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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Evaluating Pharmacokinetics and Whole Blood Bactericidal Activity Against Mycobacterium Tuberculosis of Pyrazinamide Boosted With Allopurinol in Healthy Volunteers

Conditions
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Tuberculosis

Intervention / Treatment
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* Drug: Pyrazinamide
* Drug: Allopurinol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged between 21 and 70 years old Male or female willing to comply with the study visits and procedures Willing and able to provide written informed consent Exclusion Criteria: Women who are currently pregnant or breastfeeding Body weight 50kg or below HLA-B*5801 allele positive Clinical evidence (symptoms and/or signs) suggestive of active TB Previous hypersensitivity, intolerance or allergy to pyrazinamide or allopurinol Current use of any drugs or medication known to have an interaction with pyrazinamide or allopurinol, or known to have anti-TB activity Evidence of renal or hepatic dysfunction or any clinically significant deviation from normal during screening including laboratory determinations Known hepatic disease (including chronic hepatitis), recent hepatitis (within last 6 months) or alcohol abuse Known hyperuricaemia or evidence of hyperuricaemia at screening History or current episode of gout Any other significant condition that would, in the opinion of the investigator, compromise the volunteer's safety or outcome in the trial Current participation in other clinical intervention trial or research protocol

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low dose pyrazinamide<br>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. | Drug: Pyrazinamide<br> <br> Drug: Allopurinol<br> <br> |
| Experimental: Standard dose pyrazinamide<br>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. | Drug: Pyrazinamide<br> <br> Drug: Allopurinol<br> <br> |
| Experimental: High dose pyrazinamide<br>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. | Drug: Pyrazinamide<br> <br> Drug: Allopurinol<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative whole blood bactericidal activity (WBA) | Cumulative bactericidal activity calculated as log change CFU.day | 48 hours | 

Secondary Outcome Measures

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