Nitazoxanide Pharmacokinetic Parameters in Hepatic Impaired Patients

An Open-label, Phase 1, Multiple-dose Study to Evaluate the Pharmacokinetics of Nitazoxanide 500 mg Twice Daily for 7 Days in Adult Subjects With Moderate and Severe Hepatic Impairment and Adult Healthy Control Subjects

This study is being conducted to evaluate the major Nitazoxanide (NTZ) active metabolite in adult participants with hepatic impairment and healthy adults.

Study Overview

• Status: Completed
• Conditions: Liver Diseases; Moderate Hepatic Impairment; Severe Hepatic Impairment
• Intervention / Treatment: Drug: Nitazoxanide

Detailed Description

This study is being conducted to assess the effect of hepatic impairment on the pharmacokinetics of the major Nitazoxanide active metabolite in hepatic impaired (moderate and severe according to Child-Pugh categories) and healthy control adults following repeated oral dose administration of NTZ 500 mg twice a day for 7 days.

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Florida
    • Miami Lakes, Florida, United States, 33014
      • Panax Clinical Research
    • Orlando, Florida, United States, 32802
      • Orlando Clinical Research Center

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:

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/m^2, inclusive;
3. Females participating in this study must be of non-childbearing potential or must be using highly effective contraception for the full duration of the study;
4. Negative human immunodeficiency virus antibody screens at Screening;
5. Matched to participants with moderate and/or severe hepatic impairment in age (± 10 years), BMI (± 20 percentage) and sex;
6. Participants who have chronic (≥ 6 months) 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 and must also remain stable throughout the Screening period.

Other protocol-defined inclusion criteria may apply

Exclusion Criteria:

1. A positive alcohol test result at Check-In Visit;
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 Visit;
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 a major surgical procedure within 30 days prior to Screening;
7. 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;
8. Presence or history of malignancy within the prior 3 years, with the exception of treated basal cell or squamous cell carcinoma;
9. Poor peripheral venous access;
10. Receipt of blood products within 2 months prior to Check-In Visit;
11. 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;
12. Positive serologic test for hepatitis B surface antigen or for hepatitis C virus antibody at Screening;
13. Frequent headaches (> twice a month) and/or migraines, recurrent nausea and/or vomiting, diarrhea;
14. Participants with symptomatic hypotension at Screening, whatever the decrease of blood pressure, or asymptomatic postural hypotension;
15. History of unstable diabetes mellitus;
16. Participants who have a transjugular intrahepatic portosystemic shunt and/or have undergone portacaval shunting;
17. Participant has shown evidence of hepatorenal syndrome or has creatinine clearance ≤ 60 mL/min;
18. Participants has required treatment for GI bleeding within the 6 months prior to Check-In Visit;
19. Recent history of paracentesis (< 1 months prior to Check-In Visit);
20. Participants with Wilson's disease, alpha-1 antitrypsin deficiency, glycogen storage diseases, or galactosemia;
21. Participants with anemia secondary to hepatic disease, unless hemoglobin is ≥ 8.5 g/dL and anemia symptoms are not clinically significant. Participants must have ≥ 30,000 platelets at screening and at Check-In Visit.

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

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Healthy Control Match (Normal hepatic function); NTZ 500 mg twice a day for 7 days	Drug: Nitazoxanide; 500 mg Twice Daily for 7 days; Other Names: NTZ
Experimental: Moderate Child-Pugh B (Moderate hepatic impairment); NTZ 500 mg twice a day for 7 days	Drug: Nitazoxanide; 500 mg Twice Daily for 7 days; Other Names: NTZ
Experimental: Severe Child-Pugh C (Severe hepatic impairment); NTZ 500 mg twice a day for 7 days	Drug: Nitazoxanide; 500 mg Twice Daily for 7 days; Other Names: NTZ

