Association of lenvatinib trough plasma concentrations with lenvatinib-induced toxicities in Japanese patients with thyroid cancer.

The aim of this study was to examine the association of lenvatinib-induced adverse events with the trough plasma concentration (C0) in Japanese patients with thyroid cancer. Patients received lenvatinib 24 mg as an initial dose, and sequential dose reductions were conducted based on the grade of each side effect. Assessment of adverse events, assay of lenvatinib C0, and analysis of clinical laboratory tests were performed at the same time of day and were retrospectively analyzed. There were no significant differences in lenvatinib C0 among grades of hypertension, proteinuria, hand-foot syndrome, and diarrhea. However, levels of aspartate transaminase, alanine transaminase, and total bilirubin were significantly higher in lenvatinib C0 quartile (Q) 4 (≥ 88 ng/mL) than in Q1 (< 42 ng/mL) and Q2-3 (42-88 ng/mL). Additionally, platelet counts were highest in the lowest Q1 group. The median dose of lenvatinib in patients with UGT1A1*6/*6 or *6/*28 (poor metabolizers [PMs]) was significantly lower than that in patients with UGT1A1*1/*1 (10 and 14 mg, respectively), whereas the median bilirubin levels were significant higher in UGT1A1 PMs (0.9 and 0.5 mg/dL, respectively). There were no significant differences in median lenvatinib C0 values between patients with UGT1A1*1/*1 and PMs (58.0 and 50.0 ng/mL, respectively). The threshold between the C0 and toxicity of lenvatinib may be more than 88 ng/mL. Therefore, the dose of lenvatinib could be controlled to maintain a lower C0 of less than 88 ng/mL. The target C0 for lenvatinib as the threshold between the C0 and optimal response may be in the range from 42 to 88 ng/mL; however, further studies are necessary.