{
  "abstract": "Background/Objectives: VU0467319 (VU319), an M1 muscarinic positive allosteric modulator evaluated in Phase 1 studies, exhibits subproportional dose-exposure scaling typical of poorly soluble compounds. This study applies physiologically based pharmacokinetic (PBPK) modeling to investigate the sources of divergence between IVIVE-based predictions and observed single ascending dose (SAD) clinical pharmacokinetics. Methods: A whole-body PBPK model was developed in Simcyp Simulator V24 using in vitro ADME and physicochemical inputs. Clinical pharmacokinetic data were used for sequential, hypothesis-driven model refinement of distribution, clearance, and absorption parameters. Model performance was evaluated at 60-600 mg fasted using virtual populations demographically matched to their corresponding clinical cohort. Results: A Kp scalar of 0.125 recovered model Vss within the observed Vz/F bound; a 10.7-fold downward CLint correction (32.2 to 3 µL/min/mg) reconciled clearance; and a 1 µm particle radius recovered AUC0-∞ within 6% across 60-240 mg. The model met predefined performance thresholds across the four independent verification doses (geometric mean fold error 1.45 for AUC and 1.56 for Cmax; three of four doses within 2-fold), with progressive underprediction at the highest doses (≥400 mg). Supersaturation-ratio analysis indicated that, within the model, sustained supersaturation was unlikely to explain the high-dose underprediction. The refined model reproduced the observed sub-proportional dose-exposure relationship through 240 mg, but underpredicted exposure at 400 and 600 mg. Conclusions: Structured PBPK refinement identified dissolution-limited absorption as the most likely primary contributor to IVIVE-observed divergence for VU319, with secondary contributions from clearance and distribution. These model-derived mechanisms remain hypotheses that require experimental confirmation. The workflow may provide a structured refinement framework for other low-solubility compounds where IVIVE assumptions diverge from observed pharmacokinetics.",
  "abstract_shown": true,
  "affiliations": [
    "Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA.",
    "Vanderbilt Institute for Therapeutic Advances, Vanderbilt University, Nashville, TN 37232, USA.",
    "Department of Pharmacology, School of Medicine, Vanderbilt University, Nashville, TN 37232, USA."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 4,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Akinwunmi A Abisogun",
      "orcid": "0009-0000-0498-4201"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Srinivasan Krishnan"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Craig W Lindsley"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Olivier Boutaud",
      "orcid": "0000-0002-8910-0598"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/700c1k4qjj3f1.bib",
  "cited_by": 0,
  "doi": "10.3390/pharmaceutics18101254",
  "fulltext_url": "https://europepmc.org/articles/PMC13708466",
  "id": "700c1k4qjj3f1",
  "issns": [
    "1999-4923"
  ],
  "landing_url": "https://europepmc.org/article/MED/42942786",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "3003|Drug Solubulity and Delivery Systems"
    ]
  ],
  "openalex": "W7216525639",
  "pdf_url": "https://europepmc.org/articles/PMC13708466?pdf=render",
  "pmcid": "PMC13708466",
  "pmid": "42942786",
  "published": "2026-10-02",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/700c1k4qjj3f1.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:22:24Z",
      "native_id": "MED:42942786",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42942786"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:3003|Drug Solubulity and Delivery Systems",
      "subfield": "pharmacology-toxicology"
    }
  ],
  "title": "PBPK Modeling Investigation of IVIVE-Observed Pharmacokinetic Divergence for VU0467319: A Mechanistic Refinement Workflow for Low-Solubility Compounds.",
  "title_text": "PBPK Modeling Investigation of IVIVE-Observed Pharmacokinetic Divergence for VU0467319: A Mechanistic Refinement Workflow for Low-Solubility Compounds.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:22:24Z",
  "url": "https://research.draconitic.com/paper/700c1k4qjj3f1",
  "venue": "Pharmaceutics",
  "versions": []
}