PBPK modeling revealed that voclosporin's reduced absorption when taken with food is likely caused by the drug sticking to food particles in the gut, confirming it should be taken on an empty stomach.
Negative food effect confirmedPBPK modeling successfully reproduced voclosporin's reduced bioavailability in fed vs. fasted states, identifying food adsorption as the cause
What the researchers found
PBPK modeling identified food adsorption in the GI tract as the primary mechanism behind voclosporin's negative food effect, successfully reproducing clinical pharmacokinetic profiles in both fasted and fed states.
Why it matters
For lupus nephritis patients taking voclosporin, understanding why food reduces absorption ensures proper dosing instructions. This modeling approach could also help predict food effects for other cyclic peptide drugs in development.
The numbers in context
The PBPK model successfully reproduced clinical trial observations of reduced bioavailability in the fed state.
How the study worked
Physiologically based pharmacokinetic modeling incorporating P-glycoprotein transport, CYP3A4 metabolism, and membrane permeability data from human iPSC-derived intestinal epithelial cells. Simulations were validated against clinical trial data in fasted and fed conditions and replicated in a rat model.
Who was studied
PBPK model based on clinical trial data
What this study cannot tell us
Computational modeling study — conclusions depend on the accuracy of input parameters and model assumptions. Doesn't account for all sources of patient-to-patient variability. The food adsorption mechanism is proposed based on modeling fit, not directly measured.
How to read the evidence
Moderate evidence from computational modeling validated against clinical trial data. The model's predictions matched real-world observations, but the proposed mechanism (food adsorption) is inferred from modeling, not directly measured experimentally.
When this study was published
Published in 2024, applying current PBPK modeling techniques to a relatively new lupus nephritis drug (voclosporin was FDA-approved in 2021).
The bigger picture
Cyclic peptides are an increasingly important drug class, but their oral absorption is notoriously unpredictable. This study demonstrates that PBPK modeling can identify specific mechanisms behind food effects for this challenging drug class, potentially guiding formulation strategies to improve oral bioavailability of future cyclic peptide drugs.
Questions still open
- Could formulation changes (like different excipients) overcome voclosporin's food adsorption problem?
- Does this PBPK approach reliably predict food effects for other cyclic peptide drugs?
- How much does the food effect vary with different types of meals (high-fat vs. low-fat)?
Common questions
Why does voclosporin work worse when taken with food?
What is voclosporin used for?
Read the original research
Understanding mechanisms of negative food effect for voclosporin using physiologically based pharmacokinetic modeling.
Drug metabolism and pharmacokinetics, 59, 101032
Citation
Watanabe, Ayahisa; Akazawa, Takanori; Fujiu, Motohiro. (2024). Understanding mechanisms of negative food effect for voclosporin using physiologically based pharmacokinetic modeling.. Drug metabolism and pharmacokinetics, 59, 101032. https://doi.org/10.1016/j.dmpk.2024.101032