Universität zu Köln

Suleiman, Ahmed Abbas, Frechen, Sebastian, Scheffler, Matthias ORCID: 0000-0002-9031-1368, Zander, Thomas, Nogova, Lucia, Kocher, Martin, Jaehde, Ulrich, Wolf, Juergen and Fuhr, Uwe (2015). A Modeling and Simulation Framework for Adverse Events in Erlotinib-Treated Non-Small-Cell Lung Cancer Patients. AAPS J., 17 (6). S. 1483 - 1492. NEW YORK: SPRINGER. ISSN 1550-7416

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Abstract

Treatment with erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor used for treating non-small-cell lung cancer (NSCLC) and other cancers, is frequently associated with adverse events (AE). We present a modeling and simulation framework for the most common erlotinib-induced AE, rash, and diarrhea, providing insights into erlotinib toxicity. We used the framework to investigate the safety of high-dose erlotinib pulses proposed to limit acquired resistance while treating NSCLC. Continuous-time Markov models were developed using rash and diarrhea AE data from 39 NSCLC patients treated with erlotinib (150 mg/day). Exposure and different covariates were investigated as predictors of variability. Rash was also tested as a survival predictor. Models developed were used in a simulation analysis to compare the toxicities of different regimens, including the previously mentioned pulsed strategy. Probabilities of experiencing rash or diarrhea were found to be highest early during treatment. Rash, but not diarrhea, was positively correlated with erlotinib exposure. In contrast with some common understandings, radiotherapy decreased transitioning to higher rash grades by 81% (p<0.01), and experiencing rash was not correlated with positive survival outcomes. Model simulations predicted that the proposed pulsed regimen (1600 mg/week+50 mg/day remaining week days) results in a maximum of 20% of the patients suffering from severe rash throughout the treatment course in comparison to 12% when treated with standard dosing (150 mg/day). In conclusion, the framework demonstrated that radiotherapy attenuates erlotinib-induced rash, providing an opportunity to use radiotherapy and erlotinib together, and demonstrated the tolerability of high-dose pulses intended to address acquired resistance to erlotinib.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Suleiman, Ahmed Abbas UNSPECIFIED UNSPECIFIED UNSPECIFIED Frechen, Sebastian UNSPECIFIED UNSPECIFIED UNSPECIFIED Scheffler, Matthias UNSPECIFIED orcid.org/0000-0002-9031-1368 UNSPECIFIED Zander, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Nogova, Lucia UNSPECIFIED UNSPECIFIED UNSPECIFIED Kocher, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Jaehde, Ulrich UNSPECIFIED UNSPECIFIED UNSPECIFIED Wolf, Juergen UNSPECIFIED UNSPECIFIED UNSPECIFIED Fuhr, Uwe UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-388503
DOI:	10.1208/s12248-015-9815-8
Journal or Publication Title:	AAPS J.
Volume:	17
Number:	6
Page Range:	S. 1483 - 1492
Date:	2015
Publisher:	SPRINGER
Place of Publication:	NEW YORK
ISSN:	1550-7416
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language ACQUIRED-RESISTANCE; EGFR MUTATION; PHASE-3 TRIAL; PHARMACOKINETICS; CHEMOTHERAPY; MECHANISMS; INHIBITORS; GEFITINIB; DYNAMICS; SURVIVAL Multiple languages Pharmacology & Pharmacy Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/38850