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.