eprintid: 10202887 rev_number: 15 eprint_status: archive userid: 699 dir: disk0/10/20/28/87 datestamp: 2025-01-07 11:49:30 lastmod: 2025-01-07 11:49:30 status_changed: 2025-01-07 11:49:30 type: article metadata_visibility: show sword_depositor: 699 creators_name: D'Agate, Salvatore creators_name: Velickovic, Peter creators_name: Garcia-Barrios, Noelia creators_name: Ramon-Garcia, Santiago creators_name: Della Pasqua, Oscar title: Optimizing β-lactam-containing antibiotic combination therapy for the treatment of Buruli ulcer ispublished: pub divisions: UCL divisions: B02 divisions: C08 divisions: D10 divisions: G10 keywords: Amoxicillin/clavulanic acid, Buruli ulcer, clinical trial simulations, dose rationale, pharmacokinetic–pharmacodynamic modelling note: © 2024 The Author(s). British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. abstract: AIMS: The current treatment for Buruli ulcer is based on empirical evidence of efficacy. However, there is an opportunity for shortening its duration and improving response rates. Evolving understanding of the pharmacokinetic–pharmacodynamic relationships provides the basis for a stronger dose rationale for antibiotics. In conjunction with modelling and simulation, it is possible to identify dosing regimens with the highest probability of target attainment (PTA). This investigation aims to: (i) assess the dose rationale for a new combination therapy including amoxicillin/clavulanic acid (AMX/CLV) currently in clinical trials; and (ii) compare its performance with alternative dosing regimens including rifampicin, clarithromycin and AMX/CLV. METHODS: In vitro estimates of the minimum inhibitory (MIC) concentration were selected as a measure of the antibacterial activity of different drug combinations. Clinical trial simulations were used to characterize the concentration vs. time profiles of rifampicin, clarithromycin and amoxicillin in a virtual cohort of adult and paediatric patients, considering the effect of baseline covariates on disposition parameters and interindividual variability in exposure. The PTA of each regimen was then assessed using different thresholds of the time above MIC. RESULTS: A weight-banded dosing regimen including 150–600 mg rifampicin once daily, 250–1000 mg clarithromycin and AMX/CLV 22.5 mg/kg /1000 mg twice daily ensures higher PTA than the standard of care with AMX/CLV 45 mg/kg/2000 mg once daily. CONCLUSION: The higher PTA values support the proposed 4-drug combination (rifampicin, clarithromycin, AMX/CLV) currently under clinical investigation. Our findings also suggest that higher rifampicin doses might contribute to enhanced treatment efficacy. date: 2025-01 date_type: published publisher: WILEY official_url: https://doi.org/10.1111/bcp.16209 oa_status: green full_text_type: pub language: eng primo: open primo_central: open_green verified: verified_manual elements_id: 2323817 doi: 10.1111/bcp.16209 medium: Print-Electronic lyricists_name: Della Pasqua, Oscar lyricists_id: ODELL25 actors_name: Della Pasqua, Oscar actors_id: ODELL25 actors_role: owner funding_acknowledgements: [EU] full_text_status: public publication: British Journal of Clinical Pharmacology volume: 91 number: 1 pagerange: 179-189 pages: 11 event_location: England issn: 0306-5251 citation: D'Agate, Salvatore; Velickovic, Peter; Garcia-Barrios, Noelia; Ramon-Garcia, Santiago; Della Pasqua, Oscar; (2025) Optimizing β-lactam-containing antibiotic combination therapy for the treatment of Buruli ulcer. British Journal of Clinical Pharmacology , 91 (1) pp. 179-189. 10.1111/bcp.16209 <https://doi.org/10.1111/bcp.16209>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10202887/2/Velcikovic%20Buruli%20BCP-91-179.pdf