A Modeling and Simulation Framework for Adverse Events in Erlotinib-Treated Non-Small-Cell Lung Cancer Patients.
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.
Department of Pharmacology, Clinical Pharmacology Unit, University Hospital of Cologne, Gleueler Str. 24, 50931, Cologne, Germany. ahmed.suleiman@uk-koeln.de.
Ahmed Abbas
AA
Suleiman
Department of Pharmacology, Clinical Pharmacology Unit, University Hospital of Cologne, Gleueler Str. 24, 50931, Cologne, Germany.
Sebastian
S
Frechen
Lung Cancer Group Cologne, Department I of Internal Medicine, Center for Integrated Oncology Cologne Bonn, University Hospital of Cologne, Cologne, Germany.
Matthias
M
Scheffler
Lung Cancer Group Cologne, Department I of Internal Medicine, Center for Integrated Oncology Cologne Bonn, University Hospital of Cologne, Cologne, Germany.
Thomas
T
Zander
Lung Cancer Group Cologne, Department I of Internal Medicine, Center for Integrated Oncology Cologne Bonn, University Hospital of Cologne, Cologne, Germany.
Lucia
L
Nogova
Department of Radiotherapy, University Hospital of Cologne, Cologne, Germany.
Martin
M
Kocher
Institute of Pharmacy, Clinical Pharmacy Department, University of Bonn, Bonn, Germany.
Ulrich
U
Jaehde
Lung Cancer Group Cologne, Department I of Internal Medicine, Center for Integrated Oncology Cologne Bonn, University Hospital of Cologne, Cologne, Germany.
Jürgen
J
Wolf
Department of Pharmacology, Clinical Pharmacology Unit, University Hospital of Cologne, Gleueler Str. 24, 50931, Cologne, Germany.
Uwe
U
Fuhr
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects*; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis / Q000188:drug therapy*; D003967:Diarrhea / Q000139:chemically induced; D000069347:Erlotinib Hydrochloride / Q000009:adverse effects*; D005076:Exanthema / Q000139:chemically induced; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis / Q000188:drug therapy*; D008297:Male; D008390:Markov Chains; D008875:Middle Aged; D008962:Models, Theoretical; D047428:Protein Kinase Inhibitors / Q000009:adverse effects*
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D000069347:Erlotinib Hydrochloride
NSCLC; adverse events; erlotinib; modeling