Pharmacokinetics (PK) of arsenic trioxide in cancer patients (pts) with renal dysfunction: Preliminary results

Abstract

2018 Background: Trisenox (arsenic trioxide- ATO) is approved for treatment of relapsed/refractory acute promyelocytic leukemia. This study was designed to determine the PK of ATO in adult cancer pts with renal dysfunction and to evaluate its safety. Methods: 14 pts (median age 66 yrs, 29–85) in 4 renal function (RF) groups (normal- CLCR >80 mL/min; mild dysfunction: 50–80; moderate: 30–49; severe: <30) received IV ATO 0.15 mg/kg/d twice weekly for 4 wks, followed by 2 weeks without drug. Pts were treated for 2 six-week cycles. Arsenious acid (AsIII), arsenic acid (AsV), monomethyl arsonic acid (MMA), and dimethylarsinic acid (DMA) concentrations in plasma and urine were determined by validated methods based on anion exchange HPLC combined with ICPMS. Results: AsIII was rapidly distributed throughout the body (Table). MMA and DMA concentrations reached maximum values 24 hr after ATO. Urinary excretion of all As-containing species accounted for 27% of the dose (days 1–3). No significant correlations were found between AsIII PK parameters and RF, expressed by the CLCR value, except for urinary excretion, which was linearly correlated with CLCR (p<0.01). Exposure to inactive metabolites MMA and DMA inversely correlated with RF (p<0.05). After repeated dosing, plasma concentrations and excretion of methylated metabolites in urine were greater than those observed after the 1st administration, suggesting accumulation. The only severe drug-related toxicity was 1 grade 3 hyperglycemia. Conclusions: Renal excretion does not appear to be the main elimination route for AsIII, which is extensively metabolized to MMA and DMA. Systemic exposure of patients to AsIII, the active species, appears unaffected by RF, even in pts with severe dysfunction. Some accumulation of slowly eliminated metabolites MMA and DMA occurs on repeated dosing. ATO is well-tolerated at this dose in this pt population. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Cell Therapeutics, Inc. Cell Therapeutics, Inc. Cell Therapeutics, Inc. Cell Therapeutics, Inc.