Relationship between Plasma Concentrations of Afatinib and the Onset of Diarrhea in Patients with Non-Small Cell Lung Cancer

SIMPLE SUMMARY: Higher afatinib plasma concentrations have been reported to be associated with the severity of diarrhea; however, the specific target plasma concentration of afatinib required to avoid severe diarrhea onset is unclear. We found that an afatinib AUC(0–24) of greater than or equal to 823.5 ng·h/mL and C(0) of greater than or equal to 28.5 ng/mL may be used as cut-off values for the incidence of afatinib-induced grade 2 diarrhea. A significant correlation between the AUC(0–24) and C(0) of afatinib was observed (r(2) = 0.761; p < 0.001). Therefore, we could use C(0) as a marker of therapeutic drug monitoring. In the current study, the median time to the incidence of grade 2 diarrhea in patients with a C(0) of more than 28.5 ng/mL was 16 days. Therefore, we recommend monitoring the C(0) of afatinib on day 8 after the beginning of afatinib therapy. ABSTRACT: We evaluated the area under the plasma concentration–time curve (AUC) of afatinib required to avoid the onset of grade 2 or higher diarrhea. The C(0) and AUC(0–24) of afatinib were significant higher in patients with grade 2 diarrhea than in those with grade 0–1 diarrhea. The areas under the receiver operator curves were 0.795 with the highest sensitivity (89%) and specificity (74%) at an AUC(0–24) threshold of 823.5 ng·h/mL, and 0.754 with the highest sensitivity (89%) and specificity (74%) at a C(0) threshold of 28.5 ng/mL. In Kaplan–Meier analysis based on these cut-off AUC(0–24) and C(0) values, the median time to the incidence of grade 2 diarrhea was 16 days. The predicted AUC(0–24) of afatinib from the single point of C(6) showed the highest correlation with the measured AUC(0–24) (r(2) = 0.840); however, a significant correlation between the AUC(0–24) and C(0) was also observed (r(2) = 0.761). C(0) could be used as a marker of therapeutic drug monitoring because afatinib C(0) was related to AUC(0–24). Therefore, afatinib C(0) should be monitored on day 8 after beginning therapy, and the daily dose of afatinib should be adjusted as an index with a cut-off value of 28.5 ng/mL.