Simultaneous Determination of Plasma Deferasirox and Deferasirox-Iron Complex Using an HPLC-UV System and Pharmacokinetics of Deferasirox in Patients with β-Thalassemia Major: Once-daily Versus Twice-daily Administration

Meng Yao Lu, Ning Wang, Wen Hsin Wu, Cheng Wei Lai, Pei Hsin Kuo, Po Hung Chiang, Kai Hsin Lin, Tzu Hua Wu

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Purpose Deferasirox (DEFR), when administered BID, improves iron overload and decreases DEFR-related adverse effects in patients with β-thalassemia major. However, the pharmacokinetic (PK) disposition of DEFR and the iron-DEFR complex (Fe-[DEFR]2) in this dosing strategy is unclear. Methods Chromatographic analysis was performed using a solvent delivery system coupled to an HPLC-UV detector to determine the steady-state concentrations of DEFR (CDEFR) and Fe-(DEFR)2 (CFe-[DEFR]2) in β-thalassemia major patients (n = 8) following either once-daily or BID dosing, during which the PK parameters of the 2 dosing schedules were compared. Findings An HPLC-UV system for the analysis of blood samples following solid-phase extraction was validated. Patients who received 40 mg/kg of DEFR had higher mean CDEFR and CFe-[DEFR]2 values at all sampling times. However, concentrations of iron-DEFR complex were similar in patients who received 30 or 40 mg/kg of DEFR in the once-daily group at the 6- to 24-hour sampling times. There was no significant difference in any of the PK parameters; however, DEFR administration BID increased the mean trough levels of DEFR (183.8 [157.5] μmol/L) compared with once daily (87.7 [56.8] μmol/L), whereas all the patients had increased peak levels per individual DEFR dose when they were switched from once daily to BID (139.0 [59.8] μmol/L vs 289.2 [145.8] μmol/L, respectively). Implications Splitting the dose increased the peak levels of DEFR per unit dose in all patients and tends to increase drug exposures, but there were no significant differences in DEFR PK parameter estimates. Switching from once daily to BID may be considered for patients with an inadequate response to chelation therapy to achieve optimal drug levels. Further research is needed with a larger sample size to determine the clinical importance of the significant results due to the interindividual variability of DEFR.

Original languageEnglish
Pages (from-to)1751-1760
Number of pages10
JournalClinical Therapeutics
Volume37
Issue number8
DOIs
Publication statusPublished - Aug 1 2015

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beta-Thalassemia
Iron
Pharmacokinetics
High Pressure Liquid Chromatography
deferasirox
Chelation Therapy
Iron Overload
Solid Phase Extraction
Systems Analysis
Pharmaceutical Preparations
Sample Size

Keywords

  • deferasirox-iron complex
  • dosing schedule
  • HPLC-UV
  • Key words deferasirox
  • pharmacokinetics

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Simultaneous Determination of Plasma Deferasirox and Deferasirox-Iron Complex Using an HPLC-UV System and Pharmacokinetics of Deferasirox in Patients with β-Thalassemia Major : Once-daily Versus Twice-daily Administration. / Lu, Meng Yao; Wang, Ning; Wu, Wen Hsin; Lai, Cheng Wei; Kuo, Pei Hsin; Chiang, Po Hung; Lin, Kai Hsin; Wu, Tzu Hua.

In: Clinical Therapeutics, Vol. 37, No. 8, 01.08.2015, p. 1751-1760.

Research output: Contribution to journalArticle

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abstract = "Purpose Deferasirox (DEFR), when administered BID, improves iron overload and decreases DEFR-related adverse effects in patients with β-thalassemia major. However, the pharmacokinetic (PK) disposition of DEFR and the iron-DEFR complex (Fe-[DEFR]2) in this dosing strategy is unclear. Methods Chromatographic analysis was performed using a solvent delivery system coupled to an HPLC-UV detector to determine the steady-state concentrations of DEFR (CDEFR) and Fe-(DEFR)2 (CFe-[DEFR]2) in β-thalassemia major patients (n = 8) following either once-daily or BID dosing, during which the PK parameters of the 2 dosing schedules were compared. Findings An HPLC-UV system for the analysis of blood samples following solid-phase extraction was validated. Patients who received 40 mg/kg of DEFR had higher mean CDEFR and CFe-[DEFR]2 values at all sampling times. However, concentrations of iron-DEFR complex were similar in patients who received 30 or 40 mg/kg of DEFR in the once-daily group at the 6- to 24-hour sampling times. There was no significant difference in any of the PK parameters; however, DEFR administration BID increased the mean trough levels of DEFR (183.8 [157.5] μmol/L) compared with once daily (87.7 [56.8] μmol/L), whereas all the patients had increased peak levels per individual DEFR dose when they were switched from once daily to BID (139.0 [59.8] μmol/L vs 289.2 [145.8] μmol/L, respectively). Implications Splitting the dose increased the peak levels of DEFR per unit dose in all patients and tends to increase drug exposures, but there were no significant differences in DEFR PK parameter estimates. Switching from once daily to BID may be considered for patients with an inadequate response to chelation therapy to achieve optimal drug levels. Further research is needed with a larger sample size to determine the clinical importance of the significant results due to the interindividual variability of DEFR.",
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AU - Lu, Meng Yao

