{"doi":"10.1128/aac.00354-24","title":"Population pharmacokinetics of rifabutin among HIV/TB co-infected children on lopinavir/ritonavir-based antiretroviral therapy","abstract":"ABSTRACT In adults requiring protease inhibitor (PI)-based antiretroviral therapy (ART), replacing rifampicin with rifabutin is a preferred option, but there is lack of evidence to guide rifabutin dosing in children, especially with PIs. We aimed to characterize the population pharmacokinetics of rifabutin and 25-O-desacetyl rifabutin (des-rifabutin) in children and optimize its dose. We included children from three age cohorts: (i) <1-year-old cohort and (ii) 1- to 3-year-old cohort, who were ART naïve and received 15- to 20-mg/kg/day rifabutin for 2 weeks followed by lopinavir/ritonavir (LPV/r)-based ART with 5.0- or 2.5 mg/kg/day rifabutin, respectively, while the (iii) >3-year-old cohort was ART-experienced and received 2.5-mg/kg/day rifabutin with LPV/r-based ART. Non-linear mixed-effects modeling was used to interpret the data. Monte Carlo simulations were performed to evaluate the study doses and optimize dosing using harmonized weight bands. Twenty-eight children were included, with a median age of 10 (range 0.67–15.0) years, a median weight of 11 (range 4.5–45) kg, and a median weight-for-age z score of −3.33 (range −5.15 to −1.32). A two-compartment disposition model, scaled allometrically by weight, was developed for rifabutin and des-rifabutin. LPV/r increased rifabutin bioavailability by 158% (95% confidence interval: 93.2%–246.0%) and reduced des-rifabutin clearance by 76.6% (74.4%–78.3%). Severely underweight children showed 26% (17.9%–33.7%) lower bioavailability. Compared to adult exposures, simulations resulted in higher median steady-state rifabutin and des-rifabutin exposures in 6–20 kg during tuberculosis-only treatment with 20 mg/kg/day. During LPV/r co-treatment, the 2.5-mg/kg/day dose achieved similar exposures to adults, while the 5-mg/kg/day dose resulted in higher exposures in children >7 kg. All study doses maintained a median C max of <900 µg/L. The suggested weight-band dosing matches adult exposures consistently across weights and simplifies dosing.","journal":"Antimicrobial Agents and Chemotherapy","year":2024,"id":478942,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9558,"is_data_producer":false,"deposit_databanks":null,"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":692059,"name":"Roeland E. Wasmann","orcid":"0000-0002-5769-8150","position":1,"is_corresponding":false},{"id":371679,"name":"Helen McIlleron","orcid":"0000-0002-0982-6226","position":2,"is_corresponding":false},{"id":1317921,"name":"Regina Oladokun","orcid":"0000-0002-2622-5019","position":3,"is_corresponding":false},{"id":380213,"name":"Prosper Okonkwo","orcid":"0000-0001-6822-9344","position":4,"is_corresponding":false},{"id":308898,"name":"Lubbe Wiesner","orcid":"0000-0002-9070-8699","position":5,"is_corresponding":false},{"id":308900,"name":"Paolo Denti","orcid":"0000-0001-7494-079X","position":6,"is_corresponding":false},{"id":509820,"name":"Holly Rawizza","orcid":"0000-0003-3599-1468","position":7,"is_corresponding":false},{"id":1317920,"name":"Manna Semere Gebreyesus","orcid":"0000-0001-5483-093X","position":0,"is_corresponding":true}],"reference_count":34,"raw_metadata":null,"created_at":"2026-07-19T02:06:50.355747Z","pmid":"39037240","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":[]}