Healthy
Conditions
Keywords
deferiprone, deferiprone extended release formulation, pharmacokinetics
Brief summary
The purpose of this study is to look at the pharmacokinetics of a new formulation of deferiprone (deferiprone extended release tablets) under fed and fasting conditions.
Detailed description
This is a single-center, open-label, randomized, 5-period, 5-sequence study of the pharmacokinetics of a new formulation of deferiprone, extended release tablets, in twenty healthy volunteers. In each study period, blood samples for pharmacokinetics assessment will be collected pre-dose and over 24 hours post-dose. Safety will be assessed throughout the study.
Interventions
DRUGDeferiprone extended release
Deferiprone 1000 mg extended release tablet formulation
DRUGDeferiprone immediate release
Ferriprox (deferiprone) 500 mg immediate release tablet formulation
Sponsors
ApoPharma
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 49 Years
Healthy volunteers
Yes
Inclusion criteria
1. Male or female aged ≥18 to \<50 years 2. A female volunteer of childbearing potential must agree to use an accepted contraceptive regimen from at least 28 days prior to the first administration of the study drug until at least 30 days after the last dose of the study drug 3. A sexually active male must agree that he and/or his female partner will use a medically acceptable method of contraception throughout the study and for at least 30 days following drug administration 4. Body mass index (BMI) greater than or equal to 18.5 kg/m\^2 and below 30.0 kg/m\^2 5. Body weight of at least 60 kg 6. Non- or ex smoker 7. Clinical laboratory values within the laboratory's stated normal range; if not within this range, an abnormal value must be without any clinical significance 8. Have no clinically significant diseases captured in the medical history, or evidence of clinically significant findings on physical examination and/or clinical laboratory evaluations (hematology, general biochemistry, coagulation, ECG, and urinalysis)
Exclusion criteria
1. Pregnant or breastfeeding 2. Absolute neutrophil count (ANC) \< 1.8 x 109/L at screening (no repeat can be performed) 3. History of significant hypersensitivity to deferiprone or any related products (including excipients of the formulations) as well as severe hypersensitivity reactions (such as angioedema) to any drugs 4. History or presence of gastrointestinal, liver or kidney disease, or any other conditions known to interfere with the absorption, distribution, metabolism, or excretion of drugs or known to potentiate or predispose to undesired effects 5. Presence of significant cardiovascular, pulmonary, hematologic, neurological, psychiatric, endocrine, immunologic or dermatologic disease 6. Suicidal tendency, history of seizures, history of head trauma with coma or craniotomy/trepanation, state of confusion, or clinically relevant psychiatric diseases 7. Presence of out-of-range cardiac interval (PR \< 110 msec, PR \> 220 msec, QRS \< 60 msec, QRS \>119 msec and QTcF \> 450 msec for males and \> 460 msec for females) on the screening ECG or other clinically significant ECG abnormalities 8. Maintenance therapy with any drug or significant history of drug dependency or alcohol abuse (\> 3 units of alcohol per day, intake of excessive alcohol, acute or chronic) 9. Any clinically significant illness in the previous 28 days before Day 1 of this study 10. Use of any enzyme-modifying drugs, including strong inhibitors of cytochrome P450 (CYP) enzymes (such as cimetidine, fluoxetine, quinidine, erythromycin, ciprofloxacin, fluconazole, ketoconazole, diltiazem and HIV antivirals) and strong inducers of CYP enzymes (such as barbiturates, carbamazepine, glucocorticoids, phenytoin, rifampin and St John's Wort), in the previous 28 days before Day 1 of this study 11. Any history of tuberculosis and/or prophylaxis for tuberculosis 12. Serum ferritin value below the normal limit of the reference laboratory at screening 13. Positive urine screening of alcohol and/or drugs of abuse 14. Positive results on HIV Ag/Ab Combo, Hepatitis B surface Antigen (HBsAG (B) (hepatitis B)) or anti-Hepatitis C Virus (HCV (C)) tests 15. Positive result on a serum pregnancy test 16. Receipt of an investigational product in another clinical trial in the previous 28 days before Day 1 of this study 17. Donation of 50 mL or more of blood in the previous 28 days before Day 1 of this study or donation of 500 mL or more of blood (Canadian Blood Services, Hema-Quebec, clinical studies, etc.) in the previous 56 days before Day 1 of this study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cmax for Serum Deferiprone | Samples were collected pre-dose and at 0.25, 0.5, 0.75, 1.0, 1.33, 1.66, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6.0, 8.0, 12.0, 16.0, and 24.0 hours post-dose. | Maximum measured serum concentration. Blood samples will be collected pre-dose and over a 24-hour interval post-dose |
| Tmax for Serum Deferiprone | Samples were collected pre-dose and at 0.25, 0.5, 0.75, 1.0, 1.33, 1.66, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6.0, 8.0, 12.0, 16.0, and 24.0 hours post-dose. | Time of maximum observed serum concentration. Blood samples will be collected pre-dose and over a 24-hour interval post-dose |
| AUC0-∞for Serum Deferiprone | Samples were collected pre-dose and at 0.25, 0.5, 0.75, 1.0, 1.33, 1.66, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6.0, 8.0, 12.0, 16.0, and 24.0 hours post-dose. | Area under the serum concentration time curve extrapolated to infinity. Blood samples will be collected pre-dose and over a 24-hour interval post-dose. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Adverse Events (AEs) | Throughout the trial, from the time of the first dose until the last study visit (Day 36 or early termination) | Number of subjects with AEs. AEs will include clinically significant changes from baseline in vital signs, 12-lead ECG, physical examinations, and laboratory tests. |
Countries
Canada
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Healthy Volunteers Subjects were randomized to receive five treatments in different orders:
* deferiprone ER tablets under fasting conditions
* deferiprone ER tablets under fed conditions
* deferiprone ER tablets administered as half-tablets under fed conditions
* Ferriprox IR tablets under fasting conditions
* Ferriprox IR tablets under fed conditions | 20 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 5 |
Baseline characteristics
| Characteristic | Healthy Volunteers |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 20 Participants |
| Region of Enrollment Canada | 20 participants |
| Sex: Female, Male Female | 10 Participants |
| Sex: Female, Male Male | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 5 / 18 | 2 / 16 | 3 / 16 | 1 / 16 | 3 / 16 |
| serious Total, serious adverse events | 0 / 18 | 0 / 16 | 0 / 16 | 0 / 16 | 0 / 16 |
Outcome results
Primary
AUC0-∞for Serum Deferiprone
Area under the serum concentration time curve extrapolated to infinity. Blood samples will be collected pre-dose and over a 24-hour interval post-dose.
