title: The DGAT1 inhibitor pradigastat does not induce photosensitivity in healthy human subjects: a randomized controlled trial using three defined sunlight exposure conditions.
abstract: The DGAT1 inhibitor, pradigastat, demonstrated a mild phototoxicity signal in preclinical studies. Therefore, this clinical trial was conducted to assess the risk of photosensitivity in humans. 47 healthy adults were randomized to part A (double-blind, placebo-controlled; 3 : 1 pradigastat : placebo) or part B (open-label positive control ciprofloxacin, investigator blind). Three irradiation conditions (1. full range UVB/UVA, 2. UVA only, 3. 1/2 MED from UVB/UVA + 16 J cm(-2) UVA) were applied to simulate different sunlight exposure conditions. Photosensitizing potential was assessed by determining the minimum erythemal dose (MED) and calculating the photosensitivity index (PI) at 1 and 24 h. Local skin reactions were recorded as a secondary endpoint. Following full UVB/UVA irradiation, there were no significant differences in MED or PI between groups. With UVA-only, no changes in MED or PI were observed for the pradigastat or placebo groups. For ciprofloxacin, there was a significant reduction in MED at 24 h (-32%, vs. 24 h baseline), which correlated to a PI of 1.61. The difference in mean PI between ciprofloxacin-pradigastat, and ciprofloxacin-placebo, was significant at 24 h (p < 0.001). Local skin erythema scores were comparable between pradigastat and placebo, but higher with ciprofloxacin. Pradigastat was not shown to induce photosensitivity reactions, while significant responses were seen with the positive control. These results strongly suggest that pradigastat will not induce photosensitivity reactions in individuals administered doses up to 40 mg per day, which is the highest intended clinical dose. Furthermore, the design of this clinical trial may serve as a prototype for future regulatory clinical photosensitivity studies.
authors.affiliation: Novartis Institutes for BioMedical Research (NIBR), Preclinical Safety, Basel, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Bauer
authors.affiliation: NIBR, Translational Medicine, NJ, USA.
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Soon
authors.affiliation: NIBR, Drug Metabolism & Pharmacokinetics, MA, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Kulmatycki
authors.affiliation: Novartis Pharma Co. Ltd, Shanghai, China.
authors.forename: Yuming
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Adele
authors.initials: A
authors.lastname: Noe
authors.affiliation: NIBR, Translational Medicine, NJ, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Chen
authors.affiliation: TKL Research, Inc., NJ, USA.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Dosik
authors.affiliation: NIBR, Translational Medicine, MA, USA. dan.meyers@novartis.com.
authors.forename: Dan
authors.initials: D
authors.lastname: Meyers
mesh_terms: D000085:Acetates / Q000737:chemistry / Q000494:pharmacology*; D000293:Adolescent; D000328:Adult; D000631:Aminopyridines / Q000737:chemistry / Q000494:pharmacology*; D002939:Ciprofloxacin / Q000737:chemistry / Q000494:pharmacology; D051048:Diacylglycerol O-Acyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D017319:Photosensitizing Agents / Q000737:chemistry / Q000494:pharmacology; D013472:Sunlight / Q000009:adverse effects*; D055815:Young Adult
chemical_list: D000085:Acetates; D000631:Aminopyridines; D004791:Enzyme Inhibitors; D017319:Photosensitizing Agents; C000594809:pradigastat; D002939:Ciprofloxacin; C494881:DGAT1 protein, human; D051048:Diacylglycerol O-Acyltransferase