Case report
A 75-year-old man, with no cardiovascular history and a Eastern Cooperative Oncology Group Performance Status score of 1, had a diagnosis of metastatic, synchronous NSCLC with MET exon-14 deletion. Thoracic-abdominal-pelvic computed tomography (CT) revealed pulmonary and renal metastases. Crizotinib was initiated at the recommended dose (250 mg twice a day) in March (Figure 1) (3). The diagnosis of HCV infection genotype 1A was confirmed in April (viral load 1.08 x106 IU/mL). Aspartate aminotransferase, gamma glutamyl transferase, alkaline phosphatase, bilirubin, and albumin levels; prothrombin ratio; and platelet count were within normal ranges; alanine aminotransferase level was 1.3 the upper limit of normal, and creatinine level was 111.5 µmol/L. Liver stiffness (Fibroscan) was 13.5 kPa, suggesting advanced liver disease. Hepatic steatosis was identified by ultrasonography. Therefore, after the first tumor-response evaluation showing partial tumor response and in the context of a fair cancer prognosis associated with advanced liver disease, sofosbuvir/velpatasvir (400 mg/100 mg, once daily), was started in June for 12 weeks (Figure 1) (4). The official Summary of Product Characteristics contained no information about a potential pharmacokinetic DDI (5).
Crizotinib was well tolerated, but 1 week after sofosbuvir/velpatasvir initiation, the patient experienced bilateral lower-limb edema and class III New York Heart Association dyspnea (NYHA). Electrocardiography revealed grade 2 sinus bradycardia with normal PR interval, which is a reported toxic effect of crizotinib, with heart rate decreasing from 69 to 50 beats per min before and after sofosbuvir/velpatasvir initiation, respectively. Serum electrolyte levels were normal. Transthoracic echocardiography and chest CT scan revealed no new anomalies. After a multidisciplinary consultation (oncologist, cardiologist, pharmacist), crizotinib causality was deemed possible and was withdrawn (3,6). Plasma drug monitoring showed a 1.6-fold increase in plasma trough concentration (Cmin) of crizotinib since DAA initiation and confirmed crizotinib plasma overexposure (7). In mid-July, the symptoms had resolved. Crizotinib was resumed at 200 mg twice a day and was well tolerated (Figure 1), with heart rate 62 beats per minute. Two plasma drug monitorings, performed in August and September, revealed velpatasvir plasma overexposure, Cmin 1255 and 1752 ng/mL, respectively (mean target Cmin 42 ±28 ng/mL) (8). The plasma Cmin for sofosbuvir and its major metabolite SOF-007 measured after re-initiation of crizotinib was within the normal range.
One month after sofosbuvir/velpatasvir discontinuation, crizotinib was increased to 250 mg twice a day with no toxic effects. The patient achieved sustained virologic response at 12 weeks after treatment. Cancer progression was documented 8 months after the initiation of crizotinib.