{"doi":"10.1093/jac/dkac188","title":"Pharmacokinetics of standard versus high-dose isoniazid for treatment of multidrug-resistant tuberculosis","abstract":"BACKGROUND: The WHO-endorsed shorter-course regimen for MDR-TB includes high-dose isoniazid. The pharmacokinetics of high-dose isoniazid within MDR-TB regimens has not been well described. OBJECTIVES: To characterize isoniazid pharmacokinetics at 5-15 mg/kg as monotherapy or as part of the MDR-TB treatment regimen. METHODS: We used non-linear mixed-effects modelling to evaluate the combined data from INHindsight, a 7 day early bactericidal activity study with isoniazid monotherapy, and PODRtb, an observational study of patients on MDR-TB treatment including terizidone, pyrazinamide, moxifloxacin, kanamycin, ethionamide and/or isoniazid. RESULTS: A total of 58 and 103 participants from the INHindsight and PODRtb studies, respectively, were included in the analysis. A two-compartment model with hepatic elimination best described the data. N-acetyltransferase 2 (NAT2) genotype caused multi-modal clearance, and saturable first-pass was observed beyond 10 mg/kg dosing. Saturable isoniazid kinetics predicted an increased exposure of approximately 50% beyond linearity at 20 mg/kg dosing. Participants treated with the MDR-TB regimen had a 65.6% lower AUC compared with participants on monotherapy. Ethionamide co-administration was associated with a 29% increase in isoniazid AUC. CONCLUSIONS: Markedly lower isoniazid exposures were observed in participants on combination MDR-TB treatment compared with monotherapy. Isoniazid displays saturable kinetics at doses >10 mg/kg. The safety implications of these phenomena remain unclear.","journal":"Journal of Antimicrobial Chemotherapy","year":2022,"id":276619,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.8542,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":371675,"name":"Maxwell Chirehwa","orcid":"0000-0002-1685-4882","position":1,"is_corresponding":false},{"id":501425,"name":"Elisa H. Ignatius","orcid":"0000-0002-4760-0172","position":2,"is_corresponding":false},{"id":655623,"name":"Richard Court","orcid":"0000-0002-7927-6506","position":3,"is_corresponding":false},{"id":354181,"name":"Xin Sun","orcid":"0000-0001-5909-5786","position":4,"is_corresponding":false},{"id":595786,"name":"Laura Moran","orcid":null,"position":5,"is_corresponding":false},{"id":456629,"name":"Richard Hafner","orcid":"0000-0002-3587-9559","position":6,"is_corresponding":false},{"id":308898,"name":"Lubbe Wiesner","orcid":"0000-0002-9070-8699","position":7,"is_corresponding":false},{"id":598008,"name":"Susan L. Rosenkranz","orcid":null,"position":8,"is_corresponding":false},{"id":679666,"name":"Veronique de Jager","orcid":"0000-0001-6389-5575","position":9,"is_corresponding":false},{"id":655625,"name":"Nihal de Vries","orcid":"0000-0001-7015-7247","position":10,"is_corresponding":false},{"id":656263,"name":"Joseph W. Harding","orcid":null,"position":11,"is_corresponding":false},{"id":267039,"name":"Tawanda Gumbo","orcid":"0000-0001-7592-8012","position":12,"is_corresponding":false},{"id":346886,"name":"Susan Swindells","orcid":"0000-0001-5826-6037","position":13,"is_corresponding":false},{"id":308896,"name":"Andreas H. Diacon","orcid":"0000-0001-8641-6792","position":14,"is_corresponding":false},{"id":346876,"name":"Kelly E. Dooley","orcid":"0000-0001-9013-5256","position":15,"is_corresponding":false},{"id":371679,"name":"Helen McIlleron","orcid":"0000-0002-0982-6226","position":16,"is_corresponding":false},{"id":308900,"name":"Paolo Denti","orcid":"0000-0001-7494-079X","position":17,"is_corresponding":false},{"id":376088,"name":"Kamunkhwala Gausi","orcid":"0000-0002-9002-8087","position":0,"is_corresponding":true}],"reference_count":42,"raw_metadata":null,"created_at":"2026-07-19T00:28:30.709588Z","pmid":"35678468","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":[]}