Systems approach reveals photosensitivity and PER2 level as determinants of clock‐modulator efficacy The stronger attenuating effect of light in diurnal NHPs than in nocturnal rodents leads to the interspecies variation observed in the response to PF‐670. The simulated PRCs of diurnal NHPs have a higher ratio of maximal magnitudes between advance and delay zones (A/D = 1.25) than that of the experimentally measured nocturnal mouse PRC (A/D = 0.41), which is adopted from (Comas et al, ). Here, the red line and red range represent the mean ± SD of the simulated 12‐h light PRCs of the NHP model with different gating and adaptation (Fig Aii). Similarly, the light PRC of diurnal humans has a higher A/D ratio (St Hilaire et al, ; Ruger et al, ) than that of nocturnal mice (Comas et al, ). The effect of PF‐670 can be heterogeneous due to interindividual variability in photosensitivity. Model N with a narrow high photosensitivity zone (inset) simulates a smaller magnitude of the advance zone of 12‐h light PRC than model W with a wide high photosensitivity zone. Thus, model N simulates a larger constant stable phase delay than model W when a single daily 25 mpk dose is given at ZT8 under LD 12:12. IF THIS IMAGE HAS BEEN PROVIDED BY OR IS OWNED BY A THIRD PARTY, AS INDICATED IN THE CAPTION LINE, THEN FURTHER PERMISSION MAY BE NEEDED BEFORE ANY FURTHER USE. PLEASE CONTACT WILEY'S PERMISSIONS DEPARTMENT ON PERMISSIONS@WILEY.COM OR USE THE RIGHTSLINK SERVICE BY CLICKING ON THE 'REQUEST PERMISSIONS' LINK ACCOMPANYING THIS ARTICLE. WILEY OR AUTHOR OWNED IMAGES MAY BE USED FOR NON-COMMERCIAL PURPOSES, SUBJECT TO PROPER CITATION OF THE ARTICLE, AUTHOR, AND PUBLISHER. Mol Syst Biol, Volume: 15, Issue: 7, First published: 08 July 2019, DOI: (10.15252/msb.20198838)