Effects of renal impairment on the pharmacokinetics of orally administered deferiprone

Fradette, Caroline; Pichette, Vincent; Sicard, Étienne; Stilman, Anne; Jayashankar, Shalini; Tsang, Yu Chung; Spino, Michael; Tricta, Fernando

doi:10.1111/bcp.13037

Cited by 10 publications

(8 citation statements)

References 29 publications

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“…With respect to PK, the results obtained in this trial were similar to those seen in previous studies of deferiprone in healthy subjects, in which deferiprone was shown to be rapidly absorbed from the gastrointestinal tract, appearing in the blood within 5 to 10 minutes and with peak serum concentrations occurring approximately 1 hour after administration in the fasted state (ApoPharma, internal data). They were also comparable to results reported in the literature in both non-ironoverloaded 13 and iron-overloaded subjects. [14][15][16][17] The increase in exposure to deferiprone and deferiprone 3-O-glucuronide was proportional to the increase in dose.…”

Section: Discussionsupporting

confidence: 90%

Randomized, Blinded, Placebo‐ and Positive‐Controlled Crossover Study to Determine the Effect of Deferiprone on the QTc Interval in Healthy Subjects

Fradette¹,

Rozova²,

Stilman³

et al. 2017

Clinical Pharm in Drug Dev

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This study evaluated whether deferiprone, an oral iron chelator, acts to prolong the QT interval. Fifty healthy volunteers received single doses of each of the following: therapeutic dose of deferiprone (33 mg/kg), supratherapeutic dose (50 mg/kg), placebo, or moxifloxacin, a positive control known to significantly prolong QT interval. Following each dose, subjects underwent cardiac monitoring, pharmacokinetics assessments, and safety assessments. Based on the QT interval obtained using the Fridericia correction for heart rate (QTcF), the upper bound of the 1-sided 95% confidence interval of the mean difference between deferiprone and placebo was <10 milliseconds (the threshold of concern defined by authorities) at all time points for both doses: maximum difference of 3.01 milliseconds for the therapeutic dose and 5.23 milliseconds for the supratherapeutic dose. The difference in dQTcF between moxifloxacin and placebo demonstrated that the study was adequately sensitive to detect a significant prolongation of QTcF. The concentration-response correlation analyses revealed some weak but statistically significant trends of increase in dQTcF and ddQTcF with increasing exposure to deferiprone, but these trends should have no clinical consequence even at the recommended maximum dosage. In conclusion, there was no clinically meaningful effect on QTc interval following single therapeutic or supratherapeutic doses of deferiprone.

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Section: Discussionsupporting

confidence: 90%

Randomized, Blinded, Placebo‐ and Positive‐Controlled Crossover Study to Determine the Effect of Deferiprone on the QTc Interval in Healthy Subjects

Fradette¹,

Rozova²,

Stilman³

et al. 2017

Clinical Pharm in Drug Dev

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“…Previous studies in subjects with mild to moderate liver dysfunction reported that the disposition of DFP and DFP-G was generally similar among all subjects, regardless of degree of hepatic impairment [14,22]. Similarly, previous studies comparing healthy volunteers with mild to severe renally impaired subjects demonstrated comparable drug exposure and found that no dosage adjustment of DFP is needed in patients with renal impairment [15]. These previous observations are notable because patients with SCD can experience up to a 68% increase in the prevalence of albuminuria with age [23,24].…”

Section: Discussionmentioning

confidence: 80%

“…Deferiprone (Ferriprox®) is an oral iron chelator indicated for treatment of iron overload in transfusion-dependent patients with thalassemia syndromes [ 14 ]. Its use is not associated with renal toxicity and is well tolerated in patients with decreased renal function [ 14 , 15 ]. Furthermore, systemic exposure to deferiprone (DFP) was not altered in subjects with renal impairment, and no dose adjustment was required [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

“…Its use is not associated with renal toxicity and is well tolerated in patients with decreased renal function [ 14 , 15 ]. Furthermore, systemic exposure to deferiprone (DFP) was not altered in subjects with renal impairment, and no dose adjustment was required [ 15 ]. Deferiprone was recently approved by the US Food and Drug Administration as a first-line therapy for the treatment of iron overload in pediatric and adult patients with SCD or other transfusion-dependent anemias [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

