4. Discussions and Conclusions
Herein, we reported the first population pharmacokinetic analysis for iberdomide and its major active metabolite, M12 in both healthy and RRMM subjects and assessed the effect of covariates of interest on iberdomide and M12 PK. Over the tested dose range (0.1 mg to 6 mg), iberdomide and M12 (where applicable) showed linear, time-independent PK. Subject type (MM vs. healthy subject) was a statistically significant covariate on CL/F and V1/F. Sex, AST, ALP was statistically but not clinically relevant on CL/F. Metabolite (M12) PK was consistent across doses and combinations, as demonstrated by the comparable metabolite to parent ratio. Overall, the model was robust and adequate to describe the central tendency and variabilities of the data.
Given the lack of actual input information (e.g., amount) of metabolite, mathematically the metabolite model parameters were unidentifiable. Evans et al. discussed this and suggested taking prior knowledge of metabolite volume of distribution in the model to avoid the issue12. In line with this, Bertrand et al. assumed similar volume of distribution for parent and metabolite, which enabled all the parameters to be identifiable 13. Alternatively, a more mechanistical solution was to fix the metabolite conversion ratio (e.g., fm) based on the understanding of the drug’s PK properties14. Herein, we took the former approach to develop the model for the following reasons: 1). the parsimonious structural model can adequately fit the purpose of the analysis; 2). biological evidence showed that the plasma protein binding of iberdomide and M12 was roughly comparable (78.4% vs. 67.4%; data on file, Bristol Myers Squibb), with no saturation of plasma protein binding for both molecules.
In the covariate analysis, the most influential covariates on the disposition of iberdomide were subject type (MM vs. healthy subjects), AST, ALP and sex on CL/F and subject type (MM vs. healthy subjects) on V1/F. However, the forest plot suggested that except for subject type on CL/F and V1/F, the effects of AST, ALP and sex on CL/F were marginal and unlikely to be clinically relevant.
The iberdomide PK difference between healthy subjects and those with MM was noticeable. The model estimated total clearance of iberdomide and V1/F were lower in subjects with MM as compared to healthy subjects. Based on the model, subjects with MM were expected to have higher exposure than healthy subjects for the same dose (Figure 9). However, this difference was not taken into consideration on iberdomide dosing, given the iberdomide therapeutic doses were selected solely based on data from clinical trials in RRMM. Of note, similar observation was seen with lenalidomide 15, in which higher exposure was observed in MM patients than healthy subjects. Other compounds, including pomalidomide, enasidenibCC-122 also exhibited disease specific PK 16-18.
Due to the lack of M12 data in healthy subjects in this analysis, the influence of subject type on metabolite PK (Kpm and CLm) was not assessed.
Based on the mass balance study, only 16% of the iberdomide dose was excreted as unchanged in urine, suggesting limited contribution of renal route on drug elimination. In line with this, the popPK analysis showed that renal functions (CLcr, eGFR and renal function category) had no impact on the PK parameters. It should be noted that in the current dataset, there were no subjects with severe or end-stage renal deficiency (CLcr < 30 mL/min). Therefore, the interpretation should be only focused on moderate and mild renal impairment population only.
DEX in combination with iberdomide was one of the dosing regimens in the MM-001 study. DEX is known as a CYP3A4 inducer 19,20. The popPK analysis assessed the influence of iberdomide in combination with DEX given iberdomide was a substrate for CYP3A. Post hoc analysis showed similar PK between DEX and/or DARA combo vs. iberdomide monotherapy, suggesting that the presence of DEX and/or DARA was unlikely to change iberdomide and M12 PK.
Although the hepatic function covariates were not considered as clinically relevant, it should be noted that in the current dataset, most of the subjects (93.9%) had liver tests within the limits of normal. Therefore, the dedicated hepatic impairment study (data on file, Bristol Myers Squibb) was more informative to guide dose adjustment for patients with hepatic deficiency.
Body weight (range: 41 to 172 kg), BSA (range: 1.4 to 2.7 m2), BMI (16.4 to 59.3 kg/m2) and age (19 to 82 years) were statistically non-significant. Race was found not to have any effects on iberdomide and M12 PK. The popPK dataset contained majority of Whites (73.3%), and only 2 Asians, 1 American Indian/Alaska Native and 44 Black/African Americans. Thus, the effects of race should be interpreted with cautions. Baseline disease characteristics, including ISS and ECOG had no statistically significant effects and therefore was not retained in the final model.
Given the level of exposure and the pharmacological activities, M12 PK was characterized during the clinical development of iberdomide. In the popPK analysis, M12 PK data from MM-001 cohorts A, B and E were incorporated. The objective was to assess the M12 exposure relative to the parent drug across doses and combinations. Results suggested consistent metabolite to parent ratio among the tested doses and cohorts. Additionally, the parallel PK profiles indicated that M12 PK tracked iberdomide, irrespective of time. Moreover, based on the human mass balance study in healthy subject, the metabolite to parent ratio was 0.24, which was in general comparable with that in subjects with MM (0.25 and 0.28 for Cmax and AUC, respectively) taking into account the observed variability (%CV: 29.8 to 33.1). Taken together, given the stable and time-insensitive M12 PK in relative to parent drug, the PK of iberdomide was adequate to represent the major pharmacological active exposure in the systemic circulation in the context of extent and time course.
In conclusion, the iberdomide parent-metabolite popPK model described herein was adequate to describe the PK of iberdomide and M12. Covariate analysis suggested that MM patients had lower clearance (iberdomide) and volume of distribution than healthy volunteers. Other covariates, including demographic, combination, renal and hepatic function tests had no clinically relevant impact. M12 PK in relative to iberdomide was consistent across doses and combinations.