Nitazoxanide Pharmacokinetic Parameters in Renal Impaired Subjects

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

Detailed Description
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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.

Official Title
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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

Conditions
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Renal Impairment, Renal Disease, Kidney Disease

Intervention / Treatment
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* Drug: Nitazoxanide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or females, between 18 and 80 years of age, inclusive 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 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 Matched to subjects with mild, moderate and/or severe renal impairment in age (± 15 years), BMI (± 20%) and sex 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: Positive serum pregnancy test at screening or positive urine pregnancy test Having taken NTZ at any time prior to the first study drug administration History of alcohol abuse within 1 year prior to screening 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 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 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 Strenuous exercise within 72 hours prior to check-in History of a major surgical procedure within 30 days prior to screening 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 Subjects who are taking warfarin or other highly plasma protein-bound drugs with narrow therapeutic indices Other protocol-defined exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Healthy Control Match (RF ≥ 90 mL/min)<br>500 mg Twice Daily for 7 days | Drug: Nitazoxanide<br>* 500 mg Twice Daily for 7 days<br>* Other names: NTZ;|
| Experimental: Mild Renal Impairment (RF ≥ 60 to < 90 mL/min)<br>500 mg Twice Daily for 7 days | Drug: Nitazoxanide<br>* 500 mg Twice Daily for 7 days<br>* Other names: NTZ;|
| Experimental: Moderate Renal Impairment (RF ≥ 30 to < 60 mL/min)<br>500 mg Twice Daily for 7 days | Drug: Nitazoxanide<br>* 500 mg Twice Daily for 7 days<br>* Other names: NTZ;|
| Experimental: Severe Renal Impairment (RF < 30 mL/min and not on dialysis)<br>500 mg Twice Daily for 7 days | Drug: Nitazoxanide<br>* 500 mg Twice Daily for 7 days<br>* Other names: NTZ;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pharmacokinetics, Healthy Volunteer, Renal Disease, Kidney Disease, Renal Impairment, Antiparasitic, Antiprotozoal