Elafibranor Pharmacokinetic Parameters in Hepatic Impaired Patients

An Open-label, Phase 1, Single-dose Study to Evaluate the Pharmacokinetics of Elafibranor 120 mg in Adult Subjects With Hepatic Impairment and Adult Healthy Control Subjects

This study is being conducted in order to assess the need for dose adjustment for elafibranor in patients with hepatic impairment. Pharmacokinetic parameters of elafibranor and its active metabolite (GFT1007) will be compared in hepatic impaired patients (mild, moderate and severe according to Child-Pugh categories) versus healthy participants after a single oral administration of elafibranor 120 mg.

Study Overview

• Status: Completed
• Conditions: Pharmacokinetics; Hepatic Impairment; Liver Disease
• Intervention / Treatment: Drug: Elafibranor

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Florida
    • Miami, Florida, United States, 33136
      • Division of Clinical Pharmacology, University of Miami
    • Miami, Florida, United States, 33136
      • inVentiv Health Clinical Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

- For all participants:

1. Males or females, between 18 and 75 years of age, inclusive;
2. With a minimum body weight of 50 kg and within a BMI range of 18.0 to 40.0 kg/m², inclusive;
3. Females participating in this study must be of non-childbearing potential or using highly efficient contraception for the full duration of the study
4. Negative serum pregnancy test at screening (if applicable);

5. Negative human immunodeficiency virus antibody screens at Screening;

   • For hepatically impaired participants:

6. Participants who have chronic (≥ 6 months) mild, moderate, or severe hepatic insufficiency (of any etiology) that has been clinically stable (no acute episodes of illness due to deterioration in hepatic function) for at least 1 month prior to Screening Currently on a stable medication regimen

   • For healthy volunteers with normal hepatic function:
7. Non-smokers
8. Matched to participants with Mild and/or Moderate and/or Severe hepatic impairment in age (± 10 years), BMI (± 20 percent) and gender.

Other protocol-defined inclusion criteria may apply

Exclusion Criteria:

- For all participants:

1. A positive alcohol test result at Check-in;
2. A history of alcohol abuse in the prior 2 years;
3. Positive urine screen for drugs of abuse at Screening or Check-in.
4. Strenuous exercise within 72 hours prior to Check-in;
5. Blood donation or loss of blood (excluding volume drawn at screening or menses) of 50 mL to 499 mL of blood within 30 days, or more than 499 mL within 56 days prior to the dosing;
6. History of stomach or intestinal surgery or resection that would potentially alter absorption and/or excretion of orally administered drugs except that appendectomy and hernia repair will be allowed. Bariatric surgery will not be allowed.
7. Presence or history of malignancy within the prior 3 years, with the exception of treated basal cell or squamous cell carcinoma;
8. Poor peripheral venous access;

9. Receipt of blood products within 2 months prior to Check-in;

   • For hepatically impaired participants:
10. History of unstable diabetes mellitus Subjects who have a transjugular intrahepatic portosystemic shunt and/or have undergone portacaval shunting;
11. Participant has shown evidence of hepatorenal syndrome or has creatinine clearance ≤ 60 mL/min Subject has required treatment for GI bleeding within the 6 months prior to Check in;
12. Recent history of paracentesis (< 3 months prior to Check-in);
13. Participants with Wilson's disease, alpha-1 antitrypsin deficiency, glycogen storage diseases, or galactosemia;

14. Participants with anemia secondary to hepatic disease, unless hemoglobin is ≥ 9 g/dL and anemia symptoms are not clinically significant. Subjects must have ≥ 35 000 platelets at screening and at Day -1;

    • For healthy volunteers with normal hepatic function:
15. Significant history or clinical manifestation of any metabolic (including thyroid), allergic, dermatological, hepatic, renal, hematological, pulmonary, cardiovascular (including any prior history of cardiomyopathy or cardiac failure), gastrointestinal (GI), neurological, or psychiatric disorder;
16. Positive serologic test for hepatitis B surface antigen or for hepatitis C virus antibody at Screening;
17. Frequent headaches (> twice a month) and/or migraines, recurrent nausea and/or vomiting;
18. Participants with symptomatic hypotension at Screening, whatever the decrease of blood pressure, or asymptomatic postural hypotension;
19. Cholecystectomy

Other protocol-defined exclusion criteria may apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Mild Child-Pugh A; Single oral dose of elafibranor 120mg	Drug: Elafibranor; 120mg oral single dose; Other Names: GFT505
Experimental: Moderate Child-Pugh B; Single oral dose of elafibranor 120mg	Drug: Elafibranor; 120mg oral single dose; Other Names: GFT505
Experimental: Severe Child-Pugh C; Single oral dose of elafibranor 120mg	Drug: Elafibranor; 120mg oral single dose; Other Names: GFT505
Experimental: Healthy; Single oral dose of elafibranor 120mg	Drug: Elafibranor; 120mg oral single dose; Other Names: GFT505

