Summary
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.
Similar content being viewed by others
References
Pollack VA, Savage DM, Baker DA, Tsaparikos KE, Sloan DE, Moyer JD, Barbacci EG, Pustilnik LR, Smolarek TA, Davis JA, Vaidya MP, Arnold LD, Doty JL, Iwata KK, Morin MJ (1999) Inhibition of epidermal growth factor receptor-associated tyrosine phosphorylation in human carcinomas with CP-358, 774: dynamics of receptor inhibition in situ and antitumor effects in athymic mice. J Pharmacol Exp Ther 291:739–748
Data on file with OSI Pharmaceuticals
Higgins B, Kolinsky K, Smith M, Beck G, Rashed M, Adames V, Linn M, Wheeldon E, Gand L, Birnboeck H, Hoffmann G (2004) Antitumor activity of erlotinib (OSI-774, Tarceva) alone or in combination in human non-small cell lung cancer tumor xenograft models. Anticancer Drugs 15:503–512
Hidalgo M, Siu LL, Nemunaitis J, Rizzo J, Hammond LA, Takimoto C, Eckhardt SG, Tolcher A, Britten CD, Denis L, Ferrante K, Von Hoff DD, Silberman S, Rowinsky EK (2001) Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. J Clin Oncol 19:3267–3279
Soulieres D, Senzer NN, Vokes EE, Hidalgo M, Agarwala SS, Siu LL (2004) Multicenter phase II study of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent or metastatic squamous cell cancer of the head and neck. J Clin Oncol 22:77–85
Patnaik A, Wood D, Tolcher AW, Hamilton M, Kreisberg JI, Hammond LA, Schwartz G, Beeram M, Hidalgo M, Mita MM, Wolf J, Nadler P, Rowinsky EK (2006) Phase I, pharmacokinetic, and biological study of erlotinib in combination with paclitaxel and carboplatin in patients with advanced solid tumors. Clin Cancer Res 12:7406–7413
Ratain MJ, George CM, Janisch L, Kindler HL, Ryan C, Wood DL, Nadler PI, Vokes EE (2002) Phase I trial of erlotinib (OSI-774) in combination with gemcitabine (G) and cisplatin (P) in patients with advanced solid tumors. Proc Am Soc Clin Oncol 21:76 (Abstract 2115)
Herbst RS, Prager D, Hermann R, Fehrenbacher L, Johnson BE, Sandler A, Kris MG, Tran HT, Klein P, Li X, Ramies D, Johnson DH (2005) TRIBUTE Investigator Group. TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol 23:5892–5899
Ling J, Johnson K, Miao Z, Rakhit A, Pantze M, Hamilton M, Lum B, Prakash C (2006) Metabolism and excretion of erlotinib, a small molecule inhibitor of epidermal growth factor receptor tyrosine kinase, in healthy male volunteers. Drug Metab Dispos 34:420–426
Canal PR (1998) Cisplatin, carboplatin, and platinum analogs. In: Growchow LB, Ames MM (eds) A clinicians guide to chemotherapy pharmacokinetics and pharmacodynamics. Williams and Wilkins, Baltimore, pp 345–374
Relling M, Sonnichen D (1998) Paclitaxel and Docetaxel. In: Growchow LB, Ames MM (eds) A clinicians guide to chemotherapy pharmacokinetics and pharmacodynamics. Williams and Wilkins, Baltimore, pp 3375–3394
Declaration of Helsinki. Adopted by the 18th World Medical Assembly, Helsinki, Finland, June 1964, amended by the 29th World Medical Assembly, Tokyo, Japan, October 1975, and the 35th World Medical Assembly, Venice, Italy, October, 1983
Foursorouzesh B, Hidalgo M, Takimoto C, de Bono JS, Forero L, Muralidhar B, Malik S, Patnaik A, Rizzo J, Hammond LA, Schwartz G, Goetz A, Mays T, Kiene A, Norris J, Tolcher A, Rowinsky EK, Nadler P, Wood D, Zitelli A (2002) Phase I, pharmacokinetic (PK), and biological studies of the epidermal growth factor-tyrosine kinase (EGFR-TK) inhibitor OSI-774 in combination with docetaxel. Proc Am Soc Clin Oncol 21:21 (Abstract 81)
Shepherd FA, Pereira JR, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, Campos D, Maoleekoonpiroj S, Smylie M, Martins R, van Kooten M, Dediu M, Findlay B, Tu D, Johnston D, Bezjak A, Clark G, Santabárbara P, Seymour L (2005) National Cancer Institute of Canada Clinical Trials Group. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353:123–132
Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W (2007) National Cancer Institute of Canada Clinical Trials Group. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 25:1960–1966
Gatzemeier U, Pluzanska A, Szczesna A, Kaukel E, Roubec J, De Rosa F, Milanowski J, Karnicka-Mlodkowski H, Pesek M, Serwatowski P, Ramlau R, Janaskova T, Vansteenkiste J, Strausz J, Manikhas GM, Von Pawel J (2007) Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer: the Tarceva Lung Cancer Investigation Trial. J Clin Oncol 25(12):1545–1552
Author information
Authors and Affiliations
Corresponding author
Additional 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.
Rights and permissions
About this article
Cite this article
Tran, H.T., Zinner, R.G., Blumenschein, G.R. et al. 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). Invest New Drugs 29, 499–505 (2011). https://doi.org/10.1007/s10637-009-9380-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10637-009-9380-z