Pharmacokinetics of sorafenib in patients with renal impairment undergoing hemodialysis

Department of Internal Medicine, University of Essen Medical School, Essen, Germany.
International journal of clinical pharmacology and therapeutics (Impact Factor: 1.22). 02/2009; 47(1):61-4. DOI: 10.5414/CPP47061
Source: PubMed
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Available from: Wilfried E E Eberhardt
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    ABSTRACT: Sorafenib (Nexavar(®)) has been approved for the treatment of advanced renal cell carcinoma (RCC) and hepatocellular carcinoma. There is little information on the dosage adjustment of sorafenib for patients with end-stage renal failure. Herein, we have examined the effect of hemodialysis on the pharmacokinetics of sorafenib and its major active metabolite, M-2, and assessed sorafenib-related toxicity throughout the therapy. The patient was a 54-year-old man who was diagnosed with advanced RCC. Pharmacokinetic analysis was carried out on days 9 and 183. The patient had stable disease on day 77 and showed progression on day 181. He has received about 6 months of continuous treatment with sorafenib 800 mg/day without any clinically relevant toxicity. The pharmacokinetic parameters of sorafenib such as C (max) and AUC(0-12) on day 183 were in the range of the reference values reported in patients with normal renal function. Our results suggest that sorafenib administered at a dose of 400 mg twice per day was well tolerated, at least for 6 months, for a patient undergoing hemodialysis.
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    ABSTRACT: The incidence of renal cell carcinoma is increasing globally. Targeted agents offer treatment options that were not available less than a decade ago. However, it is important to carefully select therapy for each individual patient, weighing both the drug efficacy and tolerability profile and patient-related factors, such as adherence, age and comorbidities. Based on our clinical experience in treating patients with renal cell carcinoma, this article offers our opinions on factors that characterize patients for whom sorafenib may serve as a viable first-line therapeutic option.
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    ABSTRACT: We investigated the safety and feasibility of sorafenib in patients with end-stage renal disease undergoing hemodialysis by examining the influence of pharmacokinetic parameters to their benefit and also the occurrence of drug-related adverse events of sorafenib. Ten patients with metastatic renal cell carcinoma undergoing hemodialysis received sorafenib. Initial dose was 200 mg once daily, and the dose was increased up to the maintenance dose of 200 mg twice daily. The pharmacokinetic study was performed after a steady state was reached with 200 mg twice daily in six patients. Complete response occurred in one patient, partial response in three, stable disease in four and progressive disease in two. Median progression-free survival was 6.3 months. Serious adverse events were found in nine patients, including a Grade 5 subarachnoid hemorrhage and a Grade 4 cerebellar hemorrhage. In the pharmacokinetic study, the geometric mean of maximum concentration and area under the curve from 0 to 10 h of plasma concentration were similar on the day of hemodialysis and the day off hemodialysis. These data were lower than those from Japanese people with healthy kidneys and normal kidney function. There was no association between objective response or the occurrence of serious adverse events and pharmacokinetic parameters. Treatment with sorafenib of patients with metastatic renal cell carcinoma undergoing hemodialysis appears to be feasible, but we express some concern about the higher incidence of serious adverse events even with the reduced dose. However, clinical efficacy was not compromised.
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