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area under curve from dosing time to last measurement (AUC(0-t)) of elafibranor and active metabolite	In participants with mild, moderate and severe hepatic impairment compared to healthy volunteers	pre-dose and at 0.17, 0.33, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192 and 216 hours post-dose. Additionally, after elafibranor administration at 288 and 384 hours for hepatic impaired patients
Area under curve from dosing time to infinity (AUC(0-∞)) of elafibranor and active metabolite	In participants with mild, moderate and severe hepatic impairment compared to healthy volunteers	pre-dose and at 0.17, 0.33, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192 and 216 hours post-dose. Additionally, after elafibranor administration at 288 and 384 hours for hepatic impaired patients

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma pharmacokinetics: maximum plasma drug concentration (Cmax)	for elafibranor and metabolites	pre-dose and at 0.17, 0.33, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192 and 216 hours post-dose. Additionally, after elafibranor administration at 288 and 384 hours for hepatic impaired participants
Plasma pharmacokinetics: elimination half-life (t1/2)	for elafibranor and metabolites	pre-dose and at 0.17, 0.33, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192 and 216 hours post-dose. Additionally, after elafibranor administration at 288 and 384 hours for hepatic impaired participants
Plasma pharmacokinetics: apparent volume of distribution (Vd/F)	for elafibranor	pre-dose and at 0.17, 0.33, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192 and 216 hours post-dose. Additionally, after elafibranor administration at 288 and 384 hours for hepatic impaired participants
Plasma pharmacokinetics: renal clearance (CLr)	for elafibranor and metabolites	pre-dose and at 0.17, 0.33, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192 and 216 hours post-dose. Additionally, after elafibranor administration at 288 and 384 hours for hepatic impaired participants
Plasma pharmacokinetics: apparent non renal clearance (CLnr/F)	for elafibranor	pre-dose and at 0.17, 0.33, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192 and 216 hours post-dose. Additionally, after elafibranor administration at 288 and 384 hours for hepatic impaired participants
Plasma pharmacokinetics: apparent total clearance (CL/F)	for elafibranor	pre-dose and at 0.17, 0.33, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192 and 216 hours post-dose. Additionally, after elafibranor administration at 288 and 384 hours for hepatic impaired participants
Plasma pharmacokinetics: area under the plasma concentration-time curve extrapolated from time t to infinity as a percentage of total area under the plasma concentration-time curve (%AUCextra)	for elafibranor and metabolites	pre-dose and at 0.17, 0.33, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192 and 216 hours post-dose. Additionally, after elafibranor administration at 288 and 384 hours for hepatic impaired participants
Plasma pharmacokinetics: area under curve from dosing time to last measurement (AUC(0-t)) of glucuronide metabolites and corresponding aglycones	for the glucuronide metabolites of elafibranor and corresponding aglycones	pre-dose and at 0.17, 0.33, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192 and 216 hours post-dose. Additionally, after elafibranor administration at 288 and 384 hours for hepatic impaired participants
Plasma pharmacokinetics: area under curve from dosing time to infinity (AUC(0-∞)) of glucuronide metabolites and corresponding aglycones	for the glucuronide metabolites of elafibranor and corresponding aglycones	pre-dose and at 0.17, 0.33, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192 and 216 hours post-dose. Additionally, after elafibranor administration at 288 and 384 hours for hepatic impaired patients
Urine pharmacokinetics: amount excreted (Ae)	for elafibranor and metabolites, if applicable. 24 hours urine collection from dosing to 216 hours post-dose	pre-dose and then 24, 48, 72, 96, 120, 144, 168, 192, 216 hours post-dose
Urine pharmacokinetics: cumulative amount excreted (Ae0-t)	for elafibranor and metabolites, if applicable. 24 hours urine collection from dosing to 216 hours post-dose	pre-dose and then 24, 48, 72, 96, 120, 144, 168, 192, 216 hours post-dose
Urine pharmacokinetics: percentage of dose excreted (Fe)	for elafibranor and metabolites, if applicable. 24 hours urine collection from dosing to 216 hours post-dose	pre-dose and then 24, 48, 72, 96, 120, 144, 168, 192, 216 hours post-dose
Urine pharmacokinetics: cumulative percent of dose excreted (Fe0-t)	for elafibranor and metabolites, if applicable. 24 hours urine collection from dosing to 216 hours post-dose	pre-dose and then 24, 48, 72, 96, 120, 144, 168, 192, 216 hours post-dose
Urine pharmacokinetics: renal clearance (CLR)	for elafibranor and metabolites, if applicable. 24 hours urine collection from dosing to 216 hours post-dose	pre-dose and then 24, 48, 72, 96, 120, 144, 168, 192, 216 hours post-dose

Collaborators and Investigators

• Sponsor: Genfit
• Collaborators: University of Miami; Syneos Health

Study record dates

Study Major Dates

• Study Start (Actual): December 12, 2018
• Primary Completion (Actual): June 7, 2019
• Study Completion (Actual): June 14, 2019

Study Registration Dates

• First Submitted: November 30, 2018
• First Submitted That Met QC Criteria: December 4, 2018
• First Posted (Actual): December 5, 2018

Study Record Updates

• Last Update Posted (Actual): August 22, 2019
• Last Update Submitted That Met QC Criteria: August 21, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases
• Other Study ID Numbers: GFT505-118-14

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No