Hepatic Impairment
Conditions
Keywords
Hepatic Impairment, Liver Impairment, Liver Disease, Ferriprox®, LI, DFP, Deferiprone
Brief summary
Multi-center, non-randomized, open-label, single-dose, parallel group study to determine the effect of impaired hepatic function on the PK of deferiprone and its 3-O-glucuronide metabolite following a single oral dose of 33mg/kg Ferriprox®.
Detailed description
Post-marketing study to evaluate the effect of impaired hepatic function on the pharmacokinetics (PK) of deferiprone and its 3-O-glucuronide metabolite and on the safety of Ferriprox® in subjects with mild and moderate hepatic impairment as compared to healthy volunteers.
Interventions
DRUGFerriprox®
Sponsors
ApoPharma
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
Main Inclusion Criteria: All subjects: 1. Adult males or females, 18 - 75 years of age (inclusive); 2. Body weight ≥ 50 kg; 3. Body mass index (BMI) between 19 and 32 kg/mE2 (inclusive); 4. Absolute neutrophil count (ANC) of \>1.5x10E9/L ; Healthy volunteers: 1. Medically healthy with clinically insignificant screening results (e.g., laboratory profiles, medical history, vital signs, physical examination); 2. Matched to hepatically impaired subjects in the study by age (+/- 10 years), sex and weight (+/- 15% BMI). Hepatically impaired subjects: 1. Considered clinically stable in the opinion of the Investigator; 2. Subjects with different degrees of impaired hepatic function as assessed by a Child-Pugh classification score: mild (Class A: 5-6 points) and moderate (Class B: 7-9 points) impaired hepatic function. Main
Exclusion criteria
1. For subjects with hepatic impairment, fluctuating or rapidly deteriorating hepatic function as indicated by clinical and/or laboratory signs of hepatic impairment (e.g. advanced ascites, infection of ascites, fever, or active gastrointestinal bleeding). 2. Evidence of liver impairment in healthy volunteers: hepatitis B and C; or aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin, clotting factors, serum protein that is considered clinically significant by the Investigator; 3. History or presence of significant clinically unstable respiratory, cardiovascular, pulmonary, hepatic (except for subjects assigned to one of the hepatically impaired groups), renal, hematologic, gastrointestinal, endocrine (except for subjects with hepatic impairment with clinically stable and treated diabetes, hypertension and thyroid disorders), immunologic, dermatologic, neurologic, or psychiatric disease; 4. Disorders or surgery of the gastrointestinal tract which may interfere with drug absorption or may otherwise influence the PK of the investigational medicinal product (e.g. resections of the small or large intestine, febrile conditions, chronic diarrhea, chronic vomiting, clinically unstable endocrine disease, severe infections, acute inflammations, etc.); 5. Received a pharmacological agent in another clinical trial within 28 days prior to the first dose of the study;
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| AUC0-∞ for Serum Deferiprone and Deferiprone 3-O-glucuronide | 24-hour interval | AUC (area under the curve) from zero to infinity was assessed over a 24-hour interval for analyses of deferiprone and its 3-O-glucuronide metabolite in subjects with normal hepatic function, mild hepatic impairment, or moderate hepatic impairment. Blood samples were obtained prior to dosing and at 0.25, 0.50, 0.75, 1, 1.33, 1.66, 2, 2.5, 3, 4, 6, 9, 12, 16, and 24 hours post-dose. |
| Cmax for Serum Deferiprone and Deferiprone 3-O-glucuronide | 24-hour interval | Cmax was assessed over a 24-hour interval for analyses of deferiprone and its 3-O-glucuronide metabolite in subjects with normal hepatic function, mild hepatic impairment, or moderate hepatic impairment. Blood samples were obtained prior to dosing and at 0.25, 0.50, 0.75, 1, 1.33, 1.66, 2, 2.5, 3, 4, 6, 9, 12, 16, and 24 hours post-dose. |
