Background: The value of understanding deferiprone's comparative pharmacokinetics (PK) in differing indications and human subpopulations derives from its potential versatility in treating, not only transfusional iron overload, but also conditions in which iron mishandling is localized. While some PK on deferiprone in patients with thalassemia has been published, little is known for patients without systemic iron overload, or for those requiring special consideration (e.g., children, patients with hepatic or renal impairment). Reporting of characteristics such as deferiprone's rapid absorption, extensive glucuronidation, and principally urinary excretion has been consistent, but some publications have followed false trails, and lack of IV data and the dearth of PK information in non-iron-overloaded patients have limited the overall picture. Availability of a comprehensive integration of deferiprone human PK would address misconceptions and help in predicting doses for patients with various indications currently being investigated, as well as in special populations.
Objective: To provide data on the PK of deferiprone generated from currently unpublished studies, to enable dosing guidance for deferiprone use in conditions beyond adult patients with thalassemia.
Methods: Data from PK studies, conducted as part of our development programme with deferiprone in thalassemia, sickle cell disease, and conditions without systemic iron overload, as well as in children and subjects with impaired renal function or impaired hepatic function are presented.
Results: The absolute (oral vs IV) bioavailability of deferiprone was 72% (Studies were conducted with Ferriprox™ 500 mg tablets). Following an oral dose of 1,500 mg (20 mg/kg), the mean maximum serum deferiprone concentration (Cmax) in the fasting state in non-iron-loaded healthy subjects was 20 mcg/mL, and the mean total area under the concentration-time curve (AUC) was 53 mcg·h/mL. Cmax of deferiprone occurs approximately 1 hour after a single dose in fasted subjects, but may be delayed to 2 hours in the fed state. Food decreases the Cmax of Ferriprox tablets by about a third and the AUC by 10%. Steady state is achieved on the first day of dosing and cross-study comparisons indicate dose proportionality. Protein binding of deferiprone in human plasma is ≤20%. Metabolism is predominantly UGT 1A6-mediated conjugation to form a 3-O -glucuronide, which is rapidly cleared by renal excretion (Tmax 2-4 hours in fasting subjects) and lacks iron binding capability. There is no evidence of genetic polymorphism. Most of a dose of deferiprone is rapidly eliminated from plasma, with a t½ of about 2 hours, and is excreted primarily into the urine as the glucuronide. Dose adjustment is not necessary in patients with renal impairment, as confirmed by similar total body clearance to healthy controls. Subjects with mild or moderate hepatic impairment retain sufficient capacity for glucuronidation to also not require dose adjustment. The clearance of deferiprone in children is comparable to that in adults. The pharmacokinetics in patients with Friedreich Ataxia, PKAN and Parkinson's disease, conditions in which deferiprone is currently being evaluated by various investigators, is expected to be comparable to PK in healthy volunteers.
Conclusions: Comparative IV and oral dosing of deferiprone reveals that it is extensively and rapidly absorbed from the gut. The PK of deferiprone in patients without systemic iron overload is predicted to be similar to the PK in healthy subjects. Studies in special populations demonstrate that dose adjustment in children or in patients with renal or moderate hepatic impairment is not necessary.
Spino:ApoPharma Inc.: Employment. Off Label Use: Deferiprone is approved for the treatment of iron overload in thalassemia syndromes. Connelly:ApoPharma Inc.: Employment. Tsang:ApoPharma Inc.: Employment. Fradette:ApoPharma Inc.: Employment. Tricta:ApoPharma Inc.: Employment.
Asterisk with author names denotes non-ASH members.