Nitazoxanide Pharmacokinetic Parameters in Renal Impaired Subjects

• Sponsor: Genfit (Industry)
• Overall Status: Recruiting
• CT.gov ID: NCT05368935
• Collaborator: (none)
• Enrollment: 54
• Locations: 2
• Arms: 4
• Anticipated Duration (Months): 4.2
• Patients Per Site: 27
• Patients Per Site Per Month: 6.4

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Renal Impairment; Renal Disease; Kidney Disease	Drug: Nitazoxanide	Phase 1

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 Design

• Study Type: Interventional
• Anticipated Enrollment: 54 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 Mild, Moderate, and Severe Renal Impairment and Adult Healthy Control Subjects
• Actual Study Start Date: Apr 25, 2022
• Anticipated Primary Completion Date: Sep 1, 2022
• Anticipated Study Completion Date: Sep 1, 2022

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Maximum observed plasma concentration (Cmax) [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]

   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

2. Area under the plasma concentration time curve (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 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]

   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

3. 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 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]

   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

Secondary Outcome Measures

1. Time of the maximum observed plasma concentration (Tmax) 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 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]

   Plasma pharmacokinetics

2. Apparent plasma terminal elimination half-life (t1/2) for the 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 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]

   Plasma pharmacokinetics

3. Unbound fraction in plasma defined as total concentration/unbound concentration (fu) for the 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 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]

   Plasma pharmacokinetics

4. Area under the plasma concentration-time curve from time zero to infinity (extrapolated) (AUC0-∞) for the 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 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]

   Plasma pharmacokinetics

5. Trough concentration (Ctrough) for the 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 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]

   Plasma pharmacokinetics

6. Cmax 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 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]

   Plasma pharmacokinetics

7. AUC0-12 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 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]

   Plasma pharmacokinetics

8. AUC0-t 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 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]

   Plasma pharmacokinetics

9. Amount of drug excreted in urine over the time interval between t1 and t2 (Aet1-t2) for the NTZ major active metabolites [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]

   Urine pharmacokinetics

10. Cumulative amount of drug excreted in urine from time zero until and up to infinity (Ae0-∞) for the NTZ major active metabolites [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]

    Urine pharmacokinetics

11. 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 [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]

    Urine pharmacokinetics

12. Percentage of dose excreted in urine over the time interval between t1 and t2 (Fet1-t2) for the NTZ major active metabolites [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]

    Urine pharmacokinetics

13. 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 [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]

    Urine pharmacokinetics

14. Renal clearance (CLR) for the NTZ major active metabolites [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]

    Urine pharmacokinetics

15. Cmax after the single oral administration of NTZ 500 mg for the NTZ major active metabolites [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]

    Plasma and urine pharmacokinetics

16. AUC0-12 after the single oral administration of NTZ 500 mg for the NTZ major active metabolites [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]

    Plasma and urine pharmacokinetics

17. AUC0-t after the single oral administration of NTZ 500 mg for the NTZ major active metabolites [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]

    Plasma and urine pharmacokinetics

18. AUC0-∞ after the single oral administration of NTZ 500 mg for the NTZ major active metabolites [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]

    Plasma and urine pharmacokinetics

19. Tmax after the single oral administration of NTZ 500 mg for the NTZ major active metabolites [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]

    Plasma and urine pharmacokinetics

20. t1/2 after the single oral administration of NTZ 500 mg for the NTZ major active metabolites [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]

    Plasma and urine pharmacokinetics

21. Aet1-t2 after the single oral administration of NTZ 500 mg for the NTZ major active metabolites [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]

    Plasma and urine pharmacokinetics

22. 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 [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]

    Plasma and urine pharmacokinetics

23. Fet1-t2 after the single oral administration of NTZ 500 mg for the NTZ major active metabolites [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]

    Plasma and urine pharmacokinetics

24. 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 [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]

    Plasma and urine pharmacokinetics

25. CLR after the single oral administration of NTZ 500 mg for the NTZ major active metabolites [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]

    Plasma and urine pharmacokinetics

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Panax Clinical Research	Miami Lakes	Florida	United States	33014
2	Orlando Clinical Research Center	Orlando	Florida	United States	32802

Sponsors and Collaborators

• Genfit

Investigators

• Study Director: Carol Addy, MD, Genfit

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Genfit
• ClinicalTrials.gov Identifier: NCT05368935
• Other Study ID Numbers: NTZ-122-1
• First Posted: May 10, 2022
• Last Update Posted: May 10, 2022
• Last Verified: May 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Genfit: Pharmacokinetics; Healthy Volunteer; Renal Disease; Kidney Disease; Renal Impairment; Antiparasitic; Antiprotozoal
• Additional relevant MeSH terms: Kidney Diseases; Renal Insufficiency; Nitazoxanide

Study Results

No Results Posted as of May 10, 2022