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A pharmacometric multistate model for predicting long-term treatment outcomes of patients with pulmonary TB
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala Univ, Dept Pharm, Uppsala, Sweden..ORCID iD: 0009-0008-7501-5326
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala Univ, Dept Pharm, Uppsala, Sweden..ORCID iD: 0000-0003-0547-390X
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala Univ, Dept Pharm, Uppsala, Sweden..ORCID iD: 0000-0003-1258-8297
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala Univ, Dept Pharm, Uppsala, Sweden.;Radboud Univ Nijmegen, Med Ctr, Dept Pharm, Nijmegen, Netherlands..ORCID iD: 0000-0002-0093-6445
2024 (English)In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 79, no 10, p. 2561-2569Article in journal (Refereed) Published
Abstract [en]

Background Studying long-term treatment outcomes of TB is time-consuming and impractical. Early and reliable biomarkers reflecting treatment response and capable of predicting long-term outcomes are urgently needed.Objectives To develop a pharmacometric multistate model to evaluate the link between potential predictors and long-term outcomes.Methods Data were obtained from two Phase II clinical trials (TMC207-C208 and TMC207-C209) with bedaquiline on top of a multidrug background regimen. Patients were typically followed throughout a 24 week investigational treatment period plus a 96 week follow-up period. A five-state multistate model (active TB, converted, recurrent TB, dropout, and death) was developed to describe observed transitions. Evaluated predictors included patient characteristics, baseline TB disease severity and on-treatment biomarkers.Results A fast bacterial clearance in the first 2 weeks and low TB bacterial burden at baseline increased probability to achieve conversion, whereas patients with XDR-TB were less likely to reach conversion. Higher estimated mycobacterial load at the end of 24 week treatment increased the probability of recurrence. At 120 weeks, the model predicted 55% (95% prediction interval, 50%-60%), 6.5% (4.2%-9.0%) and 7.5% (5.2%-10%) of patients in converted, recurrent TB and death states, respectively. Simulations predicted a substantial increase of recurrence after 24 weeks in patients with slow bacterial clearance regardless of baseline bacterial burden.Conclusions The developed multistate model successfully described TB treatment outcomes. The multistate modelling framework enables prediction of several outcomes simultaneously, and allows mechanistically sound investigation of novel promising predictors. This may help support future biomarker evaluation, clinical trial design and analysis.

Place, publisher, year, edition, pages
OXFORD UNIV PRESS , 2024. Vol. 79, no 10, p. 2561-2569
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-541024DOI: 10.1093/jac/dkae256ISI: 001281443200001PubMedID: 39087258OAI: oai:DiVA.org:uu-541024DiVA, id: diva2:1919817
Available from: 2024-12-10 Created: 2024-12-10 Last updated: 2024-12-10Bibliographically approved

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Lin, Yu-JouZou, YuanxiKarlsson, Mats O.Svensson, Elin

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