Model-based analysis for the population pharmacokinetics of iberdomide and its major active metabolite in healthy subjects and patients with relapsed and refractory multiple myeloma.

ABSTRACT

AIMS: A parent-metabolite population pharmacokinetic (popPK) model of iberdomide and its pharmacologically active metabolite (M12) was developed and the influence of demographic and disease-related covariates on popPK parameters was assessed based on data from 3 clinical studies of iberdomide (dose range, 0.1-6 mg) in healthy subjects (n = 81) and patients with relapsed and refractory multiple myeloma (n 245). METHODS: Nonlinear mixed effects modelling 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 2-compartment model with first-order absorption and elimination. A first-order conversion rate was used to link the 1-compartment linear elimination metabolite model with the parent model. Subject type (multiple myeloma patients vs. healthy subject) was a statistically significant covariate on apparent clearance and apparent volume of distribution for the central compartment, suggesting different PK between patients with multiple myeloma and healthy subjects. Aspartate aminotransferase and sex were statistically but not clinically relevant covariates on apparent clearance. Metabolite (M12) PK tracked the PK of iberdomide. The metabolite to parent ratio was consistent across doses and combinations. CONCLUSION: The parent-metabolite population PK model adequately described the time course PK data of iberdomide and M12. Iberdomide and M12 PK exposure were not complicated by demographic factors (age [19-82 y], body weight [41-172 kg], body surface area [1.4-2.7 m2 ], body mass index [16.4-59.3 kg/m2 ]), combination (in combination with dexamethasone and daratumumab), mild 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.