Ahmed Abbas Suleiman (1); Sebastian Frechen (1); Matthias Scheffler (2); Thomas Zander (2); Lucia Nogova (2); Martin Kocher (3); Ulrich Jaehde (4); Jürgen Wolf (2); Uwe Fuhr (1)
(1) Department of Pharmacology, Clinical Pharmacology Unit, University Hospital of Cologne, Cologne, Germany; (2) Department I of Internal Medicine, Center for Integrated Oncology Cologne Bonn, University Hospital of Cologne, Cologne, Germany; (3) Department of Radiotherapy, University Hospital Cologne, Cologne, Germany; (4) Institute of Pharmacy, Clinical Pharmacy Department, University of Bonn, Bonn, Germany
Objectives: Based on a mathematical model [1,2], the use of pulsatile high doses of erlotinib together with a continuous-low dose was suggested as a dosing regimen instead of the standard regimen (150mg/day) to minimize the development of acquired resistance in non-small cell lung cancer (NSCLC) patients. Our aim was to build a modeling and simulation framework for adverse events (AE) commonly encountered during erlotinib treatment, namely rash and diarrhea, to provide insights into erlotinib toxicity.
Methods: AE data for model development were available from 39 advanced NSCLC patients first treated with erlotinib (150mg/day oral; NCT00568841). Dates of AE incidence and resolution were recorded, and they were graded according to the National Cancer Institute-Common Toxicity Criteria (grade 1=mild, grade 2=moderate, grade 3=severe). Continuous-time Markov models [3] were developed to account for the transitioning of patients between different AE grades. Erlotinib exposure and covariates including the mutational status, radiotherapy and co-medications histories, laboratory findings and demographics were investigated for their influence on adverse events. A simulation study using the models built was conducted to compare the toxicities of different dosing regimens (standard and pulsatile regimens).
Results: Patients were more likely to experience an AE (rash or diarrhea) early during treatment, and erlotinib exposure was found to increase the risk of rash but not diarrhea. Interestingly, previous or concomitant radiotherapy decreased transitioning to higher rash grades by 81% (p<0.01). Simulations suggested the design of pulsatile regimens using the maximum tolerable weekly exposure.
Conclusions: The modeling and simulation framework developed demonstrated the tolerability of pulsatile erlotinib dosing regimens, and suggested that radiotherapy might mitigate erlotinib-induced rash.
References:
[1] Chmielecki J, et al. Optimization of dosing for EGFR-mutant non-small cell lung cancer with evolutionary cancer modeling. Sci Transl Med. 2011;3(90):90ra59.
[2] Foo J, et al. Effects of pharmacokinetic processes and varied dosing schedules on the dynamics of acquired resistance to erlotinib in EGFR-mutant lung cancer. J Thorac Oncol. 2012;7(10):1583-93.
[3] Pilla Reddy V, et al. Pharmacokinetic-pharmacodynamic modeling of severity levels of extrapyramidal side effects with markov elements. CPT Pharmacometrics Syst Pharmacol. 2012 Sep 26;1:e1
Reference: PAGE 24 () Abstr 3345 [www.page-meeting.org/?abstract=3345]
Poster: Drug/Disease modeling - Oncology