Nitazoxanide Pharmacokinetic Parameters in Renal Impaired Subjects

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 Mild, Moderate, and Severe Renal Impairment and Adult Healthy Control Subjects

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

Study Overview

• Status: Completed
• Conditions: Renal Impairment; Kidney Disease; Renal Disease
• Intervention / Treatment: Drug: Nitazoxanide

Detailed Description

This study is being conducted to assess the pharmacokinetics of the major Nitazoxanide active metabolite as well as the safety and tolerability in renal impaired (mild, moderate and severe) and healthy matched control adults following repeated oral dose administration of NTZ 500 mg twice a day for 7 days.

• Study Type: Interventional
• Enrollment (Actual): 77
• 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 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Males or females, between 18 and 80 years of age, inclusive
2. With a minimum body weight of ≥ 50.0 kg for males and ≥ 45.0 kg for females 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. Matched to subjects with mild, moderate and/or severe renal impairment in age (± 15 years), BMI (± 20%) and sex
5. The diagnosis of renal impairment has been stable, without significant change in overall disease status in the last 3 months prior to screening

Other protocol-defined inclusion criteria may apply

Exclusion Criteria:

1. Positive serum pregnancy test at screening or positive urine pregnancy test
2. Having taken NTZ at any time prior to the first study drug administration
3. History of alcohol abuse within 1 year prior to screening
4. History of drug abuse within 1 year prior to screening or recreational use of soft drugs within 1 month or hard drugs within 3 months prior to screening
5. Excessive consumption of xanthine-based drinks (> 4 cups or glasses per day), food or beverages containing xanthine derivatives or xanthine-based compounds, 48 hours prior to the first dosing
6. Donation of plasma within 7 days prior to dosing or donation or loss of 500 mL or more of whole blood within 8 weeks prior to the first dosing
7. Strenuous exercise within 72 hours prior to check-in
8. History of a major surgical procedure within 30 days prior to screening
9. Presence or history of malignancy within the prior 3 years, with the exception of treated basal cell or squamous cell carcinoma
10. Poor peripheral venous access
11. Subjects who are taking warfarin or other highly plasma protein-bound drugs with narrow therapeutic indices

