Erlotinib pharmacokinetics: a critical parameter influencing acute toxicity in elderly patients over 75 years-old
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Background Older non-small cell lung cancer (NSCLC) patients under erlotinib are reported to experience more acute toxicity. We hypothesized that modifications in erlotinib pharmacokinetics might explain this observation. Methods A monocentric prospective clinico-pharmacological study included stage IIIb/IV NSCLC consecutive pts. treated with erlotinib. The plasma concentration of erlotinib (Ce) was measured at steady state on day 15. We studied the relationship between age > 75 years, and Ce, using the Mann-Whitney U test and with the occurrence of acute toxicity, using a Fisher’s test. Results A total of 53 pts. were analyzed. Median age was 68 years (31–83), 56 % were female. All pts. > 75 years experienced toxicity: all grade acute adverse events were 1.6 fold more frequent (100 % vs 61 %; OR 95 % CI [1.9-INF]; p = 0.003). At day 15, Ce increased with age. Over 75 years old, the mean Ce was 1.5 fold higher: 2091 ng/mL (95 % CI [1476; 2706]) vs 1359 (95 % CI [1029; 1689]; p = 0.024). In pts. over 80 years old, the mean Ce was doubled: 2729 (95 % CI [1961; 3497]) vs 1358 ng/mL (95 % CI [1070; 1646]; p = 0.0019). Reduced lean body mass over 75 years (median 36.6 kg versus 49.1 kg) might account for these differences. Finally, the risk of early erlotinib discontinuation was increased by 11 in older pts. (33 % vs 3 % OR 17.2; 95 % CI [1.7; 892.5] p = .005). Conclusion The risk of overexposure to erlotinib increases with age. Reduced lean body mass may explain erlotinib pharmacokinetics and excessive acute toxicity in the elderly.
KeywordsElderly Erlotinib Pharmacokinetic Toxicity Plasma monitoring
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Conflict of interest
Pascaline Boudou-Rouquette has received honoraria from Roche and Novartis, outside the submitted work. Pr Goldwasser reports personal fees from Bayer, Roche, Fresenius, Sanofi-Avantis, Astra-Zeneca and Boeringher, outside the submitted work. Jeanne Chapron reported fees from Novartis and Astra-Zeneca outside the submitted work. Olivier Huillard has received personal fees from Bayer, MSD and Astellas.
The work was supported by the Department of Medical Oncology, Paris Descartes University, Cochin - Port Royal Hospital, AP-HP, Paris, France and the Department of Pharmacocinétique et pharmacochimie, Paris Descartes University, Cochin - Port Royal Hospital, AP-HP, Paris, France.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with 1964 Helsinki declaration and its later amendments or comparable standards.
Informed consent was obtained from all individual participants included in the study.
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