Pharmacokinetic Interaction Between Nitazoxanide and Atazanavir/Ritonavir in Healthy Volunteers

Evaluation of Pharmacokinetic Interaction Between Nitazoxanide and Atazanavir/Ritonavir in Healthy Volunteers

The goal of this study is to

1. determine the most effective biological sampling method that best describe the pharmacokinetics nitazoxanide/tizoxanide and to;
2. evaluate the clinical significance of the pharmacokinetics interaction between nitazoxanide (1000mg twice daily) and atazanavir/ritonavir (300mg/100mg).

Participants will be given 1000mg oral nitazoxanide taken twice daily for seven days. After a washout period of three weeks, they will receive 1000mg oral nitazoxanide with atazanavir/ritonavir (taken orally at 300/100 mg). Five millimetres of whole blood or swab or saliva samples will be collected from them at 0.5, 1, 2, 4, 6, 8 and 12 hours after dose on day 1, 5 and 7.

The pharmacokinetic of nitazoxanide when administered alone and alongside atazanavir/ritonavir will be compared to see if concomitant administration of nitazoxanide and atazanavir/ritonavir affect nitazoxanide pharmacokinetics

Study Overview

• Status: Completed
• Conditions: Drug Interaction
• Intervention / Treatment: Drug: Nitazoxanide; Drug: Atazanavir/ritonavir

Detailed Description

Nitazoxanide is an antiprotozoal drug with a well-understood and documented safety profile. It was first approved by the US Food and Drug Administration (FDA) in July 2004 for the treatment of diarrhoea caused by Giardia lamblia or Cryptosporidium parvum in adults (≥ 18 years) and paediatrics (1-17 years). Nitazoxanide has also demonstrated in-vitro anti-SARS-CoV-2 activity. A review of in vitro studies reporting the anti-coronavirus activity of nitazoxanide and its active metabolite, tizoxanide, is available. Nitazoxanide was among the three top inhibitors of coronavirus replication, resulting in a reduction of 6 log10 in virus titer with an IC50 of 1.0 µM. The major circulating metabolite of nitazoxanide is tizoxanide, and it has also been confirmed to have activity against SARS-CoV-216. Both suppress the cytopathic effect of SARS-CoV-2. Nitazoxanide is also active against the influenza A virus and was shown to reduce symptom duration in uncomplicated acute influenza. Since SARS-CoV-2 shares almost 80% of the genome with SARSCoV19 and almost all encoded proteins of SARS-CoV-2 are homologous to SARS-CoV proteins, nitazoxanide and its metabolite tizoxanide with demonstrated activity against SARS-CoV are likely to be effective against SARS-CoV-2. Since the virus replicates quickly, antivirals must remain active across their dosing interval. Therefore, enhanced drug concentration will be needed in the lung throughout the dosing interval.

The HIV protease inhibitor, atazanavir (boosted with ritonavir), has been shown to inhibit the major protease enzyme required for viral polyprotein processing during coronavirus replication. It also blocks pro-inflammatory cytokine production. Similar to nitazoxanide, atazanavir has been shown to achieve effective concentration in the pulmonary tissues at the approved dose of 300 mg in combination with 100 mg of ritonavir, with even more favourable ratios when compared to in vitro activities generated in human cell models.

Therefore, based on these considerations, the combination of nitazoxanide (taken orally at 1000 mg twice daily) and atazanavir/ritonavir (taken orally at 300/100 mg once daily) is being considered for selection for intervention for the treatment of COVID-19. Hence, this study wants to evaluate the clinical usefulness of the combination of these drugs. The approach is to characterise the extent of drug-drug interaction of nitazoxanide and atazanavir/ritonavir when 1000 mg nitazoxanide is taken two times daily in combination with 300/100 mg atazanavir/ritonavir before deploying the combination for the intervention.

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Nigeria
  • Osun
    • Ile-Ife, Osun, Nigeria, 220101
      • Obafemi Awolowo University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 41 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• The study population will include both male and female healthy volunteers that are eighteen years or above
• non-smokers, non-alcoholics, had not taken any medication or coffee 2 weeks before participating, were non-pregnant and non-breastfeeding

Exclusion Criteria:

• Pregnant women will be excluded from the study. Moreover, volunteers who have been on any other drugs in the last two weeks will also be excluded from the study.
• Exclusion criteria included any sickness or reaction to the study drugs.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Administration of nitazoxanide alone; Participants in this arm will receive 1000 mg of nitazoxanide tablets alone	Drug: Nitazoxanide; 1000 mg nitazoxanide tablets twice daily. The drug will be administered after meal for 5 days; Other Names: Netazox
Other: Administration of nitazoxanide plus atazanavir/ritonavir; Participants in this arm will receive 1000 mg of nitazoxanide tablets twice daily together with one tablet of atazanavir/ritonavir (300 mg/100 mg) once daily in the morning.	Drug: Nitazoxanide; 1000 mg nitazoxanide tablets twice daily. The drug will be administered after meal for 5 days; Other Names: Netazox; Drug: Atazanavir/ritonavir; 300/100 mg atazanavir/ritonavir tablets in the evening once daily, to be administered after meal for 5 days.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Minimum plasma concentration (Cmin)	Tizoxanide minimum plasma concentration with or without atazanavir/ritonavir	After the first dose (Day 1)
Minimum plasma concentration (Cmin)	Tizoxanide minimum plasma concentration with or without atazanavir/ritonavir	At Day 5
Maximum plasma concentration (Cmax)	Tizoxanide maximum plasma concentration with or without atazanavir/ritonavir	After the first dose (Day 1)
Maximum plasma concentration (Cmax)	Tizoxanide maximum plasma concentration with or without atazanavir/ritonavir	At Day 5
Area under the concentration-time curve (AUC)	Tizoxanide Area under the concentration-time curve with or without atazanavir/ritonavir	After the first dose (Day 1)
Area under the concentration-time curve (AUC)	Tizoxanide Area under the concentration-time curve with or without atazanavir/ritonavir	At Day 5

Collaborators and Investigators

• Sponsor: Obafemi Awolowo University
• Collaborators: University of Liverpool
• Investigators: Principal Investigator: Babatunde A Adeagbo, PhD, Obafemi Awolowo University

Study record dates

Study Major Dates

• Study Start (Actual): September 10, 2020
• Primary Completion (Actual): January 10, 2023
• Study Completion (Actual): January 31, 2023

Study Registration Dates

• First Submitted: December 7, 2022
• First Submitted That Met QC Criteria: January 8, 2023
• First Posted (Actual): January 11, 2023

Study Record Updates

• Last Update Posted (Actual): September 13, 2023
• Last Update Submitted That Met QC Criteria: September 11, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: drug-drug interaction; Nitazoxanide; atazanavir/ritonavir
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Antiparasitic Agents; HIV Protease Inhibitors; Viral Protease Inhibitors; Ritonavir; Atazanavir Sulfate; Nitazoxanide
• Other Study ID Numbers: IPH/OAU/12/1574

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: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No