Computer Modeling Explains Why the Lupus Drug Voclosporin Works Better on an Empty Stomach
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.
Quick Facts
What This Study 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.
Key Numbers
The PBPK model successfully reproduced clinical trial observations of reduced bioavailability in the fed state.
How They Did This
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.
Why This Research 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 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.
What This Study Doesn't 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.
Questions This Raises
- ?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)?
Trust & Context
- Key Stat:
- Negative food effect confirmed PBPK modeling successfully reproduced voclosporin's reduced bioavailability in fed vs. fasted states, identifying food adsorption as the cause
- Evidence Grade:
- 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.
- Study Age:
- Published in 2024, applying current PBPK modeling techniques to a relatively new lupus nephritis drug (voclosporin was FDA-approved in 2021).
- Original Title:
- Understanding mechanisms of negative food effect for voclosporin using physiologically based pharmacokinetic modeling.
- Published In:
- Drug metabolism and pharmacokinetics, 59, 101032 (2024)
- Authors:
- Watanabe, Ayahisa, Akazawa, Takanori, Fujiu, Motohiro
- Database ID:
- RPEP-09509
Evidence Hierarchy
Summarizes existing research on a topic.
What do these levels mean? →Frequently Asked Questions
Why does voclosporin work worse when taken with food?
Voclosporin is a very fat-soluble molecule. When you eat, the food in your stomach and intestines acts like a sponge that soaks up the drug before your body can absorb it. This 'food adsorption' means less drug reaches your bloodstream, so it's less effective. That's why the prescribing instructions say to take it on an empty stomach.
What is voclosporin used for?
Voclosporin (brand name Lupkynis) is a cyclic peptide immunosuppressant approved in 2021 for treating active lupus nephritis — a serious kidney inflammation caused by lupus. It's a modified version of cyclosporine with improved metabolic properties, and it's one of the first oral drugs specifically approved for lupus kidney disease.
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Cite This Study
https://rethinkpeptides.com/research/RPEP-09509APA
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
MLA
Watanabe, Ayahisa, et al. "Understanding mechanisms of negative food effect for voclosporin using physiologically based pharmacokinetic modeling.." Drug metabolism and pharmacokinetics, 2024. https://doi.org/10.1016/j.dmpk.2024.101032
RethinkPeptides
RethinkPeptides Research Database. "Understanding mechanisms of negative food effect for voclosp..." RPEP-09509. Retrieved from https://rethinkpeptides.com/research/watanabe-2024-understanding-mechanisms-of-negative
Access the Original Study
Study data sourced from PubMed, a service of the U.S. National Library of Medicine, National Institutes of Health.
This study breakdown was produced by the RethinkPeptides research team. We analyze and report published research findings without making health recommendations. All interpretations are based solely on the published abstract and study data.