {\hbox{AU}}{{\hbox{C}}_{0 - \infty }} \) (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 \( {\hbox{AU}}{{\hbox{C}}_{0 - \infty }} \) (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 (\( {\hbox{AU}}{{\hbox{C}}_{0 - \infty }} \)) 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.