| Tmax for Serum Deferiprone and Deferiprone 3-O-glucuronide | 24-hour interval | Tmax was assessed over a 24-hour interval for analyses of deferiprone and its 3-O-glucuronide metabolite in subjects with normal hepatic function, mild hepatic impairment, or moderate hepatic impairment. Blood samples were obtained prior to dosing and at 0.25, 0.50, 0.75, 1, 1.33, 1.66, 2, 2.5, 3, 4, 6, 9, 12, 16, and 24 hours post-dose. |
| Fe% for Urine Deferiprone and Deferiprone 3-O-glucuronide | 24-hour interval | Cumulative fraction of Ferriprox dose excreted in urine as deferiprone or deferiprone 3-O-glucuronide. Urine samples were collected at the intervals of -2 to 0 hours pre-dose, and 0-2, 2-4, 4-8, 8-12 ,and 12- 24 hours post-dose. Note: For unknown reasons, the urine samples for one subject in the moderate hepatic failure group had low or zero volume and there were no measurable levels of deferiprone or its metabolite in any of the samples. Accordingly, the urine PK results were derived both with and without this subject's data, and are here presented without them (i.e., N=6 rather than 7). |
| T1/2 for Serum Deferiprone and Deferiprone 3-O-glucuronide | 24-hour interval | T1/2 was assessed over a 24-hour interval for analyses of deferiprone and its 3-O-glucuronide metabolite in subjects with normal hepatic function, mild hepatic impairment, or moderate hepatic impairment. Blood samples were obtained prior to dosing and at 0.25, 0.50, 0.75, 1, 1.33, 1.66, 2, 2.5, 3, 4, 6, 9, 12, 16, and 24 hours post-dose. |
| CumAe for Urine Deferiprone and Deferiprone 3-O-glucuronide | 24-hour interval | Cumulative amount of deferiprone and deferiprone 3-O-glucuronide excreted in the urine. Urine samples were collected at the intervals of -2 to 0 hours pre-dose, and 0-2, 2-4, 4-8, 8-12 ,and 12- 24 hours post-dose. Note: For unknown reasons, the urine samples for one subject in the moderate hepatic failure group had low or zero volume and there were no measurable levels of deferiprone or its metabolite in any of the samples. Accordingly, the urine PK results were derived both with and without this subject's data, and are here presented without them (i.e., N=6 rather than 7). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Safety and Tolerability of Ferriprox in Subjects With or Without Hepatic Impairment. | Time of dosing until 48 hours post-dose | The number of participants who experienced adverse events following a single dose of Ferriprox, between the time of dosing and the follow-up visit (including any changes of clinical significance in physical examinations, vital signs, 12-lead ECG, and clinical laboratory tests). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Normal Hepatic Function (Healthy Volunteers) Healthy volunteers with normal hepatic function | 7 |
| Mild Hepatic Failure Mild hepatic failure as defined by Child-Pugh Class C: 5-6 points | 7 |
| Moderate Hepatic Failure Moderate hepatic failure as defined by Child-Pugh Class B: 7-9 points | 7 |
| Total | 21 |
Baseline characteristics
| Characteristic | Normal Hepatic Function (Healthy Volunteers) | Mild Hepatic Failure | Moderate Hepatic Failure | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 6 Participants | 7 Participants | 20 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 7 Participants | 6 Participants | 19 Participants |
| Region of Enrollment United States | 7 participants | 7 participants | 7 participants | 21 participants |
| Sex: Female, Male Female | 2 Participants | 0 Participants | 3 Participants | 5 Participants |
| Sex: Female, Male Male | 5 Participants | 7 Participants | 4 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 7 | 1 / 7 | 3 / 7 |
| serious Total, serious adverse events | 0 / 7 | 0 / 7 | 1 / 7 |
Outcome results
Primary
AUC0-∞ for Serum Deferiprone and Deferiprone 3-O-glucuronide
AUC (area under the curve) from zero to infinity was assessed over a 24-hour interval for analyses of deferiprone and its 3-O-glucuronide metabolite in subjects with normal hepatic function, mild hepatic impairment, or moderate hepatic impairment. Blood samples were obtained prior to dosing and at 0.25, 0.50, 0.75, 1, 1.33, 1.66, 2, 2.5, 3, 4, 6, 9, 12, 16, and 24 hours post-dose.
