Co-administration of allopurinol to increase anti-mycobacterial efficacy of pyrazinamide: evaluation in a whole-blood bactericidal activity model [PublishAheadOfPrint]

Co-administering pyrazinamide (PZA) with the xanthine oxidase inhibitor, allopurinol, increases systemic levels of the active metabolite, pyrazinoic acid (POA), but effects on bactericidal activity against tuberculosis are unknown. We randomized healthy volunteers to take a single dose of PZA (either 10mg/kg or 25mg/kg) and the same dose 7 days later co-administered with allopurinol (100mg daily, 2 days before to 1 day after PZA dose). Blood was drawn at intervals to 48 hours after each PZA dose and drug levels were measured using liquid chromatography-tandem mass spectrometry. Whole-blood bactericidal activity (WBA) was measured by inoculating blood samples with Mycobacterium tuberculosis and estimating the change in bacterial colony forming units (CFU) after 72 hours incubation. Allopurinol increased POA AUC (AUC_(0-8) 18.32h*μg/mL versus 24.63h*μg/mL for PZA alone versus PZA+allopurinol respectively; p<0.001) and C_max (2.81μg/mL versus 4.00μg/mL; p<0.001). There was no effect of allopurinol on mean cumulative WBA (0.01±0.02logCFU versus 0.00±0.02logCFU for PZA alone versus PZA+allopurinol respectively; p=0.49). Higher systemic POA levels were associated with greater WBA (p <0.001) but the relationship was evident only at low POA concentrations. The lack of an effect of allopurinol on WBA in spite of a significant increase in blood POA levels suggests that host-generated POA may be less effective than POA generated inside bacteria. Co-administration of allopurinol does not appear to be a useful strategy for increasing efficacy of PZA in clinical practice.

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