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.

A Phase 1, Multicenter, Open-Label Study to Evaluate the Pharmacokinetics of Iberdomide in Subjects with Mild, Moderate, or Severe Hepatic Impairment Compared with Healthy Subjects

“…Findings from the current study are in line with the results from an integrated popPK analysis of iberdomide, 8 in which hepatic parameters, including hepatic impairment (ie, mild or moderate), total BILI (0.2 to 3.7 mg/dL), AST (6 to 84 U/L), ALP (21 to 300 U/L) and ALT (5 to 63 U/L), were evaluated on the PK of iberdomide and none of the covariates was found to be statistically significant. Consistently, PK parameters obtained herein were generally comparable with other iberdomide clinical studies in which PK data were available, 14–16 suggesting that the current study was well-designed.…”

“…The overall PK profiles of M12 were parallel with the PK profile of parent drug (iberdomide), which was in line with the recent parent-metabolite population pharmacokinetic (popPK) analysis. 8 …”

“…Detail descriptions regarding bioanalytical methods were referred to previous publications. 8 , 14 , 15 …”

“…Iberdomide, a novel cereblon modulator, is under clinical development for hematological malignancies and inflammatory and autoimmune-mediated diseases. [1][2][3][4][5][6][7][8][9][10][11][12][13] Iberdomide plasma exposure increased proportionally with dose (0.1 to 6 mg) in human. Iberdomide was quickly absorbed with a median Tmax (time to Cmax) between 2.5 and 4 hours.…”

“…In vitro human plasma protein binding of iberdomide and M12 is approximately 78% and 67%, respectively. 16 The pharmacokinetics (PK) of M12 was characterized in an integrated population PK analysis, which showed that M12 PK tracked the PK of iberdomide and the metabolite to parent ratio was consistent across doses and time. 16 Acute and chronic liver diseases are leading causes of morbidity and mortality worldwide.…”