Time frame: 24-hour interval
Population: The PK Analysis Set consisted of all subjects who had sufficient data to derive at least one PK parameter
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Hepatic Function (Healthy Volunteers) | AUC0-∞ for Serum Deferiprone and Deferiprone 3-O-glucuronide | AUC0-∞ for serum deferiprone | 92.64 ug*hr/mL | Standard Deviation 19.221 |
| Normal Hepatic Function (Healthy Volunteers) | AUC0-∞ for Serum Deferiprone and Deferiprone 3-O-glucuronide | AUC0-∞ for serum deferiprone 3-O-glucuronide | 337.3 ug*hr/mL | Standard Deviation 45.343 |
| Mild Hepatic Failure | AUC0-∞ for Serum Deferiprone and Deferiprone 3-O-glucuronide | AUC0-∞ for serum deferiprone | 82.02 ug*hr/mL | Standard Deviation 28.213 |
| Mild Hepatic Failure | AUC0-∞ for Serum Deferiprone and Deferiprone 3-O-glucuronide | AUC0-∞ for serum deferiprone 3-O-glucuronide | 305.1 ug*hr/mL | Standard Deviation 53.651 |
| Moderate Hepatic Failure | AUC0-∞ for Serum Deferiprone and Deferiprone 3-O-glucuronide | AUC0-∞ for serum deferiprone | 105.5 ug*hr/mL | Standard Deviation 41.684 |
| Moderate Hepatic Failure | AUC0-∞ for Serum Deferiprone and Deferiprone 3-O-glucuronide | AUC0-∞ for serum deferiprone 3-O-glucuronide | 305.9 ug*hr/mL | Standard Deviation 111.75 |
Primary
Cmax for Serum Deferiprone and Deferiprone 3-O-glucuronide
Cmax was assessed over a 24-hour interval for analyses of deferiprone and its 3-O-glucuronide metabolite in subjects with normal hepatic function, mild hepatic impairment, or moderate hepatic impairment. Blood samples were obtained prior to dosing and at 0.25, 0.50, 0.75, 1, 1.33, 1.66, 2, 2.5, 3, 4, 6, 9, 12, 16, and 24 hours post-dose.
Time frame: 24-hour interval
Population: The PK Analysis Set consisted of all subjects who had sufficient data to derive at least one PK parameter
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Hepatic Function (Healthy Volunteers) | Cmax for Serum Deferiprone and Deferiprone 3-O-glucuronide | Cmax for serum deferiprone | 49.00 ug/mL | Standard Deviation 24.081 |
| Normal Hepatic Function (Healthy Volunteers) | Cmax for Serum Deferiprone and Deferiprone 3-O-glucuronide | Cmax for serum deferiprone 3-O-glucuronide | 69.03 ug/mL | Standard Deviation 9.9153 |
| Mild Hepatic Failure | Cmax for Serum Deferiprone and Deferiprone 3-O-glucuronide | Cmax for serum deferiprone | 36.26 ug/mL | Standard Deviation 8.4799 |
| Mild Hepatic Failure | Cmax for Serum Deferiprone and Deferiprone 3-O-glucuronide | Cmax for serum deferiprone 3-O-glucuronide | 56.91 ug/mL | Standard Deviation 11.416 |
| Moderate Hepatic Failure | Cmax for Serum Deferiprone and Deferiprone 3-O-glucuronide | Cmax for serum deferiprone | 35.94 ug/mL | Standard Deviation 7.8407 |
| Moderate Hepatic Failure | Cmax for Serum Deferiprone and Deferiprone 3-O-glucuronide | Cmax for serum deferiprone 3-O-glucuronide | 55.33 ug/mL | Standard Deviation 25.335 |
Primary
CumAe for Urine Deferiprone and Deferiprone 3-O-glucuronide
Cumulative amount of deferiprone and deferiprone 3-O-glucuronide excreted in the urine. Urine samples were collected at the intervals of -2 to 0 hours pre-dose, and 0-2, 2-4, 4-8, 8-12 ,and 12- 24 hours post-dose. Note: For unknown reasons, the urine samples for one subject in the moderate hepatic failure group had low or zero volume and there were no measurable levels of deferiprone or its metabolite in any of the samples. Accordingly, the urine PK results were derived both with and without this subject's data, and are here presented without them (i.e., N=6 rather than 7).
