Abstract 4509: Comparison of the pharmacokinetics of erlotinib administered in complete fasting and two hours after a meal in non-small cell lung cancer patients
Authors: Katsuya Yuki , Fujiwara Yutaka , Sunami Kuniko , Utsumi Hirofumi , Goto Yasushi , Kanda Shintaro , Horinouchi Hidehito , Nokihara Hiroshi , Yamamoto Noboru , Ohe Yuichiro , Osawa Satoko , Hamada Akinobu 
Published: August 2015

Abstract
[Background] The bioavailability of several oral anticancer drugs changes with food exposure. The recommended dose of erlotinib (E) is 150 mg daily either one hour before a meal (complete fasting) or two hours after a meal (post-meal), because of the food effect. Although the two gastric emptying states have been considered equivalent in clinical practice, no study had in fact demonstrated the fed bioequivalence in the two conditions.
[Methods] We conducted a cross-over pharmacokinetic study in Cohort A (post-meal to complete fasting) and Cohort B (complete fasting to post-meal); seven days in each fed condition period. Blood samples were obtained just before administration of E on days 1, 2, 5, 7, 8, 9, 12, and 14, and at 1, 2, 4, 6, 8, 10, and 24 hours after administration on days 7 and 14. Area under the curve from 0 to 24 hours (AUC0-24), mean residence time (MRT) from 0 to 24 hours, peak concentration (Cmax), and time to Cmax (Tmax) were estimated by noncompartment analysis. Statistical analysis in the ln-transformed AUC0-24 and Cmax of E was performed using a two-sample t-test with unequal variance, and the ratios of geometric means (GMR) were calculated for AUC0-24 and Cmax. Time to first skin rash was analyzed with a Kaplan-Meier curve compared with the log-rank test, with P &lt; 0.05 considered significant.
[Results] Twenty-five patients were randomly assigned, and 23 patients (12 in Cohort A and 11 in Cohort B) were included in the pharmacokinetic analysis. The geometric mean of AUC0-24 was significantly higher in the post-meal status than in the complete fasting status (41.5 ± 11.2 vs. 31.0 ±13.7 μg*h/mL; P &lt; .001) and GMR was 1.33, and likewise in the geometric mean of Cmax (2.64 ± 0.77 vs. 1.83 ± 0.82 μg/mL; P &lt; .001), and GMR was 1.44. Tmax was also significantly longer in the post-meal status (P = .014) while MRT was significantly longer in the complete fasting status (P &lt; .001). Alteration in AUC0-24, Cmax, Tmax, and MRT on day 7 suggested that the two gastric emptying states might differ in their absorption. However, because the concentration of E did not reach the steady state within seven days in the complete fasting group, we conducted further analyses only on day 14. No significant difference between the complete fasting and post-meal condition was seen in AUC0-24 (P = .815), nor in Cmax (P = .564). GMRs were 1.08 in Cmax, and 1.03 in AUC. In Cohort A, a skin rash appeared in 50% in eight days, and in 83% in 15 days. In Cohort B, a skin rash was seen in 64% in 8 days, and in 82% in 15 days. There was no significant association between time to first skin rash of any grade and the two conditions (P = .974).
[Conclusion] Although the AUC0-24 of E increased significantly faster in the post-meal status than in complete fasting status, there was no significant difference in pharmacokinetics in steady state and toxicitiy between the two clinically-used fed conditions of E.
Citation Format: Yuki Katsuya, Yutaka Fujiwara, Kuniko Sunami, Hirofumi Utsumi, Yasushi Goto, Shintaro Kanda, Hidehito Horinouchi, Hiroshi Nokihara, Noboru Yamamoto, Yuichiro Ohe, Satoko Osawa, Akinobu Hamada. Comparison of the pharmacokinetics of erlotinib administered in complete fasting and two hours after a meal in non-small cell lung cancer patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4509. doi:10.1158/1538-7445.AM2015-4509