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

Introduction: Iberdomide, a novel cereblon modulator (CELMoD®), is currently under clinical investigation for hematology indications. To evaluate the influence of hepatic impairment on the pharmacokinetics (PK) of iberdomide and its major active metabolite M12, a phase 1, multicenter, open-label study was conducted in healthy subjects and subjects with mild, moderate, and severe hepatic impairment.

Methods: Forty subjects were enrolled in the study and divided into five groups based on hepatic function. 1 mg iberdomide was administered and plasma samples were collected to evaluate the pharmacokinetics of iberdomide and M12.

Results: After a single dose of iberdomide (1 mg), mean iberdomide Cmax (maximum observed concentration) and AUC (area under the concentration-time curve) exposure were generally comparable between hepatic impairment (HI) subjects (severe, moderate and mild) and their respective matched normal controls. Mean Cmax and AUC exposure of the metabolite M12 were generally comparable between mild HI and matched normal subjects. However, mean Cmax of the M12 was 30% and 65% lower and AUC was 57% and 63% lower in moderate and severe HI subjects as compared to their respective matched normal controls. However, given the relatively low M12 exposure as compared to its parent drug, the observed differences were not considered clinically meaningful.

Conclusion: In summary, 1 mg single oral dose of iberdomide was generally well-tolerated. HI (mild, moderate or severe) had no clinically relevant impact on iberdomide PK and therefore, no dose adjustment is warranted.

 

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Title: Influence of Hepatic Impairment on the Pharmacokinetics of Iberdomide: A Phase 1 Study

Introduction: Iberdomide, a novel cereblon modulator (CELMoD®), is currently being investigated for its potential in hematology indications. To assess the effects of hepatic impairment on the pharmacokinetics (PK) of iberdomide and its major active metabolite M12, a phase 1, multicenter, open-label study was conducted. The study enrolled healthy subjects as well as subjects with varying degrees of hepatic impairment.

Methods: Forty subjects were enrolled in the study and divided into five groups based on their hepatic function. A single oral dose of 1 mg iberdomide was administered to all participants, and plasma samples were collected to evaluate the pharmacokinetics of iberdomide and its metabolite M12.

Results: Following the administration of a single 1 mg dose of iberdomide, the mean maximum observed concentration (Cmax) and area under the concentration-time curve (AUC) exposure of iberdomide were generally comparable between subjects with hepatic impairment (severe, moderate, and mild) and their respective matched normal controls. This suggests that hepatic impairment did not have a clinically relevant impact on the pharmacokinetics of iberdomide.

In the case of the metabolite M12, the mean Cmax and AUC exposure were generally comparable between subjects with mild hepatic impairment and their matched normal controls. However, in subjects with moderate and severe hepatic impairment, the mean Cmax of M12 was 30% and 65% lower, respectively, compared to their respective matched normal controls. Similarly, the mean AUC of M12 was 57% and 63% lower in subjects with moderate and severe hepatic impairment, respectively. Despite these differences, the low exposure of M12 relative to its parent drug iberdomide suggests that these observed variations are not considered clinically meaningful.

Conclusion: In this phase 1 study, a single oral dose of 1 mg iberdomide was generally well-tolerated by the study participants. Hepatic impairment, whether mild, moderate, or severe, did not have a clinically relevant impact on the pharmacokinetics of iberdomide. Therefore, based on these findings, no dose adjustment is warranted for iberdomide in patients with hepatic impairment. Further studies may be required to confirm these results and evaluate the safety and efficacy of iberdomide in patients with hepatic impairment.

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