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- Title
Pharmacokinetic-Pharmacodynamic Evidence From a Phase 3 Trial to Support Flat-Dosing of Rifampicin for Tuberculosis.
- Authors
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
- 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.
- Subjects
DRUG therapy for tuberculosis; CHAOS theory; PATIENT safety; DRUG side effects; RESEARCH funding; BODY weight; LOGISTIC regression analysis; DOSE-effect relationship in pharmacology; DRUG efficacy; SIMULATED patients; RIFAMPIN; PROPORTIONAL hazards models; PHARMACODYNAMICS
- Publication
Clinical Infectious Diseases, 2024, Vol 78, Issue 6, p1680
- ISSN
1058-4838
- Publication type
Article
- DOI
10.1093/cid/ciae119