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: Healthy Control Match (RF ≥ 90 mL/min); 500 mg Twice Daily for 7 days	Drug: Nitazoxanide; 500 mg Twice Daily for 7 days; Other Names: NTZ
Experimental: Mild Renal Impairment (RF ≥ 60 to < 90 mL/min); 500 mg Twice Daily for 7 days	Drug: Nitazoxanide; 500 mg Twice Daily for 7 days; Other Names: NTZ
Experimental: Moderate Renal Impairment (RF ≥ 30 to < 60 mL/min); 500 mg Twice Daily for 7 days	Drug: Nitazoxanide; 500 mg Twice Daily for 7 days; Other Names: NTZ
Experimental: Severe Renal Impairment (RF < 30 mL/min and not on dialysis); 500 mg Twice Daily 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
Maximum observed plasma concentration (Cmax)	Plasma pharmacokinetic (PK) parameters of NTZ active metabolite expressed in terms of unbound as well as total concentrations at steady-state in subjects with mild, moderate and severe renal impairment compared to healthy volunteers	Day 1: pre-dose; 1; 2; 3; 4; 5; 6; 7; 8; 10 and 12 hours post dose; Day 2-6: pre-dose; Day 7: pre-dose; 1; 2; 3; 4; 5; 6; 7; 8; 10; 12; 14; 16; 18; 24 hours (Day 8); 48 hours (Day 9); 72 hours (Day 10) and 96 hours (Day 11) post-dose
Area under the plasma concentration time curve (AUC) from time zero to the time of the last quantifiable concentration (AUC0-t)	Plasma pharmacokinetic parameters of NTZ active metabolite expressed in terms of unbound as well as total concentrations at steady-state in subjects with mild, moderate and severe renal impairment compared to healthy volunteers	Day 1: pre-dose; 1; 2; 3; 4; 5; 6; 7; 8; 10 and 12 hours post dose; Day 2-6: pre-dose; Day 7: pre-dose; 1; 2; 3; 4; 5; 6; 7; 8; 10; 12; 14; 16; 18; 24 (Day 8); 48 (Day 9); 72 (Day 10) and 96 (Day 11) hours post-dose
AUC from time zero to 12h (AUC0-12)	Plasma pharmacokinetic parameters of NTZ active metabolite expressed in terms of unbound as well as total concentrations at steady-state in subjects with mild, moderate and severe renal impairment compared to healthy volunteers	Day 1: pre-dose; 1; 2; 3; 4; 5; 6; 7; 8; 10 and 12 hours post dose; Day 2-6: pre-dose; Day 7: pre-dose; 1; 2; 3; 4; 5; 6; 7; 8; 10; 12; 14; 16; 18; 24 hours (Day 8); 48 hours (Day 9); 72 hours (Day 10) and 96 hours (Day 11) post-dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time of the maximum observed plasma concentration (Tmax) for NTZ and its major active metabolite	Plasma pharmacokinetics	Day 1: pre-dose; 1; 2; 3; 4; 5; 6; 7; 8; 10 and 12 hours post dose; Day 2-6: pre-dose; Day 7: pre-dose; 1; 2; 3; 4; 5; 6; 7; 8; 10; 12; 14; 16; 18 hours; 24 hours (Day 8); 48 hours (Day 9) ; 72 hours (Day 10) and 96 hours (Day 11) post-dose
Apparent plasma terminal elimination half-life (t1/2) for the NTZ and its major active metabolite	Plasma pharmacokinetics	Day 1: pre-dose; 1; 2; 3; 4; 5; 6; 7; 8; 10 and 12 hours post dose; Day 2-6: pre-dose; Day 7: pre-dose; 1; 2; 3; 4; 5; 6; 7; 8; 10; 12; 14; 16; 18 hours; 24 hours (Day 8); 48 hours (Day 9) ; 72 hours (Day 10) and 96 hours (Day 11) post-dose
Unbound fraction in plasma defined as total concentration/unbound concentration (fu) for the NTZ and its major active metabolite	Plasma pharmacokinetics	Day 1: pre-dose; 1; 2; 3; 4; 5; 6; 7; 8; 10 and 12 hours post dose; Day 2-6: pre-dose; Day 7: pre-dose; 1; 2; 3; 4; 5; 6; 7; 8; 10; 12; 14; 16; 18 hours; 24 hours (Day 8); 48 hours (Day 9) ; 72 hours (Day 10) and 96 hours (Day 11) post-dose
Area under the plasma concentration-time curve from time zero to infinity (extrapolated) (AUC0-∞) for the NTZ and its major active metabolite	Plasma pharmacokinetics	Day 1: pre-dose; 1; 2; 3; 4; 5; 6; 7; 8; 10 and 12 hours post dose; Day 2-6: pre-dose; Day 7: pre-dose; 1; 2; 3; 4; 5; 6; 7; 8; 10; 12; 14; 16; 18 hours; 24 hours (Day 8); 48 hours (Day 9) ; 72 hours (Day 10) and 96 hours (Day 11) post-dose
Trough concentration (Ctrough) for the NTZ and its major active metabolite	Plasma pharmacokinetics	Day 1: pre-dose; 1; 2; 3; 4; 5; 6; 7; 8; 10 and 12 hours post dose; Day 2-6: pre-dose; Day 7: pre-dose; 1; 2; 3; 4; 5; 6; 7; 8; 10; 12; 14; 16; 18 hours; 24 hours (Day 8); 48 hours (Day 9) ; 72 hours (Day 10) and 96 hours (Day 11) post-dose
