title: Integrated preclinical photosafety testing strategy for systemically applied pharmaceuticals.
abstract: Phototoxic properties of systemically applied pharmaceuticals may be the cause of serious adverse drug reactions. Therefore, a reliable preclinical photosafety assessment strategy, combining in vitro and in vivo approaches in a quantitative manner, is important and has not been described so far. Here, we report the establishment of an optimized modified murine local lymph node assay (LLNA), adapted for phototoxicity assessment of systemically applied compounds, as well as the test results for 34 drug candidates in this in vivo photo-LLNA. The drug candidates were selected based on their ability to absorb ultraviolet/visible light and the photo irritation factors (PIFs) determined in the well-established in vitro 3T3 neutral red uptake phototoxicity test. An in vivo phototoxic potential was identified for 13 of these drug candidates. The use of multiple dose levels in the described murine in vivo phototoxicity studies enabled the establishment of no- and/or lowest-observed-adverse-effect levels (NOAELs/LOAELs), also supporting human photosafety assessment. An in vitro-in vivo correlation demonstrated that a drug candidate classified as "phototoxic" in vitro is not necessarily phototoxic in vivo. However, the probability for a drug candidate to cause phototoxicity in vivo clearly correlated with the magnitude of the phototoxicity identified in vitro.
authors: Novartis Institutes for BioMedical Research, Preclinical Safety, 4002 Basel, Switzerland.
authors: Jens
authors: J
authors: Schümann
authors: Stéphanie
authors: S
authors: Boudon
authors: Peter
authors: P
authors: Ulrich
authors: Nathalie
authors: N
authors: Loll
authors: Déborah
authors: D
authors: Garcia
authors: René
authors: R
authors: Schaffner
authors: Jeannine
authors: J
authors: Streich
authors: Birgit
authors: B
authors: Kittel
authors: Daniel
authors: D
authors: Bauer
mesh_terms: D000818:Animals; D017484:Dermatitis, Phototoxic; D004353:Drug Evaluation, Preclinical; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D008198:Lymph Nodes / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D013056:Spectrophotometry, Ultraviolet; D018675:Toxicity Tests / Q000379:methods*
keywords: local lymph node assay; photoirritation factor; photosafety; phototoxicity