Pharmacokinetic Interaction Between Nitazoxanide and Atazanavir/Ritonavir in Healthy Volunteers

NCT ID: NCT05680792

Last Updated: 2023-09-13

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 17 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-09-10
• Study Completion Date: 2023-01-31

Brief Summary

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

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.

Conditions

Drug Interaction

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

Administration of nitazoxanide alone

Participants in this arm will receive 1000 mg of nitazoxanide tablets alone

Group Type: OTHER

Nitazoxanide

Intervention Type: DRUG

1000 mg nitazoxanide tablets twice daily. The drug will be administered after meal for 5 days

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.

Group Type: OTHER

Nitazoxanide

Intervention Type: DRUG

1000 mg nitazoxanide tablets twice daily. The drug will be administered after meal for 5 days

Atazanavir/ritonavir

Intervention Type: DRUG

300/100 mg atazanavir/ritonavir tablets in the evening once daily, to be administered after meal for 5 days.

Interventions

Nitazoxanide

1000 mg nitazoxanide tablets twice daily. The drug will be administered after meal for 5 days

Intervention Type: DRUG

Atazanavir/ritonavir

300/100 mg atazanavir/ritonavir tablets in the evening once daily, to be administered after meal for 5 days.

Intervention Type: DRUG

Other Intervention Names

Netazox

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 41 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

University of Liverpool

OTHER

Sponsor Role: collaborator

Obafemi Awolowo University

OTHER

Sponsor Role: lead

Responsible Party

Babatunde Adeagbo

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Babatunde A Adeagbo, PhD

Role: PRINCIPAL_INVESTIGATOR

Obafemi Awolowo University

Locations

Obafemi Awolowo University

Ile-Ife, Osun State, Nigeria

Countries

Nigeria

Other Identifiers

IPH/OAU/12/1574

Identifier Type: -

Identifier Source: org_study_id