An Open-label, Non-randomized, Parallel Group Study in Subjects With Mild and Moderate Hepatic Insufficiency and Healthy Volunteers

Phase 4

Completed

Conditions: Hepatic Impairment

Interventions: Drug: Ferriprox®

Registration Number: NCT01767103

Lead Sponsor: ApoPharma

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 21

Inclusion Criteria

All subjects:

Adult males or females, 18 - 75 years of age (inclusive);
Body weight ≥ 50 kg;
Body mass index (BMI) between 19 and 32 kg/mE2 (inclusive);
Absolute neutrophil count (ANC) of >1.5x10E9/L ;

Healthy volunteers:

Medically healthy with clinically insignificant screening results (e.g., laboratory profiles, medical history, vital signs, physical examination);
Matched to hepatically impaired subjects in the study by age (+/- 10 years), sex and weight (+/- 15% BMI).

Hepatically impaired subjects:

Considered clinically stable in the opinion of the Investigator;
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

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).
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;
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;
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.);
Received a pharmacological agent in another clinical trial within 28 days prior to the first dose of the study;

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Moderate Hepatic Failure	Ferriprox®	Subjects with moderate hepatic failure as defined by the Child-Pugh Class B: 7-9 points received a single 33 mg/kg dose of Ferriprox®.
Normal Hepatic Function (healthy volunteers)	Ferriprox®	Healthy volunteers with normal hepatic function received a single 33 mg/kg dose of Ferriprox®.
Mild Hepatic Failure	Ferriprox®	Subjects with mild hepatic failure as defined by the Child-Pugh Class C: 5-6 points received a single 33 mg/kg dose of Ferriprox®.

Primary Outcome Measures

Name	Time	Method
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.
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.
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).
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).

Secondary Outcome Measures

Name	Time	Method
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).