Time frame: Samples were collected pre-dose and at 0.25, 0.5, 0.75, 1.0, 1.33, 1.66, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6.0, 8.0, 12.0, 16.0, and 24.0 hours post-dose.
Population: The pharmacokinetic population included subjects who provided evaluable data for at least two study periods
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Extended Release, Fasting Conditions | AUC0-∞for Serum Deferiprone | 31.42 ug*h/mL | Standard Deviation 6.68 |
| Extended Release, Fed Conditions | AUC0-∞for Serum Deferiprone | 40.52 ug*h/mL | Standard Deviation 0.77 |
| Extended Release Half-tablets, Fed Conditions | AUC0-∞for Serum Deferiprone | 31.72 ug*h/mL | Standard Deviation 8.21 |
| Immediate Release, Fasting Conditions | AUC0-∞for Serum Deferiprone | 34.81 ug*h/mL | Standard Deviation 6.81 |
| Immediate Release, Fed Conditions | AUC0-∞for Serum Deferiprone | 33.02 ug*h/mL | Standard Deviation 7.19 |
Primary
Cmax for Serum Deferiprone
Maximum measured serum concentration. Blood samples will be collected pre-dose and over a 24-hour interval post-dose
Time frame: Samples were collected pre-dose and at 0.25, 0.5, 0.75, 1.0, 1.33, 1.66, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6.0, 8.0, 12.0, 16.0, and 24.0 hours post-dose.
Population: The pharmacokinetic population included subjects who provided evaluable data for at least two study periods.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Extended Release, Fasting Conditions | Cmax for Serum Deferiprone | 3.89 μg/mL | Standard Deviation 1.47 |
| Extended Release, Fed Conditions | Cmax for Serum Deferiprone | 2.76 μg/mL | Standard Deviation 1.45 |
| Extended Release Half-tablets, Fed Conditions | Cmax for Serum Deferiprone | 3.02 μg/mL | Standard Deviation 1.03 |
| Immediate Release, Fasting Conditions | Cmax for Serum Deferiprone | 13.89 μg/mL | Standard Deviation 3.84 |
| Immediate Release, Fed Conditions | Cmax for Serum Deferiprone | 9.77 μg/mL | Standard Deviation 3.6 |
Primary
Tmax for Serum Deferiprone
Time of maximum observed serum concentration. Blood samples will be collected pre-dose and over a 24-hour interval post-dose
Time frame: Samples were collected pre-dose and at 0.25, 0.5, 0.75, 1.0, 1.33, 1.66, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6.0, 8.0, 12.0, 16.0, and 24.0 hours post-dose.
Population: The pharmacokinetic population included subjects who provided evaluable data for at least two study periods
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Extended Release, Fasting Conditions | Tmax for Serum Deferiprone | 3.63 Hour | Standard Deviation 1.1 |
| Extended Release, Fed Conditions | Tmax for Serum Deferiprone | 15.66 Hour | Standard Deviation 9.33 |
| Extended Release Half-tablets, Fed Conditions | Tmax for Serum Deferiprone | 8.29 Hour | Standard Deviation 7.25 |
| Immediate Release, Fasting Conditions | Tmax for Serum Deferiprone | 0.94 Hour | Standard Deviation 0.63 |
| Immediate Release, Fed Conditions | Tmax for Serum Deferiprone | 1.91 Hour | Standard Deviation 0.95 |
Secondary
Number of Subjects With Adverse Events (AEs)
Number of subjects with AEs. AEs will include clinically significant changes from baseline in vital signs, 12-lead ECG, physical examinations, and laboratory tests.
Time frame: Throughout the trial, from the time of the first dose until the last study visit (Day 36 or early termination)
Population: The safety population included all subjects who received at least one of the investigational products under study
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Extended Release, Fasting Conditions | Number of Subjects With Adverse Events (AEs) | 5 participants |
| Extended Release, Fed Conditions | Number of Subjects With Adverse Events (AEs) | 2 participants |
| Extended Release Half-tablets, Fed Conditions | Number of Subjects With Adverse Events (AEs) | 3 participants |
| Immediate Release, Fasting Conditions | Number of Subjects With Adverse Events (AEs) | 1 participants |
| Immediate Release, Fed Conditions | Number of Subjects With Adverse Events (AEs) | 3 participants |