Arsenic trioxide

Arsenic Sesquioxide Arsenic Oxidearsenous Trioxide

Pharmacodynamic Properties

The mechanism of action of arsenic trioxide is not completely understood. Arsenic trioxide causes morphological changes and deoxyribonucleic acid (DNA) fragmentation characteristic of apoptosis in NB4 human promyelocytic leukaemia cells in vitro. Arsenic trioxide also causes damage or degradation of the fusion protein Pro-Myelocytic Leukaemia/Retinoic Acid Receptor-alpha (PML/RAR alpha).

Pharmacokinetic Properties

The inorganic, lyophilized form of arsenic trioxide, when placed into solution, immediately forms the hydrolysis product arsenious acid (AsIII). AsIII is the pharmacologically active species of arsenic trioxide.

Distribution

The volume of distribution (Vd) for AsIII is large (>400 L) indicating significant distribution into the tissues with negligible protein binding. Vd is also weight dependent, increasing with increasing body weight. Total arsenic accumulates mainly in the liver, kidney, and heart and, to a lesser extent, in the lung, hair, and nails.

Biotransformation

The metabolism of arsenic trioxide involves oxidation of arsenious acid (AsIII), the active species of arsenic trioxide, to arsenic acid (AsV ), as well as oxidative methylation to monomethylarsonic acid (MMAV) and dimethylarsinic acid (DMAV) by methyltransferases, primarily in the liver. The pentavalent metabolites, MMAV and DMAV, 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 AsIII. The extent of accumulation of these metabolites is dependent on the dosing regimen. Approximate accumulation ranged from 1.4- to 8-fold following multiple as compared to single dose administration. AsV is present in plasma only at relatively low levels.

In vitro enzymatic studies with human liver microsomes revealed that arsenic trioxide has no inhibitory activity on substrates of the major cytochrome P450 enzymes such as 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4/5, 4A9/11. Substances that are substrates for these P450 enzymes are not expected to interact with arsenic trioxide.

Elimination

Approximately 15% of the administered arsenic trioxide dose is excreted in the urine as unchanged AsIII. The methylated metabolites of AsIII (MMAV, DMAV) are primarily excreted in the urine. The plasma concentration of AsIII declines from peak plasma concentration in a biphasic manner with a mean terminal elimination half-life of 10 to 14 hours. The total clearance of AsIII over the single-dose range of 7-32 mg (administered as 0.15 mg/kg) is 49 L/h and the renal clearance is 9 L/h. Clearance is not dependent on the weight of the subject or the dose administered over the dose range studied. The mean estimated terminal elimination half-lives of the metabolites MMAV and DMAV are 32 hours and 70 hours, respectively.

Renal impairment

Plasma clearance of AsIII was not altered in patients with mild renal impairment (creatinine clearance of 50-80 mL/min) or moderate renal impairment (creatinine clearance of 30-49 mL/min). The plasma clearance of AsIII in patients with severe renal impairment (creatinine clearance less than 30 mL/min) was 40% lower when compared with patients with normal renal function.

Systemic exposure to MMAV and DMAV tended to be larger in patients with renal impairment; the clinical consequence of this is unknown but no increased toxicity was noted.

Hepatic impairment

Pharmacokinetic data from patients with hepatocellular carcinoma having mild to moderate hepatic impairment indicate that AsIII or AsV do not accumulate following twice-weekly infusions. No clear trend toward an increase in systemic exposure to AsIII, AsV, MMAV or DMAV was observed with decreasing level of hepatic function as assessed by dose-normalized (per mg dose) AUC.

Linearity/non-linearity

In the total single dose range of 7 to 32 mg (administered as 0.15 mg/kg), systemic exposure (AUC) appears to be linear. The decline from peak plasma concentration of AsIII occurs in a biphasic manner and is characterized by an initial rapid distribution phase followed by a slower terminal elimination phase. After administration at 0.15 mg/kg on a daily (n=6) or twice-weekly (n=3) regimen, an approximate 2-fold accumulation of AsIII was observed as compared to a single infusion. This accumulation was slightly more than expected based on single-dose results.

Preclinical Safety Data

Limited reproductive toxicity studies of arsenic trioxide in animals indicate embryotoxicity and teratogenicity (neural tube defects, anophthalmia and microphthalmia) at administration of 1-10 times the recommended clinical dose (mg/mĀ²). Fertility studies have not been conducted with arsenic trioxide. Arsenic compounds induce chromosomal aberrations and morphological transformations of mammalian cells in vitro and in vivo. No formal carcinogenicity studies of arsenic trioxide have been performed. However, arsenic trioxide and other inorganic arsenic compounds are recognised as human carcinogens.

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