title: Standardized UV-vis spectra as the foundation for a threshold-based, integrated photosafety evaluation.
abstract: Phototoxicity is a relatively common phenomenon and is an adverse effect of some systemic drugs. The fundamental initial step of photochemical reactivity is absorption of a photon; however, little guidance has been provided thus far regarding how ultraviolet-visible (UV-vis) light absorption spectra may be used to inform testing strategies for investigational drugs. Here we report the results of an inter-laboratory study comparing the data from harmonized UV-vis light absorption spectra obtained in methanol with data from the in vitro 3T3 Neutral Red Uptake Phototoxicity Test. Six pharmaceutical companies submitted data according to predefined quality criteria for 76 compounds covering a wide range of chemical classes showing a diverse but "positive"-enhanced distribution of photo irritation factors (22%: PIF<2, 12%: PIF 2-5, 66%: PIF>5). For compounds being formally positive (PIF value above 5) the lowest reported molar extinction coefficient (MEC) was 1700 L mol⁻¹ cm⁻¹ in methanol. However, the majority of these formally positive compounds showed MEC values being significantly higher (up to almost 40,000 L mol⁻¹ cm⁻¹). In conclusion, an MEC value of 1000 L mol⁻¹ cm⁻¹ may represent a reasonable and pragmatic threshold warranting further experimental photosafety evaluation.
authors.affiliation: Novartis Institutes of BioMedical Research, Preclinical Safety, WKL-136.1.16, 4002 Basel, Switzerland. Electronic address: daniel_manfred.bauer@novartis.com.
authors.forename: Daniel
authors.initials: D
authors.lastname: Bauer
authors.affiliation: GSK, GlaxoSmithKline, Platform Technology and Sciences, King of Prussia, PA 19406, USA.
authors.forename: Lacey A
authors.initials: LA
authors.lastname: Averett
authors.affiliation: Janssen Research and Development, Beerse, Belgium.
authors.forename: Ann
authors.initials: A
authors.lastname: De Smedt
authors.affiliation: GSK, GlaxoSmithKline, Projects Clinical Platform and Sciences, King of Prussia, PA 19406, USA.
authors.forename: Mark H
authors.initials: MH
authors.lastname: Kleinman
authors.affiliation: Hoffmann-La Roche, Non-Clinical Drug Safety, 4070 Basel, Switzerland.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Muster
authors.affiliation: Pfizer, Global Research and Development, Groton, CT 06340, USA.
authors.forename: Betty A
authors.initials: BA
authors.lastname: Pettersen
authors.affiliation: Sanofi R&D, Montpellier, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Robles
mesh_terms: D000818:Animals; D041702:BALB 3T3 Cells; D004396:Coloring Agents / Q000378:metabolism; D017484:Dermatitis, Phototoxic / Q000209:etiology*; D004353:Drug Evaluation, Preclinical / Q000379:methods / Q000592:standards; D015507:Drugs, Investigational / Q000633:toxicity*; D051379:Mice; D009499:Neutral Red / Q000378:metabolism; D012015:Reference Standards; D013056:Spectrophotometry, Ultraviolet / Q000592:standards; D013472:Sunlight
chemical_list: D004396:Coloring Agents; D015507:Drugs, Investigational; D009499:Neutral Red
keywords: Irradiation; Molar absorptivity; Molar extinction coefficient; Photoreactivity; Photosafety; Phototoxicity; Sunlight; Threshold