{
  "abstract": "Culture‐based monitoring of bacterial load is slow and susceptible to missing data, contributing to the length and cost of TB clinical trials. Non‐culture‐based alternatives, like the Tuberculosis Molecular Load Bacterial Assay (TB‐MBLA), could represent a solution. Our objectives were to evaluate TB‐MBLA as a biomarker in early bactericidal activity (EBA) studies and explore whether combining biomarkers with joint modeling could provide insight into underlying biological processes. We generated TB‐MBLA (LifeArc) data from sputum samples from all 78 patients from the PanACEA BTZ‐043 Phase Ib/IIa trial and derived a summary measure of the joint distribution of the three TB‐MBLA, colony forming units (CFU), and time‐to‐positivity (TTP) biomarkers as the first principal component derived from a probabilistic principal component analysis (pPCA). With TB‐MBLA marker and the principal component 1 (PC1) values, we reevaluated the original stage IIa dose–response and stages Ib/IIa pharmacokinetics—pharmacodynamics (PK‐PD) exposure‐response analyses, applying linear and non‐linear mixed models, respectively. For TB‐MBLA, we could not detect an exposure‐response effect in the PK‐PD analysis, in contrast with CFU and TTP. When combining biomarkers, we observed a significant but less pronounced E max exposure–response between days 0–3 compared with CFU and TTP alone. We also successfully applied pPCA as a modeling framework and show evidence that combining CFU and TTP in a joint latent component can improve detection of treatment effects compared with either biomarker alone. In this study, we present novel EBA data for the first‐in‐class antimycobacterial compound BTZ‐043 and contextualize the value of emerging bacteriological markers within the EBA trial framework.\n\nTrial Registration: ClinicalTrials.gov identifier: NCT04044001",
  "abstract_shown": true,
  "affiliations": [
    "Institute of Infectious Diseases and Tropical Medicine, LMU University Hospital Munich Germany",
    "Institute of AI for Health, Helmholtz Center Munich—German Research Center for Environmental Health Neuherberg Germany",
    "Institute for Medical Information Processing, Biometry, and Epidemiology (IBE), Pettenkofer School of Public Health LMU Medizin, Ludwig‐Maximilians‐Universität München Munich Germany",
    "Helmholtz Pioneer Campus Helmholtz Zentrum München—German Research Center for Environmental Health Neuherberg Germany",
    "Department of Pharmacy, Pharmacology, and Toxicology Radboud Institute for Medical Innovation, Radboud University Medical Center Nijmegen the Netherlands",
    "German Center for Infection Research (DZIF), Munich Partner Site Munich Germany",
    "National Institute for Medical Research‐Mbeya Medical Research Center Mbeya Tanzania",
    "UCSF Center for Tuberculosis University of California San Francisco San Francisco California USA",
    "TASK Applied Science Clinical Research Center Cape Town South Africa",
    "Department of Medicine University of Cape Town Lung Institute Cape Town South Africa",
    "Department of Pharmacy Uppsala University Uppsala Sweden",
    "Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology, Infection, and Pandemic Research Munich Germany",
    "School of Computation, Information and Technology Technical University of Munich Garching Germany",
    "Unit Global Health, Helmholtz Zentrum München—German Research Centre for Environmental Health Neuherberg Germany"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 16,
  "authors": [
    {
      "affs": [
        0,
        1,
        2,
        3
      ],
      "name": "Mairi C. W. McClean",
      "orcid": "0009-0004-2972-0877"
    },
    {
      "affs": [
        4
      ],
      "name": "Simon E. Koele",
      "orcid": "0000-0002-7011-667X"
    },
    {
      "affs": [
        0,
        5
      ],
      "name": "Julia Dreisbach",
      "orcid": "0000-0001-6625-9857"
    },
    {
      "affs": [
        0,
        5
      ],
      "name": "Susanne Mirold‐Mei"
    },
    {
      "affs": [
        6
      ],
      "name": "Fred Njeleka",
      "orcid": "0000-0002-8528-5038"
    },
    {
      "affs": [
        6
      ],
      "name": "Daniel Mapamba",
      "orcid": "0000-0001-5642-488X"
    },
    {
      "affs": [
        6
      ],
      "name": "Bariki Mtafya",
      "orcid": "0000-0003-3772-8671"
    },
    {
      "affs": [
        7
      ],
      "name": "Patrick P. J. Phillips",
      "orcid": "0000-0002-6336-7024"
    },
    {
      "affs": [
        8
      ],
      "name": "Veronique R. De Jager",
      "orcid": "0000-0001-6389-5575"
    },
    {
      "affs": [
        9
      ],
      "name": "Rodney Dawson",
      "orcid": "0000-0001-9804-1588"
    },
    {
      "affs": [
        9
      ],
      "name": "Kim Narunsky",
      "orcid": "0000-0002-7939-3710"
    },
    {
      "affs": [
        8
      ],
      "name": "Andreas H. Diacon",
      "orcid": "0000-0001-8641-6792"
    },
    {
      "affs": [
        4,
        10
      ],
      "name": "Elin M. Svensson",
      "orcid": "0000-0002-0093-6445"
    },
    {
      "affs": [
        0,
        5,
        11
      ],
      "name": "Norbert Heinrich",
      "orcid": "0000-0001-9252-7106"
    },
    {
      "affs": [
        1,
        3,
        12
      ],
      "name": "Francesco Paolo Casale",
      "orcid": "0000-0002-5450-1981"
    },
    {
      "affs": [
        0,
        5,
        11,
        13
      ],
      "name": "Michael Hoelscher",
      "orcid": "0000-0002-6937-8330"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/ctbjknzewj64b.bib",
  "cited_by": 0,
  "doi": "10.1002/psp4.70311",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13733376/",
  "id": "ctbjknzewj64b",
  "issns": [
    "2163-8306"
  ],
  "landing_url": "https://doi.org/10.1002/psp4.70311",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Article"
    ],
    [
      "openalex",
      "2725|Tuberculosis Research and Epidemiology"
    ]
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  "openalex": "W7201979650",
  "pdf_url": null,
  "pmcid": "PMC13733376",
  "pmid": "42568101",
  "published": "2026-08-07",
  "publisher": "Wiley",
  "ris": "https://research.draconitic.com/paper/ctbjknzewj64b.ris",
  "sources": [
    {
      "first_seen": "2026-11-08T12:23:10Z",
      "native_id": "PMC13733376",
      "source": "pmc",
      "url": "https://doi.org/10.1002/psp4.70311"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2725|Tuberculosis Research and Epidemiology",
      "subfield": "infectious-disease"
    }
  ],
  "title": "Modeling Treatment Response in Tuberculosis Early Bactericidal Activity Trials",
  "title_text": "Modeling Treatment Response in Tuberculosis Early Bactericidal Activity Trials",
  "type": "peer-reviewed",
  "updated_at": "2026-11-08T12:23:10Z",
  "url": "https://research.draconitic.com/paper/ctbjknzewj64b",
  "venue": "CPT: Pharmacometrics & Systems Pharmacology",
  "versions": []
}