Pharmacodynamic modeling
The pharmacodynamics of inebilizumab were assessed with an assay for peripheral CD20+ B cells, since inebilizumab interferes with the CD19+ B cell assay. A hematopoietic transit model in which inebilizumab reducing influx from pro-B cells and accelerating CD20+ B cell depletion in the blood was developed to describe the PD effect (Figure 2). The parameter estimates from the final model are summarized in Table 3. The estimated typical baseline CD20+ B cell count and lifespan were 135 cells per µL and 391 days, respectively. Only baseline B cell count was identified as a relevant PD covariate: higher baseline count was associated with more prominent B cell depletion by inebilizumab. Other covariates including age had no impact on the PD of inebilizumab.
The basic goodness-of-fit plots of the final PD model are shown in Figure S1. The conditionally weighted residual (CWRES) over the population predictions (PRED) is shown in Figure S1A to evaluate the model fit. The observations (dependent variables, DV) over the PRED and individual predictions (IPRED) are shown in Figure S1B and S1C, respectively, to diagnose any misspecification of the structural model. The spread of the CWRES is relatively consistent across the PRED range, while the regression lines in Figure S1B and S1C are close to the line of identity, indicating appropriate specification of the model structure and good model fit of the data.
The visual predictive check plots by study are presented in Figure 3. The symbol represents the observed CD20+ B cell count; the black solid and dotted lines represent the observed median at 5th and 95th percentiles, the shaded area represents the 90% confidence interval (CI) of predicted median, 5th and 95th percentiles from 200 clinical simulations.