Effects of Pharmacokinetic Processes and Varied Dosing Schedules on the Dynamics of Acquired Resistance to Erlotinib in EGFR-Mutant Lung Cancer

Introduction: Erlotinib (Tarceva) is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, which effectively targets EGFR-mutant driven non–small-cell lung cancer. However, the evolution of acquired resistance because of a second-site mutation (T790M) within EGFR remains an obstacle to successful treatment. Methods: We used mathematical modeling and available clinical trial data to predict how different pharmacokinetic parameters (fast versus slow metabolism) and dosing schedules (low dose versus high dose; missed doses with and without make-up doses) might affect the evolution of T790M-mediated resistance in mixed populations of tumor cells. Results: We found that high-dose pulses with low-dose continuous therapy impede the development of resistance to the maximum extent, both pre- and post-emergence of resistance. The probability of resistance is greater in fast versus slow drug metabolizers, suggesting a potential mechanism, unappreciated to date, influencing acquired resistance in patients. In case of required dose modifications because of toxicity, little difference is observed in terms of efficacy and resistance dynamics between the standard daily dose (150 mg/d) and 150 mg/d alternating with 100 mg/d. Missed doses are expected to lead to resistance faster, even if make-up doses are attempted. Conclusions: For existing and new kinase inhibitors, this novel framework can be used to rationally and rapidly design optimal dosing strategies to minimize the development of acquired resistance.

[1]  N. Socci,et al.  Optimization of Dosing for EGFR-Mutant Non–Small Cell Lung Cancer with Evolutionary Cancer Modeling , 2011, Science Translational Medicine.

[2]  Renato Martins,et al.  Erlotinib in previously treated non-small-cell lung cancer. , 2005, The New England journal of medicine.

[3]  S. Gabriel,et al.  EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy , 2004, Science.

[4]  R. Wilson,et al.  EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[5]  Michael E. Winter,et al.  Basic Clinical Pharmacokinetics , 1980 .

[6]  M. Ladanyi,et al.  Acquired Resistance to Epidermal Growth Factor Receptor Kinase Inhibitors Associated with a Novel T854A Mutation in a Patient with EGFR-Mutant Lung Adenocarcinoma , 2008, Clinical Cancer Research.

[7]  H. Varmus,et al.  Acquired Resistance of Lung Adenocarcinomas to Gefitinib or Erlotinib Is Associated with a Second Mutation in the EGFR Kinase Domain , 2005, PLoS medicine.

[8]  C. Sawyers,et al.  Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. , 2001, The New England journal of medicine.

[9]  Matthew Meyerson,et al.  Structures of lung cancer-derived EGFR mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity. , 2007, Cancer cell.

[10]  Franziska Michor,et al.  Evolution of Resistance to Targeted Anti-Cancer Therapies during Continuous and Pulsed Administration Strategies , 2009, PLoS Comput. Biol..

[11]  G. Clark,et al.  Effects of Smoking on the Pharmacokinetics of Erlotinib , 2006, Clinical Cancer Research.

[12]  M. Kris,et al.  Erlotinib at a Dose of 25 mg Daily for Non-small Cell Lung Cancers with EGFR Mutations , 2010, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[13]  K. Gelmon,et al.  706 POSTER A phase I dose escalation pharmacokinetic (PK) and pharmacodynamic (PD) study of weekly and twice weekly erlotinib in advanced stage solid malignancies , 2007 .

[14]  Varun Garg,et al.  Comparison of four basic models of indirect pharmacodynamic responses , 1993, Journal of Pharmacokinetics and Biopharmaceutics.

[15]  DE Mager,et al.  Development of Translational Pharmacokinetic–Pharmacodynamic Models , 2008, Clinical pharmacology and therapeutics.

[16]  F. Michor,et al.  Evolution of resistance to anti-cancer therapy during general dosing schedules. , 2010, Journal of theoretical biology.

[17]  David W. A. Bourne,et al.  Mathematical Modeling of Pharmacokinetic Data , 1995 .

[18]  Stuart Thomson,et al.  Kinetic analysis of epidermal growth factor receptor somatic mutant proteins shows increased sensitivity to the epidermal growth factor receptor tyrosine kinase inhibitor, erlotinib. , 2006, Cancer research.

[19]  Malcolm Rowland,et al.  Introduction to Pharmacokinetics and Pharmacodynamics: The Quantitative Basis of Drug Therapy , 2006 .

[20]  M. Meyerson,et al.  EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. , 2005, The New England journal of medicine.

[21]  O. Mir,et al.  Drug-induced effects on erlotinib metabolism. , 2011, The New England journal of medicine.

[22]  Christopher Weier,et al.  Transient potent BCR-ABL inhibition is sufficient to commit chronic myeloid leukemia cells irreversibly to apoptosis. , 2008, Cancer cell.

[23]  M. Meyerson,et al.  The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP , 2008, Proceedings of the National Academy of Sciences.

[24]  A. Racine‐Poon,et al.  Pharmacokinetics and pharmacodynamics of imatinib in a phase I trial with chronic myeloid leukemia patients. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.