Comparison of Pharmacokinetics and Urinary Iron Excretion of Two Single Doses of Deferiprone in ß-Thalassemia/Hemoglobin E Patients

Rodrat, Supot; Yamanont, Pavena; Tankanitlert, Jeeranut; Chantraraksri, Udom; Fucharoen, Suthat; Morales, Noppawan Phumala

doi:10.1159/000339658

Cited by 9 publications

(6 citation statements)

References 21 publications

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“…With this analysis we show how population pharmacokinetics can be used to explore the implications of different sources of variability on the exposure of the oral iron chelator DFP. The estimates of the main parameters of interest (Table ) were in line with previously published results . As shown in Figure , similar agreement was also observed for the secondary PK parameters (AUC and C max ).…”

Section: Discussionsupporting

confidence: 90%

Population pharmacokinetics of deferiprone in healthy subjects

Bellanti

Danhof

Pasqua

2014

Brit J Clinical Pharma

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AIMSTo characterize the pharmacokinetics of deferiprone in healthy subjects using a model-based approach and to assess the effect of demographic and physiological factors on drug exposure. METHODSData from 55 adult healthy subjects receiving deferiprone (solution 100 mg ml ) were used for model building purposes. A population pharmacokinetic analysis was performed using NONMEM v.7.2. The contribution of gender, age, weight and creatinine clearance (CLcr) on drug disposition was evaluated according to standard forward inclusion, backward deletion procedures. Model selection criteria were based on graphical and statistical summaries. RESULTSA one compartment model with first order oral absorption was found to describe best the pharmacokinetics of deferiprone. Simulated exposure values were comparable with previously published data. Mean AUC estimates were 45.8 and 137.4 mg l −1 h, whereas Cmax increased from 17.6 to 26.5 mg l −1 after administration of 25 and 75 mg kg −1 doses, respectively. Gender differences in the apparent volume of distribution (20%) have been identified, which are unlikely to be of clinical relevance. Furthermore, simulation scenarios reveal that dose adjustment is required for patients with reduced CLcr. Doses of 60, 40 and 25 mg kg CONCLUSIONSOur analysis has enabled the assessment of the impact of gender and CLcr on the pharmacokinetics of deferiprone. Moreover, it provides the basis for dosing recommendations in renal impairment. The implication of these covariates on systemic exposure is currently not available in the prescribing information of deferiprone. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The pharmacokinetics of deferiprone has been previously investigated in a non-compartmental manner. Deferiprone is rapidly absorbed and shows peak plasma concentrations within 45-60 min of administration. The drug is inactivated by glucuronidation and more than 90% is eliminated within 5 to 6 h of ingestion.• Despite the known contribution of renal clearance to the elimination process, there are no clear recommendations about the dose requirements for patients with renal impairment. WHAT THIS STUDY ADDS• Deferiprone exposure has not been previously assessed by population pharmacokinetic methods. In contrast to data from non-compartmental analysis, our results show a statistically significant gender effect on the volume of distribution, which ultimately may impact on peak plasma concentrations.• In addition, simulation scenarios reveal that deferiprone dose adjustment is recommended for patients with reduced creatinine clearance. , respectively.• Our analysis also raises the need to consider further evaluation of the pharmacokinetics of deferiprone in toddlers and young children, for whom current dose recommendations are not supported by pharmacokinetic data.

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Section: Discussionsupporting

confidence: 90%

Population pharmacokinetics of deferiprone in healthy subjects

Bellanti

Danhof

Pasqua

2014

Brit J Clinical Pharma

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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–iron‐overloaded and iron‐overloaded subjects . The increase in exposure to deferiprone and deferiprone 3‐ O ‐glucuronide was proportional to the increase in dose.…”

Section: Discussionsupporting

confidence: 89%

“…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. Values of the PK parameters T max , t ½ , total body clearance, and volume of distribution were similar between the 2 doses.…”

Section: Discussionmentioning

confidence: 99%

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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“…Previous studies in which DFP was administered to iron‐overloaded subjects have shown that 60% to 75% of the total dose is excreted renally as either DFP or its metabolite, DFP‐G . In the current study, 75% to 95% of the administered dose of DFP was retrieved in the urine, as either DFP or DFP‐G.…”

Section: Discussionmentioning

confidence: 99%

Effects of renal impairment on the pharmacokinetics of orally administered deferiprone

Fradette¹,

Pichette

Sicard³

et al. 2016

Brit J Clinical Pharma

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AimsIn 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).MethodsThirty‐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.ResultsRenal clearance of DFP decreased as renal impairment increased. However, based on C max, 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 C max, AUC(0,t), AUC(0,∞) and longer t max and t 1/2 in the renally impaired groups compared with HVs. The C max 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.ConclusionsThese 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.

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Comparison of Pharmacokinetics and Urinary Iron Excretion of Two Single Doses of Deferiprone in ß-Thalassemia/Hemoglobin E Patients

Cited by 9 publications

References 21 publications

Population pharmacokinetics of deferiprone in healthy subjects

Population pharmacokinetics of deferiprone in healthy subjects

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

Effects of renal impairment on the pharmacokinetics of orally administered deferiprone

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