Coadministration of Allopurinol To Increase Antimycobacterial Efficacy of Pyrazinamide as Evaluated in a Whole-Blood Bactericidal Activity Model

Abstract

Coadministering pyrazinamide (PZA) with the xanthine oxidase inhibitor allopurinol increases systemic levels of the active metabolite, pyrazinoic acid (POA), but the effects on bactericidal activity against tuberculosis are unknown. We randomized healthy volunteers to take a single dose of PZA (either 10 or 25 mg/kg of body weight) at the first visit and the same dose 7 days later, coadministered with allopurinol (100 mg daily; 2 days before to 1 day after the PZA dose). Blood was drawn at intervals until 48 h 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 CFU after 72 h of incubation. Allopurinol increased the POA area under the concentration-time curve from 0 to 8 h (AUC_0-8) (18.32 h · μg/ml versus 24.63 h · μg/ml for PZA alone versus PZA plus allopurinol) (P < 0.001) and its peak plasma concentration (C_max) (2.81 μg/ml versus 4.00 μg/ml) (P < 0.001). There was no effect of allopurinol on mean cumulative WBA (0.01 ± 0.02 ΔlogCFU versus 0.00 ± 0.02 ΔlogCFU for PZA alone versus PZA plus allopurinol) (P = 0.49). Higher systemic POA levels were associated with greater WBA levels (P < 0.001), but the relationship was evident only at low POA concentrations. The lack of an effect of allopurinol on WBA despite a significant increase in blood POA levels suggests that host-generated POA may be less effective than POA generated inside bacteria. Coadministration of allopurinol does not appear to be a useful strategy for increasing the efficacy of PZA in clinical practice. (This study has been registered at ClinicalTrials.gov under registration no. NCT02700347.).

Keywords: Mycobacterium tuberculosis; WBA; allopurinol; pyrazinamide; whole-blood bactericidal activity.

FIG 1

Pyrazinamide metabolism and the mechanism of action by which allopurinol increases the active metabolite (pyrazinoic acid). (Adapted from reference with permission.)

FIG 2

Plasma concentrations of pyrazinamide (PZA), pyrazinoic acid (POA), 5-hydroxypyrazinamide (5-OH-PZA), and 5-hydroxypyrazinoic acid (5-OH-POA), with and without allopurinol (ALLO) boosting.

FIG 3

(a) Mean WBA at individual time points from predose (0 h) to 8 h postdose. (b) Mean cumulative WBA at intervals from predose (0 h) to 8 h postdose. The “without drug (extrapolated)” curve was obtained by assuming that the individual WBA values at the 0-h time point for PZA alone remain unchanged over the subsequent 8-h interval. Error bars indicate 1 standard deviation. PZA, pyrazinamide; ALLO, allopurinol.

FIG 4

Relationship between plasma concentration of pyrazinoic acid (POA) and whole-blood bactericidal activity (WBA). Each point represents an individual blood sample in which both parameters were measured. The relationship between POA plasma concentration and WBA was assessed by use of a nonlinear mixed model with random intercepts, performed using a 4-parameter equation to describe a sigmoid curve, with the equation parameters fitted to observed values by iterative methods, using SAS. The significance of the relationship was determined using the F test. The 95% confidence intervals (CI) of the fitted curve are shown.