Predictive modeling of aspirin‐triggered resolvin D1 pharmacokinetics for the study of Sjögren's syndrome

Abstract

Objectives Sjögren's syndrome (SS) is an autoimmune disease that causes chronic inflammation of the salivary glands leading to secretory dysfunction. Previous studies demonstrated that aspirin‐triggered resolvin D1 (AT‐RvD1) reduces inflammation and restores tissue integrity in salivary glands. Specifically, progression of SS‐like features in NOD/ShiLtJ mice can be systemically halted using AT‐RvD1 prior or after disease onset to downregulate proinflammatory cytokines, upregulate anti‐inflammatory molecules, and restore saliva production. Therefore, the goal of this paper was to create a physiologically based pharmacokinetic (PBPK) model to offer a reasonable starting point for required total AT‐RvD1 dosage to be administered in future mice and humans thereby eliminating the need for excessive use of animals and humans in preclinical and clinical trials, respectively. Likewise, PBPK modeling was employed to increase the range of testable scenarios for elucidating the mechanisms under consideration. Materials and methods Pharmacokinetics following intravenous administration of a 0.1 mg/kg dose of AT‐RvD1 in NOD/ShiLtJ were predicted in both plasma and saliva using PBPK modeling with PK‐Sim® and MoBi® Version 7.4 software. Results The model provides high‐value pathways for future validation via in vivo studies in NOD/ShiLtJ to corroborate the findings themselves while also establishing this method as a means to better target drug development and clinical study design. Conclusions Clinical and basic research would benefit from knowledge of the potential offered by computer modeling. Specifically, short‐term utility of these pharmacokinetic modeling findings involves improved targeting of in vivo studies as well as longer term prospects for drug development and/or better designs for clinical trials.

Current experimental methods to investigate the impact of specialized pro-resolving lipid mediators on Sjögren’s syndrome

“…, wound healing ( 138 – 140 ) and innate immunity ( 165 ) models); however, dysregulation of SPM production in SS mouse model may occur during disease progression, as these mice do not resolve inflammation ( 1 , 44 , 46 , 48 , 166 ). With respect to virtual mathematical models ( 158 – 162 ), such techniques can provide a reasonable starting point for required total dosage to be administered while also eliminating the need for excessive animal usage, as would be the case should this estimate be derived by trial and error alone; however, a limitation of mathematical models is that the physicochemical and biological parameters used to build the RvD1 and AT-RvD1 PK/PD models are obtained either from data on from data, from the literature or estimated using algorithms ( 163 , 164 ). Therefore, it is critical to keep in mind that all such estimates must be confirmed and thus validated using models in vivo .…”

“…The target administration amount can then be introduced systemically at multiple time points, after which the degree of inflammatory resolution in the SG and the mechanisms by which this change has occurred should be determined. The validated mouse PK/PD effects obtained in mice can be extrapolated to humans by replacing the model input parameters for the mouse species with those of humans on the basis of a previously developed whole-body PK model of AT-RvD1 and extrapolation protocol for humans ( 163 , 164 ), a process of model development that will need to be replicated for exploration of future SPM to be identified and explored in this context. However, the PK model has some limitations.…”

“…Although AT-RvD1 is the subject of the figure, the same model can be applied to other specialized pro-resolving lipid mediators. This image was adapted from ( 163 ). AT-RvD1: aspirin-triggered resolvin D1; PBPK, physiologically based pharmacokinetic; PK, pharmacokinetics; SS, Sjögren’s syndrome.…”

Physiologically based pharmacokinetic modelling and simulation to predict the plasma concentration profile of schaftoside after oral administration of total flavonoids of Desmodium styracifolium

“…Parameter sensitivity analysis was performed using PBPK model established in human with the sensitivity analysis tool provided with the PK-Sim ® software ( Yellepeddi and Baker, 2020 ). C max and AUC 0-t of schaftoside were evaluated to find out the key factors that influenced the simulated schaftoside plasma concentration-time profiles.…”

Physiologically Based Pharmacokinetic Models Are Effective Support for Pediatric Drug Development

“…The PBPK model can also guide experimental designs through dose prediction ( 91 ). The risk involved in clinical trials of some drugs in neonates can be reduced through the PBPK model.…”