Model-Based Meta-analysis for the Population Pharmacokinetics of Iberdomide and Its Major Active Metabolite in Healthy Subjects and Subjects with Relapse and Refractory Multiple Myeloma

Aim A parent-metabolite population pharmacokinetic (popPK) model of iberdomide was developed and the influence of demographic and disease-related covariates on popPK parameters was assessed based on data from three clinical studies of iberdomide (dose range, 0.1 to 6 mg) in healthy subjects (N=81) and subjects with relapsed and refractory multiple myeloma (N=245). Methods Nonlinear mixed effects modeling was used to develop the popPK model based on data from 326 subjects across 3 clinical studies. Results The pharmacokinetics (PK) of iberdomide were adequately described with a two-compartment model with first-order absorption and elimination. A first order conversion rate was used to link the one-compartment linear elimination metabolite model with the parent model. Subject type (multiple myeloma subjects vs. healthy subject) was a statistically significant covariate on apparent clearance (CL/F) and apparent volume of distribution for the central compartment (V1/F), suggesting different PK between subjects with multiple myeloma and healthy subjects. Aspartate aminotransferase (AST), alkaline phosphatase (ALP) and sex were statistically but not clinically relevant covariates on CL/F. Metabolite (M12) PK tracked the PK of iberdomide. The metabolite to parent ratio was consistent across doses and combinations. Conclusion In conclusion, the parent-metabolite population pharmacokinetic model adequately described the time course PK data of iberdomide and M12. Iberdomide and M12 show robust PK exposure, not complicated by demographic factors, combination, hepatic or (mild and moderate) renal impairments. The model can be used to guide the dosing strategy for special patient population and inform future iberdomide study design.