PBPK Modeling Investigation of IVIVE-Observed Pharmacokinetic Divergence for VU0467319: A Mechanistic Refinement Workflow for Low-Solubility Compounds.
- 1Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA.
- 2Vanderbilt Institute for Therapeutic Advances, Vanderbilt University, Nashville, TN 37232, USA.
- 3Department of Pharmacology, School of Medicine, Vanderbilt University, Nashville, TN 37232, USA.
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.
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BibTeX
@article{abisogun2026pbpk,
title = {{PBPK Modeling Investigation of IVIVE-Observed Pharmacokinetic Divergence for VU0467319: A Mechanistic Refinement Workflow for Low-Solubility Compounds.}},
author = {Akinwunmi A Abisogun and Srinivasan Krishnan and Craig W Lindsley and Olivier Boutaud},
journal = {Pharmaceutics},
year = {2026},
month = oct,
doi = {10.3390/pharmaceutics18101254},
url = {https://europepmc.org/article/MED/42942786},
note = {CC BY},
}
RIS
TY - JOUR
TI - PBPK Modeling Investigation of IVIVE-Observed Pharmacokinetic Divergence for VU0467319: A Mechanistic Refinement Workflow for Low-Solubility Compounds.
AU - Akinwunmi A Abisogun
AU - Srinivasan Krishnan
AU - Craig W Lindsley
AU - Olivier Boutaud
PY - 2026
DA - 2026/10/02
JO - Pharmaceutics
DO - 10.3390/pharmaceutics18101254
UR - https://europepmc.org/article/MED/42942786
AB - 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.
SN - 1999-4923
ER -