Whole Blood Bactericidal Activity Against Mycobacterium Tuberculosis of Pyrazinamide Plus Allopurinol in Healthy Volunteers

Overview

The purpose of this study is to evaluate the bactericidal activity against Mycobacterium tuberculosis of pyrazinamide in combination with allopurinol. Pharmacokinetics (PK) and whole blood bactericidal activity (WBA) will be measured in healthy volunteers following administration of pyrazinamide alone and in combination with allopurinol.

Full Title of Study: “Evaluating Pharmacokinetics and Whole Blood Bactericidal Activity Against Mycobacterium Tuberculosis of Pyrazinamide Boosted With Allopurinol in Healthy Volunteers”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: April 2016

Detailed Description

The whole blood bactericidal activity (WBA) assay is an ex vivo model for measuring the combined effects of administered drugs, host factors and strain factors on mycobacterial sterilisation. If performed in parallel with PK measurements, the method can be used to evaluate the effect of drugs throughout the dosing cycle. The aim of this trial is to assess the WBA activity and PK data of pyrazinamide and its metabolites boosted with allopurinol in healthy volunteers.

Interventions

  • Drug: Pyrazinamide
  • Drug: Allopurinol

Arms, Groups and Cohorts

  • Experimental: Low dose pyrazinamide
    • Day 0: Pyrazinamide 10mg/kg, Day 5: Allopurinol 100mg single dose, Day 6: Allopurinol 100mg single dose, Day 7: Pyrazinamide 10mg/kg plus allopurinol 100mg single dose, Day 8: Allopurinol 100mg single dose.
  • Experimental: Standard dose pyrazinamide
    • Day 0: Pyrazinamide 25mg/kg single dose, Day 5: Allopurinol 100mg single dose, Day 6: Allopurinol 100mg single dose, Day 7: Pyrazinamide 25mg/kg plus allopurinol 100mg single dose, Day 8: Allopurinol 100mg single dose.
  • Experimental: High dose pyrazinamide
    • Day 0: Pyrazinamide 35mg/kg single dose, Day 5: Allopurinol 100mg single dose, Day 6: Allopurinol 100mg single dose, Day 7: Pyrazinamide 35mg/kg plus allopurinol 100mg single dose, Day 8: Allopurinol 100mg single dose.

Clinical Trial Outcome Measures

Primary Measures

  • Cumulative whole blood bactericidal activity (WBA)
    • Time Frame: 48 hours
    • Cumulative bactericidal activity calculated as log change CFU.day

Secondary Measures

  • Plasma concentrations of study drugs to determine the Area Under the Curve (AUC)
    • Time Frame: 48 hours
  • Plasma concentrations of study drugs to determine the Maximum Plasma Concentration (Cmax)
    • Time Frame: 48 hours
  • Plasma concentrations of study drugs to determine the drug half-life (t1/2)
    • Time Frame: 48 hours

Participating in This Clinical Trial

Inclusion Criteria

1. Aged between 21 and 70 years old 2. Male or female willing to comply with the study visits and procedures 3. Willing and able to provide written informed consent Exclusion Criteria:

1. Women who are currently pregnant or breastfeeding 2. Body weight 50kg or below 3. HLA-B*5801 allele positive 4. Clinical evidence (symptoms and/or signs) suggestive of active TB 5. Previous hypersensitivity, intolerance or allergy to pyrazinamide or allopurinol 6. Current use of any drugs or medication known to have an interaction with pyrazinamide or allopurinol, or known to have anti-TB activity 7. Evidence of renal or hepatic dysfunction or any clinically significant deviation from normal during screening including laboratory determinations 8. Known hepatic disease (including chronic hepatitis), recent hepatitis (within last 6 months) or alcohol abuse 9. Known hyperuricaemia or evidence of hyperuricaemia at screening 10. History or current episode of gout 11. Any other significant condition that would, in the opinion of the investigator, compromise the volunteer's safety or outcome in the trial 12. Current participation in other clinical intervention trial or research protocol

Gender Eligibility: All

Minimum Age: 21 Years

Maximum Age: 70 Years

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • National University Hospital, Singapore
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Nicholas Paton, Principal Investigator, National University Hospital, Singapore

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