{"doi":"10.1093/cid/ciae119","title":"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 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.","journal":"Clinical Infectious Diseases","year":2024,"id":455483,"datarank":0.30584838328120195,"base_score":1.9459101490553132,"endowment":1.9459101490553132,"self_citation_contribution":0.29188652235829704,"citation_network_contribution":0.013961860922904896,"self_endowment_contribution":0.29188652235829704,"citer_contribution":0.013961860922904896,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":6,"citers_with_citation_signal":2,"citers_with_endowment":2,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9459,"is_data_producer":true,"deposit_databanks":{"ClinicalTrials.gov":["NCT02410772"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1006753,"name":"Ava Y Xu","orcid":"0000-0002-9222-1227","position":1,"is_corresponding":false},{"id":331296,"name":"Gustavo E. Velásquez","orcid":"0000-0003-1438-0692","position":2,"is_corresponding":false},{"id":455379,"name":"Nan Zhang","orcid":"0000-0003-2878-5455","position":3,"is_corresponding":false},{"id":1279618,"name":"Vincent Chang","orcid":"0000-0001-7984-1192","position":4,"is_corresponding":false},{"id":346871,"name":"Ekaterina V. Kurbatova","orcid":"0000-0003-4636-3731","position":5,"is_corresponding":false},{"id":368483,"name":"William C. Whitworth","orcid":"0000-0001-5306-548X","position":6,"is_corresponding":false},{"id":346883,"name":"Erin Sizemore","orcid":"0000-0003-3232-0546","position":7,"is_corresponding":false},{"id":784520,"name":"Kia Bryant","orcid":"0000-0003-0785-7800","position":8,"is_corresponding":false},{"id":1199875,"name":"Wendy Carr","orcid":"0000-0002-8665-5790","position":9,"is_corresponding":false},{"id":346885,"name":"Marc Weiner","orcid":"0000-0001-8778-5485","position":10,"is_corresponding":false},{"id":346876,"name":"Kelly E. Dooley","orcid":"0000-0001-9013-5256","position":11,"is_corresponding":false},{"id":349122,"name":"Melissa Engle","orcid":null,"position":12,"is_corresponding":false},{"id":292878,"name":"Susan E. Dorman","orcid":"0000-0001-6882-9470","position":13,"is_corresponding":false},{"id":346870,"name":"Payam Nahid","orcid":"0000-0003-2811-1311","position":14,"is_corresponding":false},{"id":346886,"name":"Susan Swindells","orcid":"0000-0001-5826-6037","position":15,"is_corresponding":false},{"id":346887,"name":"Richard E. Chaisson","orcid":"0000-0003-4710-925X","position":16,"is_corresponding":false},{"id":370111,"name":"Pheona Nsubuga","orcid":null,"position":17,"is_corresponding":false},{"id":1152563,"name":"Madeleine Lourens","orcid":null,"position":18,"is_corresponding":false},{"id":308897,"name":"Rodney Dawson","orcid":"0000-0001-9804-1588","position":19,"is_corresponding":false},{"id":455381,"name":"Radojka M. Savić","orcid":"0000-0003-3143-5579","position":20,"is_corresponding":false},{"id":331405,"name":"Huy Ngo","orcid":"0000-0001-6206-1624","position":0,"is_corresponding":true}],"reference_count":37,"raw_metadata":null,"created_at":"2026-07-19T02:03:22.974789Z","pmid":"38462673","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}