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

National University Health System (NUHS)

Status and phase: Completed; Phase 1

Conditions: Tuberculosis

Treatments: Drug: Pyrazinamide; Drug: Allopurinol

Study type: Interventional

Funder types: Other

Identifiers

NCT02700347

PZA_WBA

Details and patient eligibility

About

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 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.

Enrollment: 12 patients

Sex: All

Ages: 21 to 70 years old

Volunteers: Accepts Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

---

12 participants in 3 patient groups

Low dose pyrazinamide

Experimental group

Description:

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.

Treatment:

Drug: Allopurinol

Drug: Pyrazinamide

Standard dose pyrazinamide

Experimental group

Description:

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.

Treatment:

Drug: Allopurinol

Drug: Pyrazinamide

High dose pyrazinamide

Experimental group

Description:

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.

Treatment:

Drug: Allopurinol

Drug: Pyrazinamide