Abstract
Simple SummaryHigher 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 AUC0–24 of greater than or equal to 823.5 ng·h/mL and C0 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 AUC0–24 and C0 of afatinib was observed (r2 = 0.761; p < 0.001). Therefore, we could use C0 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 C0 of more than 28.5 ng/mL was 16 days. Therefore, we recommend monitoring the C0 of afatinib on day 8 after the beginning of afatinib therapy.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 C0 and AUC0–24 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 AUC0–24 threshold of 823.5 ng·h/mL, and 0.754 with the highest sensitivity (89%) and specificity (74%) at a C0 threshold of 28.5 ng/mL. In Kaplan–Meier analysis based on these cut-off AUC0–24 and C0 values, the median time to the incidence of grade 2 diarrhea was 16 days. The predicted AUC0–24 of afatinib from the single point of C6 showed the highest correlation with the measured AUC0–24 (r2 = 0.840); however, a significant correlation between the AUC0–24 and C0 was also observed (r2 = 0.761). C0 could be used as a marker of therapeutic drug monitoring because afatinib C0 was related to AUC0–24. Therefore, afatinib C0 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.
Highlights
We found that an afatinib AUC0–24 of greater than or equal to 823.5 ng·h/mL and a C0 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
Similar to the results of these previous studies [23,24], our current findings showed that patients with lower body weight tended to have higher afatinib AUC0–24 (p = 0.070) and to develop grade 2 diarrhea (p = 0.085); the results were not significant
Our results showed that C6 was the best single predictor of the AUC0–24 of afatinib, and an equation using samples measured at two specific points (C0 and C6 ) could best be used to approximate the AUC0–24 of afatinib
Summary
Afatinib is a second-generation tyrosine kinase inhibitor and irreversible ErbB-family blocker that is used for the first-line treatment of patients with epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) [1]. Diarrhea is a common side effect associated with afatinib treatment [2,3,4,5,6,7,8], and in clinical practice, the onset of diarrhea following afatinib treatment results in temporary withdrawal or discontinuation of therapy. Among EGFR-tyrosine kinase inhibitor (TKI) treatments, afatinib causes a significantly higher rate of diarrhea than erlotinib or gefitinib [9,10,11]. In the Japanese analysis of the LUX-Lung clinical trial, 75.9% of patients administered afatinib therapy required a dose reduction owing to severe side effects, 22% of which were diarrhea of Common Terminology Criteria for Adverse Events (CTCAE) grade 3 [12]
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