Deferasirox / Deferoxamine

Pharmacokinetics

Pharmacokinetics

• Deferasirox: Oral administration once a day (dispersible or coated tablets). Bioavailability of approx. 70%. Maximum plasma concentration achieved in 1 to 3 hours. Highly bound to human plasma proteins (~99%, mainly albumin). It undergoes minor hepatic metabolism by glucuronidation (UGT1A1 and UGT1A3). Almost exclusive fecal excretion (84% of the dose excreted as iron complex via the bile-fecal route); negligible renal clearance of 8%. Prolonged half-life of 8 to 16 hours, allowing single daily dosing.
• Deferoxamine: Exclusive parenteral administration (intravenous, slow subcutaneous by needle microinfuser). No gastric absorption orally. Rapid intravascular distribution with rapid tissue clearance. Rapid plasma and tissue metabolism through nonspecific hydrolysis. Rapid biliary and renal excretion (urine acquires a characteristic "reddish-wine" brown color after the elimination of the ferrioxamine complex). Ultrashort plasma half-life of only 20 to 30 minutes, requiring continuous prolonged infusions of up to 8 - 12 hours.

Indicators and dose

Indications

• Treatment of chronic iron overload secondary to frequent blood transfusions (transfusional hemosiderosis) in adult and pediatric patients with beta-thalassemia major, sickle cell anemia, or severe chronic anemias.
• Treatment of chronic iron overload in patients with non-transfusion-dependent thalassemic syndromes (primary iron overload due to increased intestinal absorption).
• Treatment of acute systemic iron poisoning (mainly intravenous deferoxamine bolus and continuous infusion).

Dosage and Settings

• Deferasirox: Standard starting dose of 14 mg/kg once daily orally (coated tablets) or 20 mg/kg (dispersible tablets). The dosage should be adjusted monthly based on peripheral serum ferritin levels (seeking to maintain ferritin strictly below 1,000 µg/L, and temporarily suspending the drug if ferritin falls below 500 µg/L to avoid tissue toxicity due to iron underdosing).
• Deferoxamine: Prophylaxis of chronic transfusion overload by slow subcutaneous infusion administered by portable microinfusion pump in a range of 20 mg/kg to 40 mg/kg per day infused continuously over 8 to 12 hours (generally during the night's rest period), 3 to 5 times per week.

Pregnancy and Breastfeeding

FDA Category C. Minimally crosses the placenta. Studies demonstrate embryonic toxicity and delayed fetal ossification in exposed animal models. Its administration is contraindicated during pregnancy, chelation therapy being suspended from the moment of confirmation of pregnancy. Active breastfeeding is not recommended.

Security

Contraindications

Absolute

• Hypersensitivity to the active ingredient or excipients.
• Severe chronic renal failure with creatinine clearance Cl_Cr < 30 mL/min (especially Deferasirox due to direct nephrotoxicity).
• Severe active decompensated liver disease.
• Very high-risk myelodysplastic syndromes or neoplasms with poor prognosis where the benefit of chelation is clinically doubtful.

Relative

• Mild to moderate renal failure (Cl_Cr 30 - 60 mL/min).
• Frail elderly people with multiple comorbidities.
• Pre-existing hearing or visual disorders.

Adverse Effects (ADR)

• Nephrotoxicity: Increase in serum creatinine and development of reversible proteinuria, secondary to direct toxicity on renal proximal tubular cells (which may lead to acquired Fanconi Syndrome). Requires weekly monitoring of creatinine and proteinuria in 24-hour urine during the initiation of treatment.
• Gastrointestinal toxicity: Nausea, dyspepsia, diarrhea, severe gastrointestinal bleeding, and gastrointestinal perforation (reported primarily in elderly patients treated with deferasirox).
• Hearing and Visual Loss: Bilateral sensorineural hearing loss, optic neuritis and corneal opacities (cataracts) induced by extreme tissue depletion of essential trace metals in sensory tissues. Requires periodic audiometric and ophthalmological evaluations.
• Risk of Infections: Deferoxamine acts as a growth-promoting factor for certain bacteria that require iron to proliferate (such as *Yersinia enterocolitica*) and opportunistic fungi (Mucormycosis), predisposing to opportunistic sepsis. The chelator should be discontinued immediately if fever or *Yersinia* infection is suspected.

Interactions

Avoid coadministration of Deferasirox with antacids containing aluminum compounds to prevent the risk of systemic cross-metal overload. Vitamin C administered concomitantly with Deferoxamine enhances the release and mobilization of myocardial intracellular iron; However, excessive doses of vitamin C (> 200 mg/day) can precipitate acute heart failure due to bypass myocardial dysfunction, and vitamin C should be administered at least 1 hour after starting the Deferoxamine infusion.