No abstract

Sunitinib is an oral multi-target tyrosine kinase inhibitor approved for treating metastatic renal cell carcinoma (RCC). It is metabolized mainly by CYP3A4 to the pharmacologically active N-desethyl metabolite SU12662 [1]. In a phase I clinical trial, the recommended dose of sunitinib with manageable toxicity was determined to be 50 mg day −1 (4 weeks on, 2 weeks off; 4/2 schedule) [1]. Although a single dose of up to 350 mg was well tolerated [1], a case of sunitinib overdose has never been reported. Here, we report the pharmacokinetic analysis of sunitinib and a life-threatening adverse event in a patient with metastatic RCC who took 450 mg of sunitinib as a single dose together with brotizolam. Case reportA 51-year-old Japanese man underwent a nephrectomy for localized RCC. Seven and one-half years later, treatment was initiated in the patient with betamethasone and sunitinib 37.5 mg day −1 on a 2/1 schedule due to brain and multiple lung metastases. Despite a subsequent dose reduction to 25 mg day −1 due to recurrent bacterial pneumonia, his disease remained stable until 1.5 years later. However, he was brought to our hospital 9 h after a suicide attempt that involved taking 450 mg sunitinib and 14 mg brotizolam. On admission, his vital signs were stable and his physical examination was unremarkable. Significantly, laboratory data included a low haemoglobin level of 9.2 g dl −1 . Gastric lavage was not performed and plasmapheresis was refused. His consciousness deteriorated after admission, probably due to brotizolam but gradually recovered the following day with fluid replacement, although intermittent drowsiness lasted until 2 days later. His serum sunitinib concentration was 125.1 ng ml −1 at admission, increased to 321 ng ml −1 after 7.5 h, and fell below 50 ng ml −1 after 7 days (Figure 1). A peak serum SU12662 concentration of 22.5 ng ml −1 was observed after 2 days. A peak serum brotizolam concentration of 235.2 ng ml −1 was observed at admission. For 1 month, adverse events (grade 2 and above) were limited to grade 2 hypertension and increased amylase, as well as grade 3 increased lipase and lower gastrointestinal bleeding due to metastases. However, non-neutropenic sepsis due to Escherichia coli infection occurred suddenly and was treated successfully with doripenem for 4 days. Sunitinib was reinstated 2 weeks later and the patient was discharged without subsequent adverse events. DiscussionThis report describes high serum sunitinib and brotizolam concentrations caused by an overdose of sunitinib together with brotizolam and the subsequent occurrence of non-neutropenic sepsis. In this patient, tmax (16.5 h) was slightly increased compared with reported values (6-12 h) probably due to delay in the dissolution of sunitinib. By contrast, the terminal elimination half-life (134 h) of sunitinib was considerably increased compared with reported values (40-60 h) [1]. Moreover, the AUC(0,537 h) (29 515 ng ml −1 h) calculated by the trapezoidal method and Cmax (321 ng ml −1 ) were considerably higher than th...