Pharmacokinetic-Pharmacodynamic Evidence From a Phase 3 Trial to Support Flat-Dosing of Rifampicin for Tuberculosis

Abstract Background The optimal dosing strategy for rifampicin in treating drug-susceptible tuberculosis (TB) is still highly debated. In the phase 3 clinical trial Study 31/ACTG 5349 (NCT02410772), all participants in the control regimen arm received 600 mg rifampicin daily as a flat dose. Here, we...

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Veröffentlicht in:Clinical infectious diseases 2024-06, Vol.78 (6), p.1680-1689
Hauptverfasser: Ngo, Huy X, Xu, Ava Y, Velásquez, Gustavo E, Zhang, Nan, Chang, Vincent K, Kurbatova, Ekaterina V, Whitworth, William C, Sizemore, Erin, Bryant, Kia, Carr, Wendy, Weiner, Marc, Dooley, Kelly E, Engle, Melissa, Dorman, Susan E, Nahid, Payam, Swindells, Susan, Chaisson, Richard E, Nsubuga, Pheona, Lourens, Madeleine, Dawson, Rodney, Savic, Radojka M
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Sprache:eng
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Zusammenfassung:Abstract Background The optimal dosing strategy for rifampicin in treating drug-susceptible tuberculosis (TB) is still highly debated. In the phase 3 clinical trial Study 31/ACTG 5349 (NCT02410772), all participants in the control regimen arm received 600 mg rifampicin daily as a flat dose. Here, we evaluated relationships between rifampicin exposure and efficacy and safety outcomes. Methods We analyzed rifampicin concentration time profiles using population nonlinear mixed-effects models. We compared simulated rifampicin exposure from flat- and weight-banded dosing. We evaluated the effect of rifampicin exposure on stable culture conversion at 6 months; TB-related unfavorable outcomes at 9, 12, and 18 months using Cox proportional hazard models; and all trial-defined safety outcomes using logistic regression. Results Our model-derived rifampicin exposure ranged from 4.57 mg · h/L to 140.0 mg · h/L with a median of 41.8 mg · h/L. Pharmacokinetic simulations demonstrated that flat-dosed rifampicin provided exposure coverage similar to the weight-banded dose. Exposure-efficacy analysis (n = 680) showed that participants with rifampicin exposure below the median experienced similar hazards of stable culture conversion and TB-related unfavorable outcomes compared with those with exposure above the median. Exposure-safety analysis (n = 722) showed that increased rifampicin exposure was not associated with increased grade 3 or higher adverse events or serious adverse events. Conclusions Flat-dosing of rifampicin at 600 mg daily may be a reasonable alternative to the incumbent weight-banded dosing strategy for the standard-of-care 6-month regimen. Future research should assess the optimal dosing strategy for rifampicin, at doses higher than the current recommendation. Flat-dosing of rifampicin at 600 mg daily provided similar plasma exposure to conventional weight-banded dosing for drug-susceptible tuberculosis. This dosing strategy may be a reasonable alternative to weight-banded dosing in the 6-month standard-of-care regimen for drug-susceptible tuberculosis.
ISSN:1058-4838
1537-6591
1537-6591
DOI:10.1093/cid/ciae119