High-Trough Plasma Concentration of Afatinib Is Associated with Dose Reduction

Abstract

Afatinib is used to treat non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation as a second-generation EGFR-tyrosine kinase inhibitor (TKI). Early prediction of adverse effects based on the pharmacokinetics of afatinib enables support for quality of life (QOL) in patients with no change in efficacy. We examined the pharmacokinetic relationship between trough plasma concentration and adverse effects and evaluated the utility of measuring the trough plasma concentration of afatinib as the first EGFR-TKI treatment for NSCLC in a prospective multicenter study. Twenty-four patients treated with afatinib were enrolled in this study. All blood samples were collected at the trough point, and plasma concentrations were measured using high-performance liquid chromatography–tandem mass spectrometry. Logistic regression analysis for the dose reduction of afatinib was performed, and the receiver operating characteristic (ROC) curve was plotted. Although all patients started afatinib at 40 mg/day, plasma concentrations were variable, and mean and median trough plasma concentrations were 32.9 ng/mL and 32.5 ng/mL in this study, respectively. Minimum and maximum trough plasma concentrations were 10.4 ng/mL and 72.7 ng/mL, respectively. This variability was speculated to involve personal parameters such as laboratory data. However, no patient characteristics or laboratory data examined correlated with the trough plasma concentration of afatinib, except albumin. Albumin showed a weak correlation with plasma concentration (r = 0.60, p = 0.009). The trough plasma concentration of afatinib was significantly associated with the dose reduction of afatinib (p = 0.047). The area under the ROC curve (AUC) for the trough plasma concentration of afatinib was 0.81. The cut-off value was 21.4 ng/mL. The sensitivity and specificity of the cut-off as a risk factor were 0.80 and 0.75. In summary, the trough plasma concentration of afatinib was associated with continued or reduced dosage because of the onset of several adverse effects, and a threshold was seen. Adverse effects not only lower QOL but also hinder continued treatment. Measuring plasma concentrations of afatinib appears valuable to predict adverse effects and continue effective therapy.

Afatinib 30 mg in the treatment of common and uncommon EGFR-mutated advanced lung adenocarcinomas: a retrospective, single-center, longitudinal study

“…However, in the LUX-Lung trials and subsequent realworld studies, more than a quarter or even up to half of patients receiving afatinib 40 mg/d initially had to reduce the dose eventually due to AEs (2,3,(13)(14)(15)23). The high frequency of AEs related to afatinib at 40 mg/d not only lowers the quality of life of patients but can also cause treatment discontinuation (24). On the contrary, afatinib starting from 30 mg/d may be more appropriate, especially for Asians patients with NSCLC (15,25).…”

Relationship Between Osimertinib Concentration and Clinical Response in Japanese Patients With Non-small Cell Lung Cancer

“…However, these treatments are associated with severe adverse events, such as skin rash, and diarrhea, which are associated with the inhibition of wild-type EGFR in skin and small intestine (14). Plasma trough concentrations of afatinib are associated with adverse events, suggesting the utility of determining plasma concentrations (15,16).…”