Effects of renal impairment on the pharmacokinetics of sorafenib and its metabolites Free

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Sorafenib is an oral multikinase inhibitor approved for renal cell carcinoma. We evaluated the pharmacokinetics (PK) of sorafenib in subjects with normal renal function compared to subjects with mild, moderate, or severe renal impairment. Subjects were classified into 4 groups based on renal function: normal function (Cl_cr>80 mL/min); mild (Cl_cr 50-80 mL/min), moderate (Cl_cr 30-<50 mL/min), and severe impairment (Cl_cr<30 mL/min). The primary statistical analysis was based on Cl_cr determined by the Cockroft-Gault equation using subjects’ ideal body weight. As a secondary analysis, Cl_cr was also determined using subject’s actual body weight in an exploratory fashion. Subjects received one 400-mg dose of sorafenib. Plasma PK samples and urine were collected up to 144 h postdose. Thirty-two subjects were enrolled at 3 research centers. Mean age was 59 y (range, 39-74); 66% of subjects were male. AUC, C_max and half-life values for sorafenib are listed in the Table. The primary analysis showed aberrantly high AUC and C_max values for the mild group which was inconsistent with results in the moderate and severe groups. The secondary analysis re-classified several subjects from the mild group to the normal group, resulting in decreases in the AUC and C_max of the mild group and showing greater PK consistency across all four groups. PK results for sorafenib metabolites were similar to parent drug. Laboratory safety tests were consistent with kidney disease and showed no clinically relevant changes. Half of subjects reported at least 1 adverse event, the most common being headache. Most events were mild in nature. No serious AEs were observed during the study. No trend in PK parameters for sorafenib or its metabolites was observed among all the renal function groups. Renal impairment does not appear to have any consistent or clinically relevant effect on the PK of sorafenib and its metabolites, and therefore no dose adjustment is indicated.

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Pri = Primary Analysis; Sec = Secondary Analysis; CV = Coefficient of Variation