Nitazoxanide Pharmacokinetic Parameters in Renal Impaired Subjects

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Overview

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

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

Allocation

NON_RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

NONE

Enrollment

Conditions

Renal Impairment Renal Disease Kidney Disease

Interventions

NitazoxanideDRUG

500 mg Twice Daily for 7 days

Eligibility

Sex: ALLMin age: 18 YearsMax age: 80 YearsHealthy volunteers:

Medical Language ↔ Plain English

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

Locations (2)

Panax Clinical Research

Miami Lakes, Florida, United States

Orlando Clinical Research Center

Orlando, Florida, United States

Outcomes

Primary Outcomes

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

Time frame: 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

Time frame: 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)

Secondary Outcomes

Time of the maximum observed plasma concentration (Tmax) for NTZ and its major active metabolite

Plasma pharmacokinetics

Time frame: 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

Data from ClinicalTrials.gov

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Apparent plasma terminal elimination half-life (t1/2) for the NTZ and its major active metabolite

Plasma pharmacokinetics

Unbound fraction in plasma defined as total concentration/unbound concentration (fu) for the NTZ and its major active metabolite

Plasma pharmacokinetics

Area under the plasma concentration-time curve from time zero to infinity (extrapolated) (AUC0-∞) for the NTZ and its major active metabolite

Plasma pharmacokinetics

Trough concentration (Ctrough) for the NTZ and its major active metabolite

Plasma pharmacokinetics

Cmax for the NTZ major active metabolite

Plasma pharmacokinetics

AUC0-12 for the NTZ major active metabolite

Plasma pharmacokinetics

AUC0-t for the NTZ major active metabolite

Plasma pharmacokinetics

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

Urine pharmacokinetics

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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