Pharmacokinetic Interaction Between Nitazoxanide and Atazanavir/Ritonavir in Healthy Volunteers
Condition: Drug Interaction
Study type: Interventional

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.
    

Intervention name(s): Nitazoxanide; Atazanavir/ritonavir
Intervention type(s): Drug; Drug
Intervention description(s): 1000 mg nitazoxanide tablets twice daily. The drug will be administered after meal for 5 days; 300/100 mg atazanavir/ritonavir tablets in the evening once daily, to be administered after meal for 5 days.
Other intervention name(s): Netazox
Intervention MeSH terms: Ritonavir; Atazanavir Sulfate; Nitazoxanide
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Single (Participant)
Primary purpose: Treatment
Keywords: Nitazoxanide; atazanavir/ritonavir; drug-drug interaction