TY - JOUR
T1 - 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)
AU - Tran, Hai T.
AU - Zinner, Ralph G.
AU - Blumenschein, George R.
AU - Oh, Yun W.
AU - Papadimitrakopoulou, Vassiliki A.
AU - Kim, Edward S.
AU - Lu, Charles
AU - Malik, Mubashira
AU - Lum, Bert L.
AU - Herbst, Roy S.
N1 - Funding Information:
This research was supported by a grant from Genentech, Inc., an ASCO Career Development Award, and an M. D. Anderson Cancer Center Physician Scientist Program Award to Dr. Roy S. Herbst. H.T.Tran(*).R.G.Zinner.G.R.BlumenscheinJr.. V. A. Papadimitrakopoulou.E. S. Kim.C. Lu.R. S. Herbst 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 e-mail: htran@mdanderson.org
PY - 2011/6
Y1 - 2011/6
N2 - 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 AUC0-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/M2) were 11.7 (3.4) and 12.7 (6.7) in the placebo and erlotinib treatment groups, respectively. The resultant paclitaxel AUC0-∞ (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 AUC0-∞ (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.
AB - 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 AUC0-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/M2) were 11.7 (3.4) and 12.7 (6.7) in the placebo and erlotinib treatment groups, respectively. The resultant paclitaxel AUC0-∞ (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 AUC0-∞ (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.
KW - EGFR inhibitor
KW - Erlotinib
KW - Lung cancer
KW - NSCLC
KW - Pharmacokinetics
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U2 - 10.1007/s10637-009-9380-z
DO - 10.1007/s10637-009-9380-z
M3 - Article
C2 - 20094773
AN - SCOPUS:78650434919
SN - 0167-6997
VL - 29
SP - 499
EP - 505
JO - Investigational New Drugs
JF - Investigational New Drugs
IS - 3
ER -