AU - Wang, Ning

AU - Wu, Wen Hsin

AU - Lai, Cheng Wei

AU - Kuo, Pei Hsin

AU - Chiang, Po Hung

AU - Lin, Kai Hsin

AU - Wu, Tzu Hua

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N2 - Purpose Deferasirox (DEFR), when administered BID, improves iron overload and decreases DEFR-related adverse effects in patients with β-thalassemia major. However, the pharmacokinetic (PK) disposition of DEFR and the iron-DEFR complex (Fe-[DEFR]2) in this dosing strategy is unclear. Methods Chromatographic analysis was performed using a solvent delivery system coupled to an HPLC-UV detector to determine the steady-state concentrations of DEFR (CDEFR) and Fe-(DEFR)2 (CFe-[DEFR]2) in β-thalassemia major patients (n = 8) following either once-daily or BID dosing, during which the PK parameters of the 2 dosing schedules were compared. Findings An HPLC-UV system for the analysis of blood samples following solid-phase extraction was validated. Patients who received 40 mg/kg of DEFR had higher mean CDEFR and CFe-[DEFR]2 values at all sampling times. However, concentrations of iron-DEFR complex were similar in patients who received 30 or 40 mg/kg of DEFR in the once-daily group at the 6- to 24-hour sampling times. There was no significant difference in any of the PK parameters; however, DEFR administration BID increased the mean trough levels of DEFR (183.8 [157.5] μmol/L) compared with once daily (87.7 [56.8] μmol/L), whereas all the patients had increased peak levels per individual DEFR dose when they were switched from once daily to BID (139.0 [59.8] μmol/L vs 289.2 [145.8] μmol/L, respectively). Implications Splitting the dose increased the peak levels of DEFR per unit dose in all patients and tends to increase drug exposures, but there were no significant differences in DEFR PK parameter estimates. Switching from once daily to BID may be considered for patients with an inadequate response to chelation therapy to achieve optimal drug levels. Further research is needed with a larger sample size to determine the clinical importance of the significant results due to the interindividual variability of DEFR.

AB - Purpose Deferasirox (DEFR), when administered BID, improves iron overload and decreases DEFR-related adverse effects in patients with β-thalassemia major. However, the pharmacokinetic (PK) disposition of DEFR and the iron-DEFR complex (Fe-[DEFR]2) in this dosing strategy is unclear. Methods Chromatographic analysis was performed using a solvent delivery system coupled to an HPLC-UV detector to determine the steady-state concentrations of DEFR (CDEFR) and Fe-(DEFR)2 (CFe-[DEFR]2) in β-thalassemia major patients (n = 8) following either once-daily or BID dosing, during which the PK parameters of the 2 dosing schedules were compared. Findings An HPLC-UV system for the analysis of blood samples following solid-phase extraction was validated. Patients who received 40 mg/kg of DEFR had higher mean CDEFR and CFe-[DEFR]2 values at all sampling times. However, concentrations of iron-DEFR complex were similar in patients who received 30 or 40 mg/kg of DEFR in the once-daily group at the 6- to 24-hour sampling times. There was no significant difference in any of the PK parameters; however, DEFR administration BID increased the mean trough levels of DEFR (183.8 [157.5] μmol/L) compared with once daily (87.7 [56.8] μmol/L), whereas all the patients had increased peak levels per individual DEFR dose when they were switched from once daily to BID (139.0 [59.8] μmol/L vs 289.2 [145.8] μmol/L, respectively). Implications Splitting the dose increased the peak levels of DEFR per unit dose in all patients and tends to increase drug exposures, but there were no significant differences in DEFR PK parameter estimates. Switching from once daily to BID may be considered for patients with an inadequate response to chelation therapy to achieve optimal drug levels. Further research is needed with a larger sample size to determine the clinical importance of the significant results due to the interindividual variability of DEFR.

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