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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Low dose pyrazinamide | Experimental | 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. |
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| Standard dose pyrazinamide | Experimental | 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. |
|
| High dose pyrazinamide | Experimental | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Pyrazinamide | Drug |
| ||
| Allopurinol |
| Measure | Description | Time Frame |
|---|---|---|
| Cumulative whole blood bactericidal activity (WBA) | Cumulative bactericidal activity calculated as log change CFU.day | 48 hours |
| 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 | |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Nicholas Paton | National University Hospital, Singapore | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| National University Hospital, Singapore | Singapore | Singapore |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 28739782 | Derived | Naftalin CM, Verma R, Gurumurthy M, Lu Q, Zimmerman M, Yeo BCM, Tan KH, Lin W, Yu B, Dartois V, Paton NI. Coadministration of Allopurinol To Increase Antimycobacterial Efficacy of Pyrazinamide as Evaluated in a Whole-Blood Bactericidal Activity Model. Antimicrob Agents Chemother. 2017 Sep 22;61(10):e00482-17. doi: 10.1128/AAC.00482-17. Print 2017 Oct. |
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| ID | Term |
|---|---|
| D014376 | Tuberculosis |
| ID | Term |
|---|---|
| D009164 | Mycobacterium Infections |
| D000193 | Actinomycetales Infections |
| D016908 | Gram-Positive Bacterial Infections |
| D001424 | Bacterial Infections |
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| ID | Term |
|---|---|
| D011718 | Pyrazinamide |
| D000493 | Allopurinol |
| ID | Term |
|---|---|
| D011719 | Pyrazines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D011687 | Purines |
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| Drug |
|
| Plasma concentrations of study drugs to determine the drug half-life (t1/2) |
| 48 hours |
| D001423 | Bacterial Infections and Mycoses |
| D007239 | Infections |
| D006574 |
| Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |