title: A pharmacokinetic and safety study of intravenous arsenic trioxide in adult cancer patients with renal impairment.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medicine, Indiana University, 535 Barnhill Drive, Indianapolis, IN 46202, USA. chsweene@iupui.edu
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Sweeney
authors.forename: Chris
authors.initials: C
authors.lastname: Takimoto
authors.forename: Leslie
authors.initials: L
authors.lastname: Wood
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Porter
authors.forename: William G
authors.initials: WG
authors.lastname: Tracewell
authors.forename: Mona
authors.initials: M
authors.lastname: Darwish
authors.forename: Denise M
authors.initials: DM
authors.lastname: D'Andrea
authors.forename: Scot C
authors.initials: SC
authors.lastname: Remick
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D001711:Biotransformation; D005260:Female; D006801:Humans; D017567:Karnofsky Performance Status; D007674:Kidney Diseases / Q000150:complications / Q000378:metabolism*; D008297:Male; D008745:Methylation; D008875:Middle Aged; D009369:Neoplasms / Q000150:complications / Q000378:metabolism*; D010087:Oxides / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; D010087:Oxides; D000077237:Arsenic Trioxide