Time frame: 24-hour interval
Population: The PK Analysis Set consisted of all subjects who had sufficient data to derive at least one PK parameter. The data of one subject in the moderate hepatic failure group were dropped due to low or zero volume of urine samples.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Hepatic Function (Healthy Volunteers) | CumAe for Urine Deferiprone and Deferiprone 3-O-glucuronide | CumAe of urine deferiprone | 69.0 mg | Standard Deviation 25.9 |
| Normal Hepatic Function (Healthy Volunteers) | CumAe for Urine Deferiprone and Deferiprone 3-O-glucuronide | CumAe of urine deferiprone 3-O-glucuronide | 6670 mg | Standard Deviation 2520 |
| Mild Hepatic Failure | CumAe for Urine Deferiprone and Deferiprone 3-O-glucuronide | CumAe of urine deferiprone | 59.5 mg | Standard Deviation 19.4 |
| Mild Hepatic Failure | CumAe for Urine Deferiprone and Deferiprone 3-O-glucuronide | CumAe of urine deferiprone 3-O-glucuronide | 6787 mg | Standard Deviation 619 |
| Moderate Hepatic Failure | CumAe for Urine Deferiprone and Deferiprone 3-O-glucuronide | CumAe of urine deferiprone | 62.9 mg | Standard Deviation 31.1 |
| Moderate Hepatic Failure | CumAe for Urine Deferiprone and Deferiprone 3-O-glucuronide | CumAe of urine deferiprone 3-O-glucuronide | 5979 mg | Standard Deviation 887 |
Primary
Fe% for Urine Deferiprone and Deferiprone 3-O-glucuronide
Cumulative fraction of Ferriprox dose excreted in urine as deferiprone or deferiprone 3-O-glucuronide. Urine samples were collected at the intervals of -2 to 0 hours pre-dose, and 0-2, 2-4, 4-8, 8-12 ,and 12- 24 hours post-dose. Note: For unknown reasons, the urine samples for one subject in the moderate hepatic failure group had low or zero volume and there were no measurable levels of deferiprone or its metabolite in any of the samples. Accordingly, the urine PK results were derived both with and without this subject's data, and are here presented without them (i.e., N=6 rather than 7).
Time frame: 24-hour interval
Population: The PK Analysis Set consisted of all subjects who had sufficient data to derive at least one PK parameter. The data of one subject in the moderate hepatic failure group were dropped due to low or zero volume of urine samples.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Hepatic Function (Healthy Volunteers) | Fe% for Urine Deferiprone and Deferiprone 3-O-glucuronide | Fe of urine deferiprone | 2.56 percentage of dose excreted in urine | Standard Deviation 0.773 |
| Normal Hepatic Function (Healthy Volunteers) | Fe% for Urine Deferiprone and Deferiprone 3-O-glucuronide | Fe of urine 3-O-glucuronide | 109 percentage of dose excreted in urine | Standard Deviation 32.4 |
| Mild Hepatic Failure | Fe% for Urine Deferiprone and Deferiprone 3-O-glucuronide | Fe of urine deferiprone | 2.18 percentage of dose excreted in urine | Standard Deviation 0.669 |
| Mild Hepatic Failure | Fe% for Urine Deferiprone and Deferiprone 3-O-glucuronide | Fe of urine 3-O-glucuronide | 110 percentage of dose excreted in urine | Standard Deviation 14 |
| Moderate Hepatic Failure | Fe% for Urine Deferiprone and Deferiprone 3-O-glucuronide | Fe of urine deferiprone | 2.36 percentage of dose excreted in urine | Standard Deviation 1.2 |
| Moderate Hepatic Failure | Fe% for Urine Deferiprone and Deferiprone 3-O-glucuronide | Fe of urine 3-O-glucuronide | 97.7 percentage of dose excreted in urine | Standard Deviation 13.7 |
Primary
T1/2 for Serum Deferiprone and Deferiprone 3-O-glucuronide
T1/2 was assessed over a 24-hour interval for analyses of deferiprone and its 3-O-glucuronide metabolite in subjects with normal hepatic function, mild hepatic impairment, or moderate hepatic impairment. Blood samples were obtained prior to dosing and at 0.25, 0.50, 0.75, 1, 1.33, 1.66, 2, 2.5, 3, 4, 6, 9, 12, 16, and 24 hours post-dose.
