Effects of renal impairment on the pharmacokinetics of orally administered deferiprone.
In light of the growing recognition of renal disease in thalassemia, it is important to understand the impact of renal impairment on the pharmacokinetics of iron chelators. This study evaluated the pharmacokinetics and safety of the iron chelator deferiprone (DFP) in subjects with renal impairment in comparison with healthy volunteers (HVs).



Thirty-two subjects were categorized into four groups based on degree of renal impairment: none, mild, moderate or severe, as determined by estimated glomerular filtration rate (eGFR). All subjects received a single oral dose of 33 mg kg(-1) DFP, provided serum and urine samples for pharmacokinetic assessment over 24 h and were monitored for safety.



Renal clearance of DFP decreased as renal impairment increased. However, based on Cmax , AUC(0,t) and AUC(0,∞), there were no significant group differences in systemic exposure, because less than 4% of the drug was excreted unchanged in the urine. DFP is extensively metabolized to a renally excreted, pharmacologically inactive metabolite, deferiprone 3-O-glucuronide (DFP-G), which exhibited higher Cmax , AUC(0,t), AUC(0,∞) and longer tmax and t1/2 in the renally impaired groups compared with HVs. The Cmax and AUCs of DFP-G increased as eGFR decreased. Overall, 75%-95% of the dose was retrieved in urine, either as DFP or DFP-G, regardless of severity of renal impairment. With respect to safety, DFP was well tolerated.



These data suggest that no adjustment of the DFP dosage regimen in patients with renal impairment is necessary, as there were no significant changes in the systemic exposure to the drug.
ApoPharma Inc., 200 Barmac Drive, Toronto, Ontario, M9L 2Z7, Canada.
Caroline
C
Fradette
Hôpital Maisonneuve-Rosemont, 5415 Assomption Boulevard, Montreal, Quebec, H1T 2M4, Canada.
Vincent
V
Pichette
Algorithme Pharma, 575 Armand-Frappier Blvd., Laval, Quebec, H7V 4B3, Canada.
Éric
É
Sicard
ApoPharma Inc., 200 Barmac Drive, Toronto, Ontario, M9L 2Z7, Canada.
Anne
A
Stilman
ApoPharma Inc., 200 Barmac Drive, Toronto, Ontario, M9L 2Z7, Canada.
Shalini
S
Jayashankar
ApoPharma Inc., 200 Barmac Drive, Toronto, Ontario, M9L 2Z7, Canada.
Yu Chung
YC
Tsang
ApoPharma Inc., 200 Barmac Drive, Toronto, Ontario, M9L 2Z7, Canada.|Leslie Dan Faculty of Pharmacy, 144 College St, Toronto, Ontario, M5S 3M2, Canada.
Michael
M
Spino
ApoPharma Inc., 200 Barmac Drive, Toronto, Ontario, M9L 2Z7, Canada. ftricta@apopharma.com.
Fernando
F
Tricta
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000077543:Deferiprone; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D007502:Iron Chelating Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D011728:Pyridones / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D051437:Renal Insufficiency / Q000378:metabolism*
D007502:Iron Chelating Agents; D011728:Pyridones; D000077543:Deferiprone
Ferriprox; deferiprone; deferiprone glucuronide; pharmacokinetics; renal impairment