Cmax for the NTZ major active metabolite	Plasma pharmacokinetics	Day 1: pre-dose; 1; 2; 3; 4; 5; 6; 7; 8; 10 and 12 hours post dose; Day 2-6: pre-dose; Day 7: pre-dose; 1; 2; 3; 4; 5; 6; 7; 8; 10; 12; 14; 16; 18 hours; 24 hours (Day 8); 48 hours (Day 9) ; 72 hours (Day 10) and 96 hours (Day 11) post-dose
AUC0-12 for the NTZ major active metabolite	Plasma pharmacokinetics	Day 1: pre-dose; 1; 2; 3; 4; 5; 6; 7; 8; 10 and 12 hours post dose; Day 2-6: pre-dose; Day 7: pre-dose; 1; 2; 3; 4; 5; 6; 7; 8; 10; 12; 14; 16; 18 hours; 24 hours (Day 8); 48 hours (Day 9) ; 72 hours (Day 10) and 96 hours (Day 11) post-dose
AUC0-t for the NTZ major active metabolite	Plasma pharmacokinetics	Day 1: pre-dose; 1; 2; 3; 4; 5; 6; 7; 8; 10 and 12 hours post dose; Day 2-6: pre-dose; Day 7: pre-dose; 1; 2; 3; 4; 5; 6; 7; 8; 10; 12; 14; 16; 18 hours; 24 hours (Day 8); 48 hours (Day 9) ; 72 hours (Day 10) and 96 hours (Day 11) post-dose
Amount of drug excreted in urine over the time interval between t1 and t2 (Aet1-t2) for the NTZ major active metabolites	Urine pharmacokinetics	Day (D) 1: pre-dose, 0-4 hours (h); 4-8 h; and 8-12 h post-morning dose; D7: 0-4 h; 4-8 h; 8-12 h; 12- 24 h; 24-48 h; 48-72 h and 72-96 h post-dose
Cumulative amount of drug excreted in urine from time zero until and up to infinity (Ae0-∞) for the NTZ major active metabolites	Urine pharmacokinetics	Day (D) 1: pre-dose, 0-4 hours (h); 4-8 h; and 8-12 h post-morning dose; D7: 0-4 h; 4-8 h; 8-12 h; 12- 24 h; 24-48 h; 48-72 h and 72-96 h post-dose
Cumulative amount of drug excreted in urine from time zero until the last measured concentration at time t (Ae0-t) for the NTZ major active metabolites	Urine pharmacokinetics	Day (D) 1: pre-dose, 0-4 hours (h); 4-8 h; and 8-12 h post-morning dose; D7: 0-4 h; 4-8 h; 8-12 h; 12- 24 h; 24-48 h; 48-72 h and 72-96 h post-dose
Percentage of dose excreted in urine over the time interval between t1 and t2 (Fet1-t2) for the NTZ major active metabolites	Urine pharmacokinetics	Day (D) 1: pre-dose, 0-4 hours (h); 4-8 h; and 8-12 h post-morning dose; D7: 0-4 h; 4-8 h; 8-12 h; 12- 24 h; 24-48 h; 48-72 h and 72-96 h post-dose
Cumulative percent of dose excreted in urine from time zero until the last measured concentration at time t (Fe0-t) for the NTZ major active metabolites	Urine pharmacokinetics	Day (D) 1: pre-dose, 0-4 hours (h); 4-8 h; and 8-12 h post-morning dose; D7: 0-4 h; 4-8 h; 8-12 h; 12- 24 h; 24-48 h; 48-72 h and 72-96 h post-dose
Renal clearance (CLR) for the NTZ major active metabolites	Urine pharmacokinetics	Day (D) 1: pre-dose, 0-4 hours (h); 4-8 h; and 8-12 h post-morning dose; D7: 0-4 h; 4-8 h; 8-12 h; 12- 24 h; 24-48 h; 48-72 h and 72-96 h post-dose
Cmax after the single oral administration of NTZ 500 mg for the NTZ major active metabolites	Plasma and urine pharmacokinetics	D1:predose;1;2;3;4;5;6;7;8;10;12h post dose; D2-6:predose; D7:predose;1;2;3;4;5;6;7;8;10;12;14;16;18; 24(D8);48(D9);72(D10) and 96(11)h post-dose.Urine:D1 predose; 0-4; 4-8; 8-12 h post morning dose; D7 0-4;4-8;8-12;12- 24;24-48;48-72;72-96h post-dose
AUC0-12 after the single oral administration of NTZ 500 mg for the NTZ major active metabolites	Plasma and urine pharmacokinetics	D1:predose;1;2;3;4;5;6;7;8;10;12h post dose; D2-6:predose; D7:predose;1;2;3;4;5;6;7;8;10;12;14;16;18; 24(D8);48(D9);72(D10) and 96(11)h post-dose.Urine:D1 predose; 0-4; 4-8; 8-12 h post morning dose; D7 0-4;4-8;8-12;12- 24;24-48;48-72;72-96h post-dose
AUC0-t after the single oral administration of NTZ 500 mg for the NTZ major active metabolites	Plasma and urine pharmacokinetics	D1:predose;1;2;3;4;5;6;7;8;10;12h post dose; D2-6:predose; D7:predose;1;2;3;4;5;6;7;8;10;12;14;16;18; 24(D8);48(D9);72(D10) and 96(11)h post-dose.Urine:D1 predose; 0-4; 4-8; 8-12 h post morning dose; D7 0-4;4-8;8-12;12- 24;24-48;48-72;72-96h post-dose
