Integrated preclinical photosafety testing strategy for systemically applied pharmaceuticals
Jens Schümann1, Stéphanie Boudon, Peter Ulrich
1Novartis Institutes for BioMedical Research, Preclinical Safety, 4002 Basel, Switzerland.
Summary
A novel in vivo photo-LLNA assay effectively assesses drug photosafety. While in vitro tests predict potential phototoxicity, this method confirms in vivo risks, aiding drug development and patient safety.
Area of Science:
- Pharmacology
- Toxicology
- Drug Development
Background:
- Systemic pharmaceuticals can cause serious adverse drug reactions due to phototoxic properties.
- A reliable preclinical photosafety assessment combining in vitro and in vivo methods is crucial but not yet established.
Purpose of the Study:
- To establish an optimized in vivo assay for photosafety assessment of systemically applied drugs.
- To evaluate the correlation between in vitro and in vivo phototoxicity findings.
Main Methods:
- An optimized modified murine local lymph node assay (LLNA) was adapted for phototoxicity assessment (in vivo photo-LLNA).
- 34 drug candidates were tested, selected based on UV/Vis light absorption and in vitro 3T3 neutral red uptake phototoxicity test results.
- Multiple dose levels were used to determine no- and/or lowest-observed-adverse-effect levels (NOAELs/LOAELs).
Main Results:
- An in vivo phototoxic potential was identified for 13 out of 34 drug candidates.
- An in vitro-in vivo correlation showed that in vitro phototoxicity does not always translate to in vivo phototoxicity.
- The magnitude of in vitro phototoxicity correlated with the probability of in vivo phototoxicity.
Conclusions:
- The developed in vivo photo-LLNA is a valuable tool for preclinical photosafety assessment.
- Quantitative in vivo data, including NOAELs/LOAELs, support human photosafety evaluations.
- A comprehensive photosafety strategy requires both in vitro and in vivo testing for accurate risk assessment.
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