Contributions
Abstract: PB1760
Type: Publication Only
Session title: Sickle cell disease
Background
Repeated blood transfusions are a mainstay treatment for the management of sickle cell disease (SCD), but often cause transfusion-dependent iron overload (TDI) in patients. Deferiprone (Ferriprox®) is an oral iron chelator indicated for the treatment of TDI due to thalassemia and has been investigated as a treatment for TDI in patients with SCD and other anemias. Unlike other chelation therapies, deferiprone is well tolerated in patients with decreased renal function, a common complication in SCD patients (Nath and Hebbel 2015). Previous studies in healthy adult volunteers have characterized the pharmacokinetic (PK) and safety profiles of deferiprone and its metabolite, deferiprone 3-O glucuronide, but the PK of deferiprone in SCD patients has not been established.
Aims
The present study aims to characterize the PK profile of deferiprone in patients with SCD and evaluate whether alterations in its metabolism and excretion necessitate dosing adjustments.
Methods
In this phase I, single-center, non-randomized, open-label, single-dose study (NCT01835496), patients with a diagnosis of SCD were administered a single 1500 mg dose of deferiprone under fasting conditions. Blood and urine samples were collected pre-dose and over a 10-hour post-dose period for PK assessments of deferiprone and deferiprone 3-O glucuronide. Patients were monitored throughout the study for adverse events (AEs) and returned to the study site 7 ± 3 days for a final follow-up and safety assessment.
Results
Eight patients with SCD (3 males and 5 females) were enrolled and completed the study. All patients were black, with a mean ± SD age of 33.0 ± 5.9 years. Following drug administration, serum levels of deferiprone and deferiprone 3-O-glucuronide rose rapidly with maximum concentrations (Cmax) reached at 1.0 and 2.8 hours post-dose, respectively. The mean ± SD Cmax for deferiprone was 17.6 ± 5.8 mg/mL and for deferiprone 3-O- glucuronide was 33.0 ± 11.8 mg/mL. The peak in serum levels of deferiprone and deferiprone 3-O-glucuronide were followed by a rapid decline with a half-life of 1.5 and 1.6 hours, respectively. Less than 4% of administered drug was excreted unchanged in urine samples, while the majority was metabolized and excreted as deferiprone 3-O-glucuronide. Two patients reported mild AEs. One patient experienced sore throat, headache, fatigue, and fever and the other patient reported abdominal pain. None of the AEs were considered related to the study drug. Furthermore, vital sign measurements and laboratory test results found no indications of clinical concern.
Conclusion
The pharmacokinetics of deferiprone in SCD patients were consistent with values reported in previous PK studies in healthy adult volunteers, suggesting no special dosing adjustments are indicated. The safety profile of deferiprone and deferiprone 3-O glucuronide, was found to be favorable with no safety concerns. Because the sample size is small the latter results should be interpreted with caution. However, these findings provide insight for the treatment of TDI in SCD patients with limited chelation therapy treatment options.
Keyword(s): Deferiprone, Iron chelation, Iron overload, Sickle cell anemia
Abstract: PB1760
Type: Publication Only
Session title: Sickle cell disease
Background
Repeated blood transfusions are a mainstay treatment for the management of sickle cell disease (SCD), but often cause transfusion-dependent iron overload (TDI) in patients. Deferiprone (Ferriprox®) is an oral iron chelator indicated for the treatment of TDI due to thalassemia and has been investigated as a treatment for TDI in patients with SCD and other anemias. Unlike other chelation therapies, deferiprone is well tolerated in patients with decreased renal function, a common complication in SCD patients (Nath and Hebbel 2015). Previous studies in healthy adult volunteers have characterized the pharmacokinetic (PK) and safety profiles of deferiprone and its metabolite, deferiprone 3-O glucuronide, but the PK of deferiprone in SCD patients has not been established.
Aims
The present study aims to characterize the PK profile of deferiprone in patients with SCD and evaluate whether alterations in its metabolism and excretion necessitate dosing adjustments.
Methods
In this phase I, single-center, non-randomized, open-label, single-dose study (NCT01835496), patients with a diagnosis of SCD were administered a single 1500 mg dose of deferiprone under fasting conditions. Blood and urine samples were collected pre-dose and over a 10-hour post-dose period for PK assessments of deferiprone and deferiprone 3-O glucuronide. Patients were monitored throughout the study for adverse events (AEs) and returned to the study site 7 ± 3 days for a final follow-up and safety assessment.
Results
Eight patients with SCD (3 males and 5 females) were enrolled and completed the study. All patients were black, with a mean ± SD age of 33.0 ± 5.9 years. Following drug administration, serum levels of deferiprone and deferiprone 3-O-glucuronide rose rapidly with maximum concentrations (Cmax) reached at 1.0 and 2.8 hours post-dose, respectively. The mean ± SD Cmax for deferiprone was 17.6 ± 5.8 mg/mL and for deferiprone 3-O- glucuronide was 33.0 ± 11.8 mg/mL. The peak in serum levels of deferiprone and deferiprone 3-O-glucuronide were followed by a rapid decline with a half-life of 1.5 and 1.6 hours, respectively. Less than 4% of administered drug was excreted unchanged in urine samples, while the majority was metabolized and excreted as deferiprone 3-O-glucuronide. Two patients reported mild AEs. One patient experienced sore throat, headache, fatigue, and fever and the other patient reported abdominal pain. None of the AEs were considered related to the study drug. Furthermore, vital sign measurements and laboratory test results found no indications of clinical concern.
Conclusion
The pharmacokinetics of deferiprone in SCD patients were consistent with values reported in previous PK studies in healthy adult volunteers, suggesting no special dosing adjustments are indicated. The safety profile of deferiprone and deferiprone 3-O glucuronide, was found to be favorable with no safety concerns. Because the sample size is small the latter results should be interpreted with caution. However, these findings provide insight for the treatment of TDI in SCD patients with limited chelation therapy treatment options.
Keyword(s): Deferiprone, Iron chelation, Iron overload, Sickle cell anemia