AUC0-∞ after the single oral administration of NTZ 500 mg for the NTZ major active metabolites	Plasma and urine pharmacokinetics	D1:predose;1;2;3;4;5;6;7;8;10;12h post dose; D2-6:predose; D7:predose;1;2;3;4;5;6;7;8;10;12;14;16;18; 24(D8);48(D9);72(D10) and 96(11)h post-dose.Urine:D1 predose; 0-4; 4-8; 8-12 h post morning dose; D7 0-4;4-8;8-12;12- 24;24-48;48-72;72-96h post-dose
Tmax after the single oral administration of NTZ 500 mg for the NTZ major active metabolites	Plasma and urine pharmacokinetics	D1:predose;1;2;3;4;5;6;7;8;10;12h post dose; D2-6:predose; D7:predose;1;2;3;4;5;6;7;8;10;12;14;16;18; 24(D8);48(D9);72(D10) and 96(11)h post-dose.Urine:D1 predose; 0-4; 4-8; 8-12 h post morning dose; D7 0-4;4-8;8-12;12- 24;24-48;48-72;72-96h post-dose
t1/2 after the single oral administration of NTZ 500 mg for the NTZ major active metabolites	Plasma and urine pharmacokinetics	D1:predose;1;2;3;4;5;6;7;8;10;12h post dose; D2-6:predose; D7:predose;1;2;3;4;5;6;7;8;10;12;14;16;18; 24(D8);48(D9);72(D10) and 96(11)h post-dose.Urine:D1 predose; 0-4; 4-8; 8-12 h post morning dose; D7 0-4;4-8;8-12;12- 24;24-48;48-72;72-96h post-dose
Aet1-t2 after the single oral administration of NTZ 500 mg for the NTZ major active metabolites	Plasma and urine pharmacokinetics	D1:predose;1;2;3;4;5;6;7;8;10;12h post dose; D2-6:predose; D7:predose;1;2;3;4;5;6;7;8;10;12;14;16;18; 24(D8);48(D9);72(D10) and 96(11)h post-dose.Urine:D1 predose; 0-4; 4-8; 8-12 h post morning dose; D7 0-4;4-8;8-12;12- 24;24-48;48-72;72-96h post-dose
Amount of drug excreted in urine from time zero to 12h (Ae0-12) after the single oral administration of NTZ 500 mg for the NTZ major active metabolites	Plasma and urine pharmacokinetics	D1:predose;1;2;3;4;5;6;7;8;10;12h post dose; D2-6:predose; D7:predose;1;2;3;4;5;6;7;8;10;12;14;16;18; 24(D8);48(D9);72(D10) and 96(11)h post-dose.Urine:D1 predose; 0-4; 4-8; 8-12 h post morning dose; D7 0-4;4-8;8-12;12- 24;24-48;48-72;72-96h post-dose
Fet1-t2 after the single oral administration of NTZ 500 mg for the NTZ major active metabolites	Plasma and urine pharmacokinetics	D1:predose;1;2;3;4;5;6;7;8;10;12h post dose; D2-6:predose; D7:predose;1;2;3;4;5;6;7;8;10;12;14;16;18; 24(D8);48(D9);72(D10) and 96(11)h post-dose.Urine:D1 predose; 0-4; 4-8; 8-12 h post morning dose; D7 0-4;4-8;8-12;12- 24;24-48;48-72;72-96h post-dose
Cumulative percent of dose excreted in urine from time zero to 12h (Fe0-12) after the single oral administration of NTZ 500 mg for the NTZ major active metabolites	Plasma and urine pharmacokinetics	D1:predose;1;2;3;4;5;6;7;8;10;12h post dose; D2-6:predose; D7:predose;1;2;3;4;5;6;7;8;10;12;14;16;18; 24(D8);48(D9);72(D10) and 96(11)h post-dose.Urine:D1 predose; 0-4; 4-8; 8-12 h post morning dose; D7 0-4;4-8;8-12;12- 24;24-48;48-72;72-96h post-dose
CLR after the single oral administration of NTZ 500 mg for the NTZ major active metabolites	Plasma and urine pharmacokinetics	D1:predose;1;2;3;4;5;6;7;8;10;12h post dose; D2-6:predose; D7:predose;1;2;3;4;5;6;7;8;10;12;14;16;18; 24(D8);48(D9);72(D10) and 96(11)h post-dose.Urine:D1 predose; 0-4; 4-8; 8-12 h post morning dose; D7 0-4;4-8;8-12;12- 24;24-48;48-72;72-96h post-dose

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Actual): April 25, 2022
• Primary Completion (Actual): September 4, 2022
• Study Completion (Actual): September 9, 2022

Study Registration Dates

• First Submitted: April 12, 2022
• First Submitted That Met QC Criteria: May 6, 2022
• First Posted (Actual): May 10, 2022

Study Record Updates

• Last Update Posted (Actual): October 28, 2022
• Last Update Submitted That Met QC Criteria: October 27, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: Healthy Volunteer; Pharmacokinetics; Renal Impairment; Kidney Disease; Antiparasitic; Antiprotozoal; Renal Disease
• Additional Relevant MeSH Terms: Urologic Diseases; Kidney Diseases; Renal Insufficiency; Anti-Infective Agents; Antiparasitic Agents; Nitazoxanide
• Other Study ID Numbers: NTZ-122-1

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