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Ketoconazole/osilodrostat/paclitaxel Liver intolerance, drug-drug interaction and rebound effect: 3 case reports

In a case series, one woman [age at the time of event onset not stated] and two men aged 39 years and 70 years were described; of whom 2 patients (the woman and the man aged 39 years) developed liver intolerance during treatment with ketoconazole for severe hypercortisolism. The third patient (the man aged 70 years) developed liver intolerance in the form of hepatitis following the concurrent administration of paclitaxel and ketoconazole, and developed rebound effect in the form of elevated plasma cortisol level following the withdrawal of osilodrostat [routes not stated; not all dosages stated]. Case 1: The woman with severe hypercortisolism secondary to small cell lung carcinoma, started receiving treatment with ketoconazole. However, she developed liver intolerance related to the ketoconazole therapy [outcome not stated], and the ketoconazole therapy was discontinued. Subsequently, she started receiving treatment with metyrapone along with unspecified chemotherapy. She was effectively treated for 2 years, after which the metyrapone therapy was changed to osilodrostat due to shortage of availability (at the age of 51 years). Thereafter, her plasma cortisol concentrations remained in the target range. Eventually, she died due to tumoral burden [immediate cause of death not stated]. Case 2: The 39-year-old man with severe hypercortisolism secondary to adrenal carcinoma, started receiving treatment with ketoconazole 1200 mg/day. However after 10 days of treatment, he developed liver intolerance [outcome not stated], and the ketoconazole therapy was discontinued. Thereafter, his treatment was started with osilodrostat and mitotane along with unspecified chemotherapy. Case 3: The 70-year-old man with severe hypercortisolism secondary to small cell lung carcinoma, started receiving treatment with paclitaxel, metyrapone and ketoconazole 1200 mg/day (plasma cortisol level was 1970 nmol/L). After market shortage of metyrapone, osilodrostat was started at 1 mg/day. With the combined ketoconazole and osilodrostat treatment, his plasma cortisol level was maintained. Later, small cell lung carcinoma recurred, and the plasma cortisol level increased to 900 nmol/L. Hence, the dose of osilodrostat was increased to 4 mg/day for 14 days, and the cortisol level decreased by 50%. Subsequently, he developed liver intolerance in the form of hepatitis due to a pharmacological interaction between paclitaxel and ketoconazole. Hence, both paclitaxel and ketoconazole were discontinued [outcome of hepatitis not stated]. Additionally, osilodrostat was stopped. However, after 1 week of osilodrostat withdrawal, his plasma cortisol level increased to 1200 nmol/L from approximately 450 nmol/L (rebound effect). Therefore, osilodrostat was reinitiated at 7 mg/day, and the plasma cortisol level stabilised in 7 days. Later, the dose was decreased to 6 mg/day and hydrocortisone was added to the treatment regimen due to gradually dec