A Mixed-effect Pharmacokinetic Model of R835, a Novel Dual IRAK1/4, in Healthy Volunteers After Administration of the Prodrug R289
Authors: Gordi Toufigh , Hanan Nathan , Yan Lucy , Samant Bhushan , Chow Andrew 
Published: February 2025

Objectives: R289 is a prodrug of R835, a potent and selective dual inhibitor of IL-1 receptor associated kinase 1 (IRAK1) and IRAK4 that blocks inflammatory cytokine production. R289 is under clinical investigation for treatment of Lower-risk Myelodysplastic Syndrome. The current study aims to characterize the PK properties of the active compound R835 and its major metabolite R466 after single and repeated doses of R289 in healthy volunteers.Methods: R289 was administered in a capsule formulation as single (20, 80, 250, 500, and 960 mg) or multiple doses (500 and 960 mg BID, 14 days). R289 could be measured in only a handful of samples at levels near the assay LLOQ: no PK analysis of R289 was performed. R835 and R466 plasma concentration data (n=869 and 781, respectively) from 37 volunteers were used to develop a compartmental PK model utilizing a mixed-effect modeling approach. First, separate models were developed for each analyte. The models were subsequently combined, using a fixed R835/R466 conversion factor. A subset of data not used in model development, at a dose level not included in the original data set (single 750 mg dose of R289), was reserved for model validation. Results: An integrated model described the PK of the two analytes well. R835 underwent a rapid and saturable absorption phase followed by bi-exponential decay, with elimination described by two processes: a metabolic conversion to R466, fixed at 12.5%, and a non-R466 elimination. The metabolite, R466, concentration-time course was best described by a one-compartment model. Dose-normalized R835 and R466 AUC and Cmax estimates decreased with increasing R289 dose. Furthermore, upon R289 BID dosing, R835 and R466 trough concentrations were consistently higher in the morning compared to evening samples, with no apparent changes in the distribution or clearance of either compound. R835 absorption was described using a Weibull model and a single transient compartment. The model accounted for the saturable absorption using a two-parameter nonlinear function, estimating the maximum decrease in relative bioavailability (F) and the dose producing a 50% decrease in F, using the 500 mg dose as reference. The apparent diurnal PK differences were accounted for by estimating a covariate effect on F following the evening dose. A VPC analysis captured most of the observations, indicating good model performance. Furthermore, the model predicted R835 and R466 concentrations in the validation analysis subset well, confirming the validity of the model in simulating unknown dosing regimens. Conclusions: A mixed-effect model, that simultaneously describes the PK properties of R835 and its metabolite R466, was developed. The model included several features to account for the complex R835 absorption PK profiles following oral dosing of R289, including saturable absorption and diurnal variability in bioavailability. The model indicates disposition PK of R835 to be linear and stationary.Citations: N/A