3.3 Covariate Analysis
Covariates of interest which were presented in Table 1 were included in
the covariate model development using the COSSAC algorithm. The
covariate search results showed that inclusion of ALP, AST, Sex, Subject
Type (MM vs. Healthy Subjects) on CL/F and Subject Type (MM vs. Healthy
Subjects) on V1/F significantly improved the model fitting. The output
of the final model was summarized in Table 3.
Most of the PK parameters for the final model were estimated with good
precision (i.e., small % relative standard error (RSE)), suggesting
adequate reliability. However, the covariates (ALP, AST and sex) on CL/F
were estimated with relatively low confidence (%RSE > 30).
This was likely attributed to the marginal effects of such covariates on
PK parameters. To validate this point, a forest plot (Figure 3) was
generated which showed that the influence of ALP (1st tertile and 3rd
tertile vs. 2nd tertile [reference]), AST (1st tertile and 3rd
tertile vs. 2nd tertile [reference]) and sex (female vs. male
[reference]) was in small magnitude (≥ 80% and ≤ 125%), and
therefore, was unlikely to be clinically meaningful.
Subject type was a significant covariate on CL/F and V1/F. Based on the
forest plot, MM patients showed 238% higher CL/F and 84% lower V1/F as
compared to healthy subjects (Figure 3). It should be noted that the
CL/F only constituted part of total iberdomide clearance. The metabolism
clearance, which can be calculated as Kpm*V1, was believed to largely
contribute to the iberdomide clearance. In fact, the total iberdomide
clearance for typical MM subjects (9.48 L/hr) was even lower than that
of healthy subjects (20.41 L/hr) (Table 4). Notably, the model estimated
clearance for healthy subjects were in line with the published results
based on non-compartmental analysis8, indicating good
model performance.
Renal function was examined on the PK of iberdomide and M12. The impact
of CLcr, eGFR and renal function category on PK parameters, including
CL/F, V1/F, CLm and Kpm were assessed. Figure 4 showed that no
correlation was observed between CLcr and eGFR versus PK parameters and
the PK parameters were comparable among renal function groups. These
results suggested that moderate and mild renal impairment (CLcr ≥ 30
mL/min) was unlike to change the PK exposure of iberdomide and M12.
Combinations (DEX and/or DARA) were assessed as a covariate. Figure 5
showed comparable PK among different combos, suggesting that combination
had no impact on the PK of iberdomide and M12.
Other covariates, including age, body weight, BMI, BSA and baseline
disease factors (e.g., ECOG) were not significant in the model and
therefore, were not retained in the final model.