Pharmacokinetics, Metabolism, and Disposition of Deferasirox in β-Thalassemic Patients with Transfusion-Dependent Iron Overload Who Are at Pharmacokinetic Steady State

Abstract

ABSTRACT:Deferasirox (ICL670) is a novel once-daily, orally administered iron chelator to treat chronic iron overload in patients with transfusiondependent anemias. Absorption, distribution, metabolism, and excretion of [ 14 C]deferasirox at pharmacokinetic steady state was investigated in five adult ␤-thalassemic patients. Deferasirox (1000 mg) was given orally once daily for 6 days to achieve steady state. On day 7, patients received a single oral 1000-mg dose (ϳ20 mg/kg) of [ 14 C]deferasirox (2.5 MBq). Blood, plasma, feces, and urine samples collected over 7 days were analyzed for radioactivity, deferasirox, its iron complex Fe-[deferasirox] 2 , and metabolites. Deferasirox was well absorbed. Deferasirox and its iron complex accounted for 87 and 10%, respectively, of the radioactivity in plasma (area under the curve at steady state). Excretion occurred largely in the feces (84% of dose), and 60% of the radioactivity in the feces was identified as deferasirox. Apparently unchanged deferasirox in feces was partly attributable to incomplete intestinal absorption and partly to hepatobiliary elimination of deferasirox (including first-pass elimination) and of its glucuronide. Renal excretion was only 8% of the dose and included mainly the glucuronide M6. Oxidative metabolism by cytochrome 450 enzymes to M1 [5-hydroxy (OH) deferasirox, presumably by CYP1A] and M4 (5-OH deferasirox, by CYP2D6) was minor (6 and 2% of the dose, respectively). Direct and indirect evidence indicates that the main pathway of deferasirox metabolism is via glucuronidation to metabolites M3 (acyl glucuronide) and M6 (2-O-glucuronide).In patients with transfusion-dependent anemias, toxic and potentially lethal levels of iron accumulate over time. Humans are unable to actively eliminate iron from the body, once it has been acquired. Toxic and eventually lethal levels of iron accumulate as a result of repeated transfusions, e.g., in ␤-thalassemia major, or because of excessive dietary iron uptake in anemias and hereditary hemochromatosis (Barton, 2007). The harmful effects of chronic iron overload can lead to damage of the liver, heart, and endocrine glands, resulting in organ compromise and death. For the last 40 years, deferoxamine (Desferal) has been the standard of care for removal of excess body iron. The poor oral bioavailability and the short plasma half-life of deferoxamine necessitate its administration as slow subcutaneous or intravenous infusions. As a result, the most common difficulty associated with long-term deferoxamine is erratic compliance with therapy (Kushner et al., 2001). The need for an iron chelator that can be given orally has been recognized for a long time.Deferasirox (ICL670, Exjade; Novartis Pharma AG, Basel, Switzerland) is a potent and specific iron chelator, recently approved as first-line therapy for blood transfusion-related iron overload; it binds Fe 3ϩ in a 2:1 ratio (Nick et al., 2002). The recommended initial daily dose is 20 mg/kg b.wt., rounded to the nearest available tablet strength; the currently rec...

Update on Iron Chelators in Thalassemia

“…16,19,21 Recent availability of an intravenous preparation of deferasirox (for investigational use only) has allowed pharmacokinetic assessments of bioavailability and volume of distribution, 22 and a radiolabeled form allows detailed description of metabolism in thalassemic patients. 23 We have studied patients with inadequate responses in liver iron or ferritin at doses above 30 mg/kg and compared them against patients with good response at lower doses. The two groups are distinguished by much lower exposure (area under the concentration/time curve) in the poor responders, an effect likely due to differential bioavailability (and not compliance or transfusion burden alone).…”

A new HPLC UV validated method for therapeutic monitoring of deferasirox in thalassaemic patients

“…In recent years, numerous papers have reported the use of high throughput bioanalytical procedures for the quantification of iron chelating drugs [8], [10], [13], [19], [20], [21], [22] and [23]. Those reporting the use of high performance liquid chromatography coupled with ultraviolet determination (HPLC UV) methods [8], [10], [13], [20] and [23], all applied methodology developed by Rouan in 2001 [19].…”

“…Those reporting the use of high performance liquid chromatography coupled with ultraviolet determination (HPLC UV) methods [8], [10], [13], [20] and [23], all applied methodology developed by Rouan in 2001 [19]. More recently liquid chromatographic methods based on mass spectrometry (LC MS MS) detection have been developed to this purpose [21] and [22], although MS facilities are not always available in standard hospital laboratories.…”

Management of the Thalassemias

“…The synthetic chelator deferasirox is a bis-hydroxyphenyl-triazole that, in contrast to deferoxamine, is well absorbed from the gastrointestinal tract and cleared from the circulation slowly with a plasma half-life of 11 -19 h, supporting once-daily oral dosing Nisbet-Brown et al 2003;Waldmeier et al 2010). Because of low water solubility of the free ligand, deferasirox is administered as a suspension in water or fruit juice (Novartis Pharmaceuticals 2010).…”

“…Hepatocytes readily take up deferasirox, which chelates hepatocellular iron. Deferasirox-iron complexes are excreted in the bile (Waldmeier et al 2010).…”