Deferasirox displays pharmacokinetic properties consistent with a once-daily oral iron chelator: moderate oral absorption, very high plasma protein binding, predominantly hepatic glucuronidation and biliary elimination of the iron complex. The PK profile is the foundation of weight-based daily dosing, the food-administration rule and the drug-interaction pattern observed in clinical practice.
Absorption #
Following oral administration of the dispersible tablet, deferasirox is absorbed with a median time to peak plasma concentration (Tmax) of approximately 1.5ÔÇô4 hours. Absolute oral bioavailability of the dispersible tablet on an empty stomach is around 70%, and increases further when administered with food: high-fat or standard meals raise systemic exposure (AUC) by approximately 15ÔÇô30%. To minimise food-related variability and maintain reproducible exposure, the dispersible tablet should be administered at least 30 minutes before food, at the same time each day, ideally first thing in the morning.
Tablet disintegration in water or juice produces a uniform suspension that is rapidly absorbed; chewing or swallowing the tablet whole is not recommended because it has not been characterised in PK studies and may alter the absorption profile.
Distribution #
| Plasma protein binding | ~99% (predominantly to serum albumin; not displaced clinically by warfarin, salicylates or diazepam) |
|---|---|
| Volume of distribution at steady state | ~14 L in adults ÔÇö small and consistent with restriction to plasma compartment |
| Plasma:blood ratio | ~0.6 ÔÇö deferasirox is essentially confined to plasma rather than partitioned into red cells |
| CSF / breast milk | Limited data. Penetration into breast milk has not been quantified in humans; treatment during breast-feeding is not recommended. |
The high plasma binding keeps deferasirox in the vascular compartment, where it can intercept labile plasma iron (LPI) and non-transferrin-bound iron (NTBI), the two pools most strongly implicated in tissue iron loading.
Metabolism #
Deferasirox is primarily metabolised by glucuronidation, mediated by UGT1A1 and to a lesser extent UGT1A3, producing pharmacologically inactive acyl-glucuronide metabolites. Cytochrome P450-mediated oxidation contributes only a minor fraction (Ôëê8%) of total metabolism. Deferasirox itself is a moderate inhibitor of CYP3A4, CYP2C8 and CYP1A2 and an inducer of CYP3A4, which underpins the key drug-interaction profile (see Drug Interactions). Genetic polymorphism of UGT1A1 (e.g. *28 / Gilbert phenotype) may modestly elevate exposure but routine genotyping is not recommended.
Elimination #
| Terminal half-life (t1/2) | Approximately 8ÔÇô16 hours, supporting once-daily dosing |
|---|---|
| Apparent oral clearance (CL/F) | ~3 L/h in adults; ~4 L/h in children |
| Excretion route | Predominantly biliary ÔÇö the deferasirox-iron (Fe-DFX2) complex is secreted into bile and lost in faeces; Ôëê60% of dose recovered in faeces. Renal excretion of unchanged drug is minor (<8%). |
| Iron mass balance | One mole of mobilised Fe3+ is excreted per two moles of administered deferasirox. |
The 8ÔÇô16 hour half-life supports convenient once-daily dosing while maintaining a therapeutic plasma concentration sufficient to drive continuous iron mobilisation between doses, even with occasional missed administration.
Linearity & Steady State #
Deferasirox exhibits approximately linear, dose-proportional pharmacokinetics across the clinical dose range (5ÔÇô40 mg/kg/day). Steady-state plasma concentrations are reached within 7 days of repeat once-daily administration. Trough concentrations and AUC at 30 mg/kg/day are typically in the range required to produce sustained negative iron balance in transfusion-dependent patients.
Special Populations ÔÇö PK Considerations #
- Paediatrics (age 2 and above): systemic exposure (AUC) is broadly comparable to adults on a mg/kg basis after weight-based dosing; clearance is modestly higher in younger children, but no per-kg dose adjustment is required.
- Geriatrics (65 years): no clinically meaningful PK differences observed; clinical monitoring of renal and hepatic function drives dose decisions rather than PK adjustment.
- Hepatic impairment: exposure is increased in moderate impairment (Child-Pugh B); reduce starting dose by 50% and intensify monitoring. Avoid in severe impairment (Child-Pugh C).
- Renal impairment: deferasirox is not eliminated renally to a significant extent, but renal toxicity has been reported and the drug is contraindicated when CrCl < 60 mL/min. Dose-modification rules apply when serum creatinine rises 33% above baseline.
- Race / ethnicity: no clinically meaningful PK differences identified across Caucasian, African and Asian patients in pivotal studies.
PK-Driven Clinical Implications #
The PK profile ÔÇö high protein binding, predominantly biliary elimination, dose-proportional exposure, once-daily dosing convenience and UGT-mediated metabolism ÔÇö directly supports deferasiroxÔÇÖs position as a long-term oral chelator suitable for outpatient use. Practical consequences include:
- Food-fasted dosing rule (30 min before food) to ensure reproducible AUC.
- Caution with UGT inducers (e.g. rifampicin, phenytoin) which can lower deferasirox exposure and reduce chelation efficacy.
- Monitoring of CYP3A4 / CYP2C8 substrates with narrow therapeutic indices when co-administered (see Drug Interactions).
- Caution in hepatic impairment, where exposure can rise and amplify dose-related adverse events.
- Stable trough levels support consistent ferritin and LIC trends, allowing protocol-driven dose titration as described in the Monitoring Guidelines.
Reference Range Summary #
| Parameter | Typical adult value (10 mg/kg dose) |
|---|---|
| Cmax | ~10ÔÇô14 ┬Ág/mL |
| AUC0ÔÇô24 | ~150ÔÇô180 ┬Ág┬Àh/mL |
| Tmax | 1.5ÔÇô4 h |
| t1/2 | 8ÔÇô16 h |
| Protein binding | ~99% |
References: deferasirox SmPC (EU); FDA prescribing information (Exjade / Jadenu). PK ranges reflect reported population means; individual values vary with dose, body weight, hepatic function and genetic UGT1A1 status.