Time frame: 24-hour interval
Population: The PK Analysis Set consisted of all subjects who had sufficient data to derive at least one PK parameter
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Hepatic Function (Healthy Volunteers) | T1/2 for Serum Deferiprone and Deferiprone 3-O-glucuronide | T1/2 for serum deferiprone | 1.994 hour | Standard Deviation 0.26971 |
| Normal Hepatic Function (Healthy Volunteers) | T1/2 for Serum Deferiprone and Deferiprone 3-O-glucuronide | T1/2 for deferiprone 3-O-glu | 2.621 hour | Standard Deviation 0.35653 |
| Mild Hepatic Failure | T1/2 for Serum Deferiprone and Deferiprone 3-O-glucuronide | T1/2 for serum deferiprone | 1.855 hour | Standard Deviation 0.4537 |
| Mild Hepatic Failure | T1/2 for Serum Deferiprone and Deferiprone 3-O-glucuronide | T1/2 for deferiprone 3-O-glu | 2.518 hour | Standard Deviation 0.55679 |
| Moderate Hepatic Failure | T1/2 for Serum Deferiprone and Deferiprone 3-O-glucuronide | T1/2 for serum deferiprone | 2.180 hour | Standard Deviation 0.83153 |
| Moderate Hepatic Failure | T1/2 for Serum Deferiprone and Deferiprone 3-O-glucuronide | T1/2 for deferiprone 3-O-glu | 2.479 hour | Standard Deviation 0.67212 |
Primary
Tmax for Serum Deferiprone and Deferiprone 3-O-glucuronide
Tmax was assessed over a 24-hour interval for analyses of deferiprone and its 3-O-glucuronide metabolite in subjects with normal hepatic function, mild hepatic impairment, or moderate hepatic impairment. Blood samples were obtained prior to dosing and at 0.25, 0.50, 0.75, 1, 1.33, 1.66, 2, 2.5, 3, 4, 6, 9, 12, 16, and 24 hours post-dose.
Time frame: 24-hour interval
Population: The PK Analysis Set consisted of all subjects who had sufficient data to derive at least one PK parameter
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Normal Hepatic Function (Healthy Volunteers) | Tmax for Serum Deferiprone and Deferiprone 3-O-glucuronide | Tmax of deferiprone | 0.7500 hour |
| Normal Hepatic Function (Healthy Volunteers) | Tmax for Serum Deferiprone and Deferiprone 3-O-glucuronide | Tmax of deferiprone 3-O-glucuronide | 2.000 hour |
| Mild Hepatic Failure | Tmax for Serum Deferiprone and Deferiprone 3-O-glucuronide | Tmax of deferiprone | 0.7500 hour |
| Mild Hepatic Failure | Tmax for Serum Deferiprone and Deferiprone 3-O-glucuronide | Tmax of deferiprone 3-O-glucuronide | 3.000 hour |
| Moderate Hepatic Failure | Tmax for Serum Deferiprone and Deferiprone 3-O-glucuronide | Tmax of deferiprone | 0.7500 hour |
| Moderate Hepatic Failure | Tmax for Serum Deferiprone and Deferiprone 3-O-glucuronide | Tmax of deferiprone 3-O-glucuronide | 3.000 hour |
Secondary
Safety and Tolerability of Ferriprox in Subjects With or Without Hepatic Impairment.
The number of participants who experienced adverse events following a single dose of Ferriprox, between the time of dosing and the follow-up visit (including any changes of clinical significance in physical examinations, vital signs, 12-lead ECG, and clinical laboratory tests).
Time frame: Time of dosing until 48 hours post-dose
Population: The Safety Analysis Set consisted of all subjects who received study medication and had at least one safety assessment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Normal Hepatic Function (Healthy Volunteers) | Safety and Tolerability of Ferriprox in Subjects With or Without Hepatic Impairment. | 0 participants |
| Mild Hepatic Failure | Safety and Tolerability of Ferriprox in Subjects With or Without Hepatic Impairment. | 1 participants |
| Moderate Hepatic Failure | Safety and Tolerability of Ferriprox in Subjects With or Without Hepatic Impairment. | 3 participants |