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.