Translational PBPK Modeling and Exposure-Response Analysis of AT-RvD1 for Treating Sjögren's Disease

Sjögren's disease (SD) is an autoimmune condition characterized by chronic inflammation and impaired secretory function of the salivary glands (SG). The proresolving lipid mediator AT-RvD1 restores SG function in SD-like mice; however, its tissue pharmacokinetics, exposure-response relationships, and human dose predictions remain poorly understood. Therefore, this exploratory study characterizes AT-RvD1 tissue pharmacokinetics, develops an SG-focused physiologically based pharmacokinetic (PBPK) model, explores the relationship between SG exposure and secretory response, and predicts human exposures relevant to clinical development. Following intravenous administration of AT-RvD1 to SD-like mice, concentrations were quantified in serum, submandibular gland (SMG), heart, lung, liver, and kidney. These data were used to evaluate a PBPK model incorporating the SG as the target site of action. PBPK-predicted cumulative SMG exposure was subsequently compared with the saliva flow rate obtained after chronic AT-RvD1 treatment. The mouse model was then used to predict systemic and SG exposure in a virtual human population across an exploratory dose range. The PBPK model described systemic and tissue pharmacokinetics, with average fold error and absolute average fold error values within predefined acceptance criteria. Human PBPK simulations predicted dose-dependent increases in SG exposure and identified 1.5 mg/kg as a candidate dose at which predicted concentrations exceeded the preclinical pharmacological reference concentration in more than 90% of simulated subjects. Collectively, these analyses provide an experimentally informed PBPK framework for exploring AT-RvD1 tissue exposure, exposure-response relationships, and candidate doses for future clinical evaluation in SD.