12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Exjade (deferasirox) is an orally active chelator that is selective for iron (as Fe3+). It is a tridentate ligand that binds iron with high affinity in a 2:1 ratio. Although deferasirox has very low affinity for zinc and copper there are variable decreases in the serum concentration of these trace metals after the administration of deferasirox. The clinical significance of these decreases is uncertain.
Pharmacodynamic effects tested in an iron balance metabolic study showed that deferasirox (10, 20 and 40 mg/kg per day) was able to induce a mean net iron excretion (0.119, 0.329 and 0.445 mg Fe/kg body weight per day, respectively) within the clinically relevant range (0.1-0.5 mg/kg per day). Iron excretion was predominantly fecal.
Exjade is absorbed following oral administration with median times to maximum plasma concentration (tmax) of about 1.5-4 hours. The Cmax and AUC of deferasirox increase approximately linearly with dose after both single administration and under steady-state conditions. Exposure to deferasirox increased by an accumulation factor of 1.3-2.3 after multiple doses. The absolute bioavailability (AUC) of deferasirox tablets for oral suspension is 70% compared to an intravenous dose. The bioavailability (AUC) of deferasirox was variably increased when taken with a meal.
Deferasirox is highly (~99%) protein bound almost exclusively to serum albumin. The percentage of deferasirox confined to the blood cells was 5% in humans. The volume of distribution at steady state (Vss) of deferasirox is 14.37 ± 2.69 L in adults.
Glucuronidation is the main metabolic pathway for deferasirox, with subsequent biliary excretion. Deconjugation of glucuronidates in the intestine and subsequent reabsorption (enterohepatic recycling) is likely to occur. Deferasirox is mainly glucuronidated by UGT1A1 and to a lesser extent UGT1A3. CYP450-catalyzed (oxidative) metabolism of deferasirox appears to be minor in humans (about 8%).
Deferasirox and metabolites are primarily (84% of the dose) excreted in the feces. Renal excretion of deferasirox and metabolites is minimal (8% of the administered dose). The mean elimination half-life (t1/2) ranged from 8-16 hours following oral administration.
Pharmacokinetics in Special Populations
Pediatric: Following oral administration of single or multiple doses, systemic exposure of adolescents and children to deferasirox was less than in adult patients. In children <6 years of age, systemic exposure was about 50% lower than in adults.
Geriatric: The pharmacokinetics of deferasirox have not been studied in geriatric patients (65 years of age or older).
Gender: Females have a moderately lower apparent clearance (by 17.5%) for deferasirox compared to males.
Renal Insufficiency: Deferasirox is minimally (8%) excreted via the kidney.
Hepatic Impairment: Deferasirox is principally excreted by glucuronidation and is minimally (8%) metabolized by oxidative cytochrome P450 enzymes. Exjade treatment has been initiated in patients with baseline liver transaminase levels up to 5 times the upper limit of the normal range. The pharmacokinetics of deferasirox were not influenced by such transaminase levels.
12.4 QT Prolongation
The effect of 20 and 40 mg/kg per day of deferasirox on the QT interval was evaluated in a single-dose, double-blind, randomized, placebo- and active-controlled (moxifloxacin 400 mg), parallel group study in 182 healthy male and female volunteers age 18-65 years. No evidence of prolongation of the QTc interval was observed in this study.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
A 104-week oral carcinogenicity study in Wistar rats showed no evidence of carcinogenicity from deferasirox at doses up to 60 mg/kg per day (about 0.48 times the recommended human oral dose based on body surface area). A 26-week oral carcinogenicity study in p53 (+/-) transgenic mice has shown no evidence of carcinogenicity from deferasirox at doses up to 200 mg/kg per day (about 0.81 times the recommended human oral dose based on body surface area) in males and 300 mg/kg per day (about 1.21 times the recommended human oral dose based on body surface area) in females.
Deferasirox was negative in the Ames test and chromosome aberration test with human peripheral blood lymphocytes. It was positive in 1 of 3 in -vivo oral rat micronucleus tests.
Deferasirox at oral doses up to 75 mg/kg per day (about 0.6 times the recommended human oral dose based on body surface area) was found to have no adverse effect on fertility and reproductive performance of male and female rats.