Discussion

Here we present a patient with a chronic toxicity following 16 days of ingestion of a double dose (900 mg) of encorafenib. To the best of our knowledge, this is the first case report that described a detailed course of this intoxication, including the followed approach.
A prior report on encorafenib intoxications was mentioned in the product label (1). However, instead of a chronic intoxication it concerned an acute overdose. In 3 out of the 14 patients, kidney dysfunction (hypercreatinemia of grade 3) was observed after ingestion of 600 to 800 mg encorafenib. The highest administered dose, as a result of a dosing mistake, occurred in a patient who ingested a dose of encorafenib of 600 mg twice during one day (total dose of 1200 mg). The adverse events reported by this patient were events of nausea, vomiting and blurred vision grade 1, all disappearing afterwards. In general, the patient described in our case report showed also mild symptoms. Kidney function was not affected by this chronic intoxication, whereas liver values (mainly LD, GGT) were slightly increased. The ECG showed a slightly prolonged QTc interval. It has to be noted however, that increased LD and/or GGT does not have to be caused by the chronic intoxication, but may also be caused by the liver metastases. The mild symptoms occurring after the chronic intoxication also match with the plasma concentration level of 2110 ng/mL 3 hours after the last intake. In literature information is available on maximum concentrations (Cmax) achieved after around 2 hours of administration of therapeutic encorafenib dosages. Delord et al. reported a median Cmax of 3800 ng/mL in 6 patients with long-term use (15 days) of encorafenib 450 mg (8), while Sparidanset al. a Cmax of 1527 ng/mL in one patient who ingested 200 mg encorafenib (7). As encorafenib exhibits linear pharmacokinetics the above-mentioned Cmax can be extrapolated to an expected Cmax of 3436 ng/mL after administration of 450 mg. There seems to be no accumulation of encorafenib within the body as the accumulation ratio is 0.63 and with long-term use of encorafenib 0.45 (due to auto induction). Furthermore encorafenib has a short half-life, causing this Cmax reference value levels described in literature after one daily dosing to applied as a reference values in this case report. Extrapolating the plasma concentration level of 2110 ng/mL results in a Cmax (at 2 hours) of 2354.6 ng/mL being inline and far from increased in comparison with the reference concentrations reported in literature.
In conclusion, the fact that during long-term exposure to a double dose of encorafenib, both adverse events and plasma concentration level were acceptable, treatment can consist of closely monitoring the most important lab parameters (kidney, liver, QTc). This information may be useful for further treatment of intoxications with encorafenib.