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.