Adjunctive use of celecoxib with anti-tuberculosis drugs: evaluation in a whole-blood bactericidal activity model

Abstract

COX-2 inhibition may be of benefit in the treatment of tuberculosis (TB) through a number of pathways including efflux pump inhibition (increasing intracellular TB drug levels) and diverse effects on inflammation and the immune response. We investigated celecoxib (a COX-2 inhibitor) alone and with standard anti-tuberculosis drugs in the whole-blood bactericidal activity (WBA) model. Healthy volunteers took a single dose of celecoxib (400 mg), followed (after 1 week) by a single dose of either rifampicin (10 mg/kg) or pyrazinamide (25 mg/kg), followed (after 2 or 7 days respectively) by the same anti-tuberculosis drug with celecoxib. WBA was measured at intervals until 8 hours post-dose (by inoculating blood samples with Mycobacterium tuberculosis and estimating the change in bacterial colony forming units after 72 hours incubation). Celecoxib had no activity alone in the WBA assay (cumulative WBA over 8 hours post-dose: 0.03 ± 0.01ΔlogCFU, p = 1.00 versus zero). Celecoxib did not increase cumulative WBA of standard TB drugs (mean cumulative WBA -0.10 ± 0.13ΔlogCFU versus -0.10 ± 0.12ΔlogCFU for TB drugs alone versus TB drugs and celecoxib; mean difference -0.01, 95% CI -0.02 to 0.00; p = 0.16). The lack of benefit of celecoxib suggests that efflux pump inhibition or eicosanoid pathway-related responses are of limited importance in mycobacterial killing in the WBA assay.

Figure 1

Plasma drug concentration of rifampicin (upper left panel), pyrazinamide (upper right panel), celecoxib in the RIF group (lower left panel), and celecoxib in the PZA group (lower right panel) at individual time-points up to 8 hours after dose. On each panel plots of plasma concentration are separate for two study visits where a drug or its combination with another drug is administered. Abbreviations: C, celecoxib; RIF, rifampicin; PZA, pyrazinamide.

Figure 2

(a) Mean WBA at individual time-points up to 8 hours after dose. (b) Mean cumulative WBA at intervals up to 8 hours post-dose. The curve of “Without drug (extrapolated)” was obtained by assuming that the individual WBA values at 0 hour time-point (pre-dose) of celecoxib alone remain unchanged over a subsequent 8-hour interval. Abbreviations: C, celecoxib; RIF, rifampicin; PZA, pyrazinamide.

Figure 3

Relationship between plasma concentration of TB drug and WBA. Each point represents an individual blood sample at which both parameters were measured. (a) Rifampicin plasma concentration and WBA. The fitted model between WBA (y) and pyrazinamide concentration (x) was $y=0.35-3.64\frac{{\left(x/4.42\right)}^{0.87}}{1+{\left(x/4.42\right)}^{0.87}}$ in RIF alone and $y=0.33-3.60\frac{{\left(x/3.71\right)}^{0.76}}{1+{\left(x/3.71\right)}^{0.76}}$ in RIF+ C (p = 0.80 for comparison of model between RIF alone and RIF+ C). (b) Pyrazinamide plasma concentration and WBA. The fitted model between WBA (y) and pyrazinamide concentration (x) was $y=0.43-0.59\frac{{\left(x/19.94\right)}^{0.54}}{1+{\left(x/19.94\right)}^{0.54}}$ in PZA alone and $y=0.26-0.51\frac{{\left(x/19.88\right)}^{0.50}}{1+{\left(x/19.88\right)}^{0.50}}$ in PZA+C (p = 0.57 for comparison of model between PZA alone and PZA+ C). Abbreviations: C, celecoxib; RIF, rifampicin; PZA, pyrazinamide.