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The pharmacokinetic and safety profile of single-dose deferiprone in subjects with sickle cell disease

Soulières

Mercier-Ross

Fradette³

et al. 2022

Ann Hematol

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Patients with sickle cell disease (SCD) who undergo repeated blood transfusions often develop iron overload. Deferiprone (Ferriprox®) is an oral iron chelator indicated for the treatment of transfusional iron overload due to thalassemia syndromes and has been recently approved as a treatment for iron overload in adult and pediatric patients with SCD and other anemias. The present study aims to characterize the pharmacokinetic (PK) profile of deferiprone (DFP) in adult subjects with SCD. In this phase I, open-label study, subjects with SCD were administered a single 1500 mg dose of DFP. Blood and urine samples were collected for PK assessments of DFP and its main metabolite, deferiprone 3-O-glucuronide (DFP-G). Eight subjects were enrolled and completed the study. Following drug administration, serum levels of DFP and DFP-G rose to maximum concentrations at 1.0 and 2.8 h post-dose, respectively. The half-lives of DFP and DFP-G were 1.5 and 1.6 h, respectively. The majority of administered drug was metabolized and excreted as DFP-G, with less than 4% excreted unchanged in urine up to 10 h post-dose. Subjects received a safety assessment 7 (± 3) days post-dose. Two subjects reported mild adverse events unrelated to the study drug, and no other safety concerns were reported. The PK profile of DFP in SCD subjects is consistent with previous reports in healthy adult volunteers, suggesting no special dosing adjustments are indicated for this population. These findings provide valuable insight for treating iron overload in patients with SCD, who have limited chelation therapy treatment options (trial registration number: NCT01835496, date of registration: April 19, 2013).

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“…For instance, if a drug has high renal clearance as a percentage of total body clearance in an unchanged form, then mild or moderate renal impairment could alter AUC by twofold or more [5,6]. Conversely, where the percent unchanged drug (or active metabolite) excreted in urine is low, then severe renal impairment may have no effect [7]. In addition, alterations in drug absorption, bioavailability, and plasma protein binding capacity can also occur in a renal impaired population (review in [8]), further affecting drug exposure.…”

Section: Introductionmentioning

confidence: 99%

Update and trends on pharmacokinetic studies in patients with impaired renal function: practical insight into application of the FDA and EMA guidelines

Paglialunga

Offman

Ichhpurani

et al. 2017

Expert Review of Clinical Pharmacology

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Introduction: The incidence of kidney dysfunction increases with age and is highly prevalent among patients with hypertension. Since many therapeutic compounds are primarily eliminated through the kidneys, impaired renal function can have negative consequences on drug disposition, efficacy and safety. Therefore, regulatory agencies such as the Food and Drug Administration (FDA) and European Medicines Agency (EMA) have issued detailed guidelines for new drug applications to determine posology requirements for patients with renal impairment. Areas covered: The current review highlights and contrasts agency requirements for pharmacokinetic renal impairment clinical studies. While many of the guidelines are similar among the two agencies, glomerular filtration rate (GFR) determination and reporting differ. Design considerations for a reduced, full or dialysis renal impairment study, as well as modifications to the FDA's draft guidance are discussed. Furthermore, scenarios where pharmacokinetic modelling analysis can benefit a drug development program are also reviewed. Moreover, practical solutions for patient recruitment challenges are addressed. Expert commentary: We summarize how 'one size does not fit all' for GFR assessment, and recommend when to use certain modalities. Finally, we highlight the need for the pharmaceutical industry to engage therapeutic experts to assist in protocol development for renal impairment studies, as these experts understand the nuances of this special population and recommended guidelines. ARTICLE HISTORY

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Effects of renal impairment on the pharmacokinetics of orally administered deferiprone

Cited by 10 publications

References 29 publications

Randomized, Blinded, Placebo‐ and Positive‐Controlled Crossover Study to Determine the Effect of Deferiprone on the QTc Interval in Healthy Subjects

Randomized, Blinded, Placebo‐ and Positive‐Controlled Crossover Study to Determine the Effect of Deferiprone on the QTc Interval in Healthy Subjects

The pharmacokinetic and safety profile of single-dose deferiprone in subjects with sickle cell disease

Update and trends on pharmacokinetic studies in patients with impaired renal function: practical insight into application of the FDA and EMA guidelines

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