Abstract
Iberdomide is a BCS III CELMoD™ agent currently under development for treatment of multiple myeloma. Five formulations were used during clinical development, starting with active ingredient in gelatin capsule (AIC), followed by subsequent formulations in gelatin (F1), HPMC capsules (F2 and F3), and finally the intended commercial form (ICF). A food effect study with the Phase I AIC formulation showed no food effect and two relative bioavailability studies bridging from AIC to formulation F1 and F2 showed similar systemic exposure. Modeling and simulation, based on in vitro dissolution, was used to bridge gaps in clinical data to demonstrate lack of a food effect across all formulations including ICF. First, a previously developed population pharmacokinetic (PK) model showed that formulation was not a covariate on iberdomide PK. Then a physiologically-based pharmacokinetic model (PBPK) informed by in vitro biorelevant dissolution was used to mechanistically describe iberdomide absorption. While minor differences between formulations were noted in their in vitro dissolution, PBPK modeling showed lack of a food effect across all five formulations. Sensitivity analysis using the PBPK model demonstrated that iberdomide permeability and total amount of drug released from formulation are the most sensitive parameters in defining the systemic exposure of iberdomide, in agreement with iberdomide’s BCS III classification where drug release from drug product, and not solubility, is the rate-limiting step of dissolution. Based on the totality of evidence, which included clinical and in vitro data supplemented by modeling and simulation, no food effect is expected with the ICF. Graphical Abstract