Figure Legend:
Figure 1. Concentration - time profiles of iberdomide and M12
by study. [A]. Iberdomide; [B]. M12. Solid circles represent
observed concentrations, which were grouped by dose level.
Figure 2. The joint population pharmacokinetic model of
iberdomide and M12. The model comprises two parts: parent (iberdomide)
and metabolite (M12). The parent model is a two-compartment with
first-order absorption incorporating a lag time and first-order
elimination. The metabolite model is a one compartment model with first
order elimination. A first order conversion rate described the
transformation from parent to metabolite.
Figure 3. Forest plot of significant covariates on apparent
clearance (CL/F, A) and apparent volume of distribution of the central
compartment (V1/F, B). Data are shown as median (90% confidence
interval). (A) References are 2nd tertile of AST (17 to 23 U/L), healthy
subject, 2nd tertile of ALP (55.0 to 72.5 U/L) and male subjects,
respectively. (B). Reference is healthy subject.
Figure 4. Correlation between renal function and population PK
parameters. Solid circles are individual PK parameters generated from
the model. Blue line represented the locally weighted smoothing line.
CLcr = creatinine clearance; EGFR = estimate glomerular filtration rate.
Figure 5. Correlation between combinations and population PK
parameters. Solid circles are individual PK parameters generated from
the model. dex = dexamethasone; dara = daratumumab.
Figure 6. Visual predictive check plots of iberdomide and M12.
[A]. iberdomide concentration; unit: umol/L; [B]. M12
concentration; unit: umol/L. The blue dots show the observed
concentration data. The solid blue lines show the empirical 10th, 50th,
and 90th percentiles calculated directly from the population data. The
blue-shaded areas denote the confidence intervals of the 10th and 90th
percentiles from the model; and the pink shaded area shows the 50th
percentile.
Figure 7. Metabolite to parent ratio by cohort and dose from
CC-220-MM-001 study. [A and B]: Cmax ratio; [C and D]: AUC
ratio. Cmax = maximum concentration; AUC = area under the concentration
- time profile over one dosing interval (24 hours).
Figure 8. Simulated concentration - time profile of iberdomide
(red) and M12 (blue) for a typical subject from CC-220-MM-001 study on
1.6 mg, 21/28 day schedule.
Figure 9. Simulated iberdomide concentration - time profile for
a typical healthy subject (red) and multiple myeloma patients (blue) on
1.6 mg, 21/28 day schedule.