Crizotinib/everolimus interaction
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Various toxicities: case report A 53-year-old woman developed nausea, purpura, iridopsia, taste disorders and oedema of face and extremities secondary to crizotinib toxicity following concomitant administration of crizotinib and everolimus. Additionally, she developed renal dysfunction during treatment with everolimus. The woman, who had undergone liver kidney transplantation in 1996, had been receiving immunosuppressant drug therapy with everolimus 0.75 mg/day, along with mycophenolate mofetil and methylprednisolone. Subsequently, she was diagnosed with stage IV (pT4N1 M1a) lung adenocarcinoma. From November 2015, she received six courses of carboplatin and albumin suspension type paclitaxel therapy with non-complete response. From December 2016, she received seven courses of gemcitabine with partial response. In February 2018, an increase in lung lesions was observed. Subsequently, she started receiving crizotinib as a third-line treatment. During crizotinib administration, she was receiving everolimus, which had a competitive inhibitory effect on CYP3A4, and was associated with the renal dysfunction. Laboratory investigation revealed WBC 4260 /µL, RBC 477 x 104/µL, haemoglobin 11.7 g/dL, blood urea nitrogen 24.4 mg/dL, creatinine 1.18 mg/dL and estimated glomerular filtration rate 38 mL/miniute/1.73m2. Thus, she started receiving crizotinib 200mg twice daily (reduced from the usual dose) [routes not stated]. However, she developed adverse events including grade II nausea and oedema of the face and extremities, grade I purpura and iridopsia, which were associated with crizotinib administration. It was considered that crizotinib blood level increased by the inhibition of crizotinib metabolism by everolimus, through CYP3A4 inhibitory effect. The blood level of everolimus was found to be increased from 1.2 to 6.9 ng/mL on day 21 following the start of crizotinib. Everolimus was then discontinued, which resulted in the improvement of purpura, iridopsia and oedema of the face and extremities. After everolimus withdrawal, the blood concentration of everolimus decreased rapidly. Immunosuppressant drug therapy was maintained by increasing the dose of mycophenolate mofetil, which was not involved in CYP3A4 metabolism. However, the woman’s nausea persisted, and developed grade II taste disorders as a new adverse event [time to reactions onsets not stated]. As the adverse events were considered to be caused by increased crizotinib blood levels (reached to toxic level) due to renal dysfunction, the dose of crizotinib was revised to 250mg once daily from day 63, and then to 200mg once daily from day 82 of crizotinib initiation. From day 84, crizotinib dose was gradually reduced to 200mg on alternate days for 3 weeks, which resulted in reduction in the adverse events of crizotinib [not all outcomes stated]. Takao S, et al. The administration of crizotinib to a ROSl-positive advanced non-small cell lung carcinoma patient under immunosuppressive therapy after renal transplantation: A case report. Haigan / Japanese Journal
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