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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
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  • Yiming Cheng,
  • Yongjun Xue,
  • Lu Chen,
  • Mark Masin,
  • Paulo Maciag,
  • Teresa Peluso,
  • Simon Zhou,
  • Yan Li
Yiming Cheng
Bristol-Myers Squibb Co Summit

Corresponding Author:[email protected]

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Yongjun Xue
Bristol Myers Squibb Co
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Lu Chen
Bristol Myers Squibb Co
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Mark Masin
Bristol-Myers Squibb Europe Moyen-Orient Afrique SARL
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Paulo Maciag
Bristol-Myers Squibb Co Summit
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Teresa Peluso
Bristol-Myers Squibb Europe Moyen-Orient Afrique SARL
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Simon Zhou
Bristol-Myers Squibb Co Summit
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Yan Li
Bristol-Myers Squibb Co Summit
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Abstract

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.
21 Mar 2022Submitted to British Journal of Clinical Pharmacology
22 Mar 2022Submission Checks Completed
22 Mar 2022Assigned to Editor
24 Apr 2022Reviewer(s) Assigned
10 May 2022Review(s) Completed, Editorial Evaluation Pending
25 May 2022Editorial Decision: Revise Major
21 Jun 20221st Revision Received
22 Jun 2022Submission Checks Completed
22 Jun 2022Assigned to Editor
22 Jun 2022Review(s) Completed, Editorial Evaluation Pending
26 Jun 2022Reviewer(s) Assigned
19 Jul 2022Editorial Decision: Revise Minor
25 Jul 20222nd Revision Received
26 Jul 2022Submission Checks Completed
26 Jul 2022Assigned to Editor
26 Jul 2022Review(s) Completed, Editorial Evaluation Pending
15 Aug 2022Editorial Decision: Accept