Nitazoxanide Pharmacokinetic Parameters in Hepatic Impaired Patients

Sponsor

Genfit (Industry)

Overall Status

Completed

CT.gov ID

NCT05116826

Collaborator

(none)

Enrollment

Locations

Arms

5.2

Actual Duration (Months)

12.5

Patients Per Site

2.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Moderate Hepatic Impairment Severe Hepatic Impairment Liver Diseases	Drug: Nitazoxanide	Phase 1

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 Design

Study Type:

Interventional

Actual Enrollment :

25 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Basic Science

Official Title:

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

Actual Study Start Date :

Nov 5, 2021

Actual Primary Completion Date :

Apr 8, 2022

Actual Study Completion Date :

Apr 13, 2022

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

Area under the plasma concentration time curve (AUC) from time zero to 12h (AUC0-12) [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]
In participants with moderate and severe hepatic impairment compared to healthy volunteers
AUC from time zero to the time of the last quantifiable concentration (AUC0-t) [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]
In participants with moderate and severe hepatic impairment compared to healthy volunteers
Maximum observed plasma concentration (Cmax), [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]
In participants with moderate and severe hepatic impairment compared to healthy volunteers

Secondary Outcome Measures

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) [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]
For NTZ and its major active metabolite
Plasma pharmacokinetics: Tmax, AUC0-12, AUC0-t, AUC0-∞, Cmax, t1/2, %AUCextrap and Ctrough. [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]
For the NTZ major active metabolite
Urine pharmacokinetics: amount of drug excreted (Ae), cumulative amount of drug excreted (Ae0-t), and renal clearance (CLR) [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]
For the NTZ major active metabolites
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. [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]
For the NTZ major active metabolites

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Males or females, between 18 and 75 years of age, inclusive;
With a minimum body weight of 50 kg and within a BMI range of 18.0 to 40.0 kg/m^2, inclusive;
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;
Negative human immunodeficiency virus antibody screens at Screening;
Matched to participants with moderate and/or severe hepatic impairment in age (± 10 years), BMI (± 20 percentage) and sex;
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:

A positive alcohol test result at Check-In Visit;
A history of alcohol abuse in the prior 2 years;
Positive urine screen for drugs of abuse at Screening or Check-In;
Strenuous exercise within 72 hours prior to Check-In Visit;
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;
History of a major surgical procedure within 30 days prior to Screening;
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;
Presence or history of malignancy within the prior 3 years, with the exception of treated basal cell or squamous cell carcinoma;
Poor peripheral venous access;
Receipt of blood products within 2 months prior to Check-In Visit;
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;
Positive serologic test for hepatitis B surface antigen or for hepatitis C virus antibody at Screening;
Frequent headaches (> twice a month) and/or migraines, recurrent nausea and/or vomiting, diarrhea;
Participants with symptomatic hypotension at Screening, whatever the decrease of blood pressure, or asymptomatic postural hypotension;
History of unstable diabetes mellitus;
Participants who have a transjugular intrahepatic portosystemic shunt and/or have undergone portacaval shunting;
Participant has shown evidence of hepatorenal syndrome or has creatinine clearance ≤ 60 mL/min;
Participants has required treatment for GI bleeding within the 6 months prior to Check-In Visit;
Recent history of paracentesis (< 1 months prior to Check-In Visit);
Participants with Wilson's disease, alpha-1 antitrypsin deficiency, glycogen storage diseases, or galactosemia;
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.