A pharmacokinetic and safety study of intravenous arsenic trioxide in adult cancer patients with renal impairment.

Purpose: This study evaluated the pharmacokinetic and safety profiles of arsenic trioxide given twice per week in adult cancer patients with advanced malignancies and varying degrees of renal function.

Methods: Patients received intravenous arsenic trioxide 0.15 mg/kg twice weekly for 4 weeks, followed by a 2-week rest period. The pharmacokinetic profiles of the pharmacologically active arsenical species, arsenious acid (As(III)), and its metabolites, monomethylarsonic acid (MMA(V)) and dimethylarsinic acid (DMA(V)), were evaluated during the first cycle for 72 h following doses on days 1 and 22. Safety assessments were made at each treatment visit.

Results: Twenty patients received an average of 11 doses. Compared with normal renal function, mild to severe renal impairment decreased urinary excretion of As(III) and increased exposure to MMA(V) and DMA(V) 1.4- to 8-fold after multiple dose administration. Only severe renal impairment substantially increased exposure to As(III) (AUC(0-t ) increased by 18% after a single dose and 40% after multiple doses). The safety profile of arsenic trioxide after limited treatment on a twice-per-week schedule was comparable across all renal function groups.

Conclusion: Renal impairment did increase the systemic exposure to arsenic and its methylated metabolites following standard daily dosing of arsenic trioxide. The data from the limited number of patients with severe renal dysfunction did not suggest that severe renal impairment affected the safety profile of arsenic trioxide in cancer patients who received limited treatment with arsenic trioxide.