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

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 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.

Effects of CYP3A4/5 and ABC transporter polymorphisms on osimertinib plasma concentrations in Japanese patients with non-small cell lung cancer

“…Therefore, the lack of relationship between the osimertinib AUC and rash or diarrhea in the current study may not have been related to differences in osimertinib exposure between our current study and the previous study [3]. Similar to the previous study [3], the CTCAE grades of rash and diarrhea induced by osimertinib in our study were 1 or 2, and the frequencies of these side effects were lower (n = 5 and 6, respectively) than those in studies of other EGFR-TKIs, such as ge tinib and afatinib [15,24,25]. Therefore, additional studies with larger sample sizes may be needed to evaluate the target plasma concentration of osimertinib required to avoid the onset of rash or diarrhea.…”

FDA-Approved Drug Screening in Patient-Derived Organoids Demonstrates Potential of Drug Repurposing for Rare Cystic Fibrosis Genotypes

“…In the secondary screen, several TKIs were found to elevate CFTR function, such as Afatinib and Erlotinib. Interactions between CFTR and TKIs such as Afatinib have indeed previously been described, for example in the context of RTK inhibitor induced diarrhea 29 . A recent study describes that EGFR TKIs potentiated the activity of potassium and CFTR chloride channels in T84 cell monolayers and rat models 30 .…”

Mechanism and treatment of diarrhea associated with tyrosine kinase inhibitors

“…Tyrosine kinase inhibitors are primarily metabolized by cytochrome P450 (CYP) 3A4 and transported by efflux ATP-binding cassette (ABC) transporter B1 and G2 [ 59 ]. Afatinib plasma concentration correlates with the severity of diarrhea in the early phase of treatment [ 60 , 61 ]. Patients carrying the A allele of ABCG2 C421A have higher afatinib plasma concentrations and more severe diarrhea [ 60 ].…”