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area under the plasma concentration time curve (AUC) from time zero to 12h (AUC0-12)	In participants with moderate and severe hepatic impairment compared to healthy volunteers	Day 1: pre-dose; 1; 2; 3; 4; 5; 6; 7; 8; 10 and 12 hours post dose Day 7: pre-dose; 1; 2; 3; 4; 5; 6; 7; 8; 10; 12; 14; 16; 18; 24; and 48 hours post dose
AUC from time zero to the time of the last quantifiable concentration (AUC0-t)	In participants with moderate and severe hepatic impairment compared to healthy volunteers	Day 1: pre-dose; 1; 2; 3; 4; 5; 6; 7; 8; 10 and 12 hours post dose Day 7: pre-dose; 1; 2; 3; 4; 5; 6; 7; 8; 10; 12; 14; 16; 18; 24; and 48 hours post dose
Maximum observed plasma concentration (Cmax),	In participants with moderate and severe hepatic impairment compared to healthy volunteers	Day 1: pre-dose; 1; 2; 3; 4; 5; 6; 7; 8; 10 and 12 hours post dose Day 7: pre-dose; 1; 2; 3; 4; 5; 6; 7; 8; 10; 12; 14; 16; 18; 24; and 48 hours post dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma pharmacokinetics: time of the maximum observed plasma concentration (Tmax), apparent plasma terminal elimination half life (t1/2), AUC from time zero to infinity (AUC0-∞), trough concentration (Ctrough) and percentage of extrapolated (%AUCextrap)	For NTZ and its major active metabolite	Day 1: pre-dose; 1; 2; 3; 4; 5; 6; 7; 8; 10 and 12 hours post dose Day 7: pre-dose; 1; 2; 3; 4; 5; 6; 7; 8; 10; 12; 14; 16; 18; 24; and 48 hours post dose
Plasma pharmacokinetics: Tmax, AUC0-12, AUC0-t, AUC0-∞, Cmax, t1/2, %AUCextrap and Ctrough.	For the NTZ major active metabolite	Day 1: pre-dose; 1; 2; 3; 4; 5; 6; 7; 8; 10 and 12 hours post dose Day 7: pre-dose; 1; 2; 3; 4; 5; 6; 7; 8; 10; 12; 14; 16; 18; 24; and 48 hours post dose
Urine pharmacokinetics: amount of drug excreted (Ae), cumulative amount of drug excreted (Ae0-t), and renal clearance (CLR)	For the NTZ major active metabolites	Day-1: pre-dose, Day 1: 0-4 h, 4-8 h, 8-12, 12-24 h post-dose; Day 7: 0-4 h, 4-8 h, 8-12 h, 12-24 h, 24-48 h post-dose
Plasma and urine pharmacokinetics: After the single oral administration of NTZ 500 mg: Cmax, AUC0-12, AUC0-t, AUC0-∞ , Tmax, t1/2, %AUCextrap, Ae0-∞, Ae0-t and CLR.	For the NTZ major active metabolites	Plasma:Day 1: pre-dose; 1; 2; 3; 4; 5; 6; 7; 8; 10, 12 h post dose Day 7: pre-dose; 1; 2; 3; 4; 5; 6; 7; 8; 10; 12; 14; 16; 18; 24; and 48 h post dose Urine:Day-1: pre-dose, Day 1: 24 hours urine collection post-dose; Day 7: 48 hours urine collection

Collaborators and Investigators

• Sponsor: Genfit
• Investigators: Study Director: Carol Addy, MD, Genfit

Study record dates

Study Major Dates

• Study Start (Actual): November 5, 2021
• Primary Completion (Actual): April 8, 2022
• Study Completion (Actual): April 13, 2022

Study Registration Dates

• First Submitted: November 1, 2021
• First Submitted That Met QC Criteria: November 1, 2021
• First Posted (Actual): November 11, 2021

Study Record Updates

• Last Update Posted (Actual): October 14, 2022
• Last Update Submitted That Met QC Criteria: October 12, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: Healthy Volunteer; Pharmacokinetics; Liver Disease; Hepatic Impairment; Antiparasitic; Antiprotozoal
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Anti-Infective Agents; Antiparasitic Agents; Nitazoxanide
• Other Study ID Numbers: NTZ-121-1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No