The inorganic, lyophilized form of arsenic trioxide, when placed into solution, immediately forms the hydrolysis product arsenious acid (As III). As III is the pharmacologically active species of arsenic trioxide. Monomethylarsonic acid (MMA V), and dimethylarsinic acid (DMA V) are the main pentavalent metabolites formed during metabolism, in addition to arsenic acid (As V) a product of AsIIIoxidation. The pharmacokinetics of arsenical species ([As III], [As V], [MMA V], [DMA V]) were determined in 6 APL patients following once-daily doses of 0.15 mg/kg for 5 days per week. Over the total single-dose range of 7 to 32 mg (administered as 0.15 mg/kg), systemic exposure (AUC) appears to be linear. Peak plasma concentrations of arsenious acid (As III), the primary active arsenical species were reached at the end of infusion (2 hours). Plasma concentration of As III declined in a biphasic manner with a mean elimination half-life of 10 to 14 hours and is characterized by an initial rapid distribution phase followed by a slower terminal elimination phase. The daily exposure to As III(mean AUC0-24) was 194 ng·hr/mL (n=5) on Day 1 of Cycle 1 and 332 ng·hr/mL (n=6) on Day 25 of Cycle 1, which represents an approximate 2-fold accumulation. The primary pentavalent metabolites, MMA Vand DMA V, are slow to appear in plasma (approximately 10-24 hours after first administration of arsenic trioxide), but, due to their longer half-life, accumulate more upon multiple dosing than does As III. The mean estimated terminal elimination half-lives of the metabolites MMA V and DMA V are 32 hours and 72 hours, respectively. Approximate accumulation ranged from 1.4- to 8-fold following multiple dosing as compared to single dose administration. AsVis present in plasma only at relatively low levels. 

Distribution

The volume of distribution (V ss) for As III is large (mean 562 L, N=10) indicating that As III is widely distributed throughout body tissues. V ss is also dependent on body weight and increases as body weight increases. 

Elimination

Metabolism

Much of the As III is distributed to the tissues where it is methylated to the less cytotoxic metabolites, monomethylarsonic acid (MMA V) and dimethylarsinic acid (DMA V) by methyltransferases primarily in the liver. The metabolism of arsenic trioxide also involves oxidation of As III to As V, which may occur in numerous tissues via enzymatic or nonenzymatic processes. As V is present in plasma only at relatively low levels following administration of arsenic trioxide. 

Excretion

Approximately 15% of the administered arsenic trioxide injection dose is excreted in the urine as unchanged As III. The methylated metabolites of As III (MMA V, DMA V) are primarily excreted in the urine. The total clearance of As III is 49 L/h and the renal clearance is 9 L/h. Clearance is not dependent on body weight or dose administered over the range of 7-32 mg. 

Specific Populations

Patients with Renal Impairment

The effect of renal impairment on the pharmacokinetics of As III, As V, and the pentavalent metabolites MMA V and DMA V was evaluated in 20 patients with advanced malignancies. Patients were classified as having normal renal function (creatinine clearance [CrCl] > 80 mL/min, n=6), mild renal impairment (CrCl 50-80 mL/min, n=5), moderate renal impairment (CrCl 30-49 mL/min, n=6), or severe renal impairment (CrCl < 30 mL/min, n=3). Following twice weekly administration of 0.15 mg/kg over a 2-hour infusion, the mean AUC 0-∞ for As III was comparable among the normal, mild and moderate renal impairment groups. However, in the severe renal impairment group, the mean AUC 0-∞ for As III was approximately 48% higher than that in the normal group. 

Systemic exposure to MMA V and DMA V tended to be larger in patients with renal impairment; however, the clinical consequences of this increased exposure are not known. As V plasma levels were generally below the limit of assay quantitation in patients with impaired renal function [see Use in Specific Populations ( 8.6) ]. The use of arsenic trioxide in patients on dialysis has not been studied. 

Patients with Hepatic Impairment

The effect of pharmacokinetics of As III, As V, and the pentavalent metabolites MMA V and DMA V was evaluated following administration of 0.25-0.50 mg/kg of arsenic trioxide in patients with hepatocellular carcinoma. Patients were classified as having normal hepatic function (n=4), mild hepatic impairment (Child-Pugh class A, n=12), moderate hepatic impairment (Child-Pugh class B, n=3), or severe hepatic impairment (Child-Pugh class C, n=1). No clear trend toward an increase in systemic exposure to As III, As V, MMA V or DMA V was observed with decreasing level of hepatic function as assessed by dose-normalized (per mg dose) AUC in the mild and moderate hepatic impairment groups. However, the one patient with severe hepatic impairment had mean dose-normalized AUC 0-24 and C max values 40% and 70% higher, respectively, than those patients with normal hepatic function. The mean dose-normalized trough plasma levels for both MMAVand DMAV in this severely hepatically impaired patient were 2.2-fold and 4.7-fold higher, respectively, than those in the patients with normal hepatic function [see Use in Specific Populations ( 8.7) ]. 

Pediatric Patients

Following IV administration of 0.15 mg/kg/day of arsenic trioxide in 10 APL patients (median age = 13.5 years, range 4-20 years), the daily exposure to As III (mean AUC 0-24h) was 317 ng·hr/mL on Day 1 of Cycle 1 [see Use in Specific Populations ( 8.4) ]. 

Drug Interaction Studies

No formal assessments of pharmacokinetic drug-drug interactions between arsenic trioxide injection and other drugs have been conducted. The methyltransferases responsible for metabolizing arsenic trioxide are not members of the cytochrome P450 family of isoenzymes. In vitro incubation of arsenic trioxide with human liver microsomes showed no inhibitory activity on substrates of the major cytochrome P450 (CYP) enzymes such as 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4/5, and 4A9/11. The pharmacokinetics of drugs that are substrates for these CYP enzymes are not expected to be affected by concomitant treatment with arsenic trioxide.