Case presentation

In this case presentation we report on a 63 year old man treated for BRAF-mutated metastatic melanoma spread to lymph nodes, pleural cavity, lungs, liver as well as a suspected asymptomatic brain metastasis. Initially, the patient received dabrafenib in combination with trametinib resulting in excellent clinical and radiological response. Due to grade 2 pyrexia and chills the patient’s treatment was discontinued and he was switched to ipilimumab in combination with nivolumab. After 2 courses he developed grade 3 colitis treated first with prednison and subsequently with infliximab. Unfortunately he showed progressive disease with new peritoneal metastases. In addition, he was in clinical distress caused by pleural effusion and ascites. He was re-challenged with dabrafenib plus trametinib, which again resulted in significant clinical and radiological response. However chills grade 2 also reoccurred and he was switched to encorafenib in combination with binimetinib, a regime known with low prevalence of pyrexia or chills as adverse events (5, 6). At that moment medication used by the patient was paracetamol 1000 mg QID p.r.n., omeprazole 40 mg BID, metoclopramide 10 mg TID p.r.n; cotrimoxazol 480 mg QD, fluconazole 100 mg QD; salbutamol QID p.r.n; gastilox chewable tablet TID. Prednisolone dose was 10 mg QD for 1 week, followed by 5 mg or 10 mg every other day, for the next week, followed by 5mg QD for a week, after which prednisolone intake stopped. For encorafenib the dose prescribed was 450 mg QD (08.00h), consisting of 6 capsules of 75 mg and 45 mg BID (08.00h and 18.00h), consisting of 3 tablets of 15 mg for binimetinib.
Sixteen days after having started the new oral oncolytic therapy the patient came to the hospital mentioning an upset stomach, bloating, occasional vomiting, and muscle pain probably caused by him working in and around the house. After an in depth anamneses of the patient it seemed that he had taken a double dose (900 mg QD instead of 450 mg QD) encorafenib in combination with the prescribed dose of binimetinib (45 mg BID) for 16 days. After inquiring about the reason for taking this double dose, the patient confirmed that the nurse practitioner had discussed the medication prescription correctly with him, but he himself had not read the prescription with enough detail (flyer was too full with confusing pictograms). Additionally, due to the covid-19 pandemic, his medication was delivered at home, so he missed the additional information normally given at the first dispensing by the pharmacy. To treat the patient’s chronic intoxication it was decided to opt for an observational approach, sustained by the fact that the product label did not mention any specific treatment in case of an overdose encorafenib and the patient did not mention suffering from any serious conditions besides the above-mentioned. Based on the most occurring adverse events of encorafenib, liver values, kidney function parameters and QTc interval were measured (Table 1). It can be concluded that 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 of 447 ms (reference value <420 ms).
Based on the pharmacokinetic profile of encorafenib such as short half-life =6.32 hours (1) which is independent of the dose and non-saturable absorption of encorafenib, no signs of accumulation and no delayed intoxication related symptoms were to be expected. However, because of lacking literature on encorafenib pharmacokinetics in case of a chronic intoxication it was decided to monitor plasma levels 3 hours after the last dose. Levels were measured at the Department of Pharmacy & Pharmacology, Netherlands Cancer Institute, Amsterdam, the Netherlands, using a liquid chromatography-tandem mass spectrometric assay (7). This level turned out to be 2110 ng/mL
It was decided to re-start the treatment with encorafenib in combination with binimetinib. As the patient had ingested a double dose of encorafenib for 16 days, he no longer had any encorafenib tablets available at home. As a new supply would be available after the weekend, it was decided to re-start encorafenib as well as binimetinib after 3 days after the last dose.