Predictive performance of the published model
The predictive performance of the published population PK model for rFIX-Fc was evaluated by comparing the model-predicted and observed FIX activity levels. Figure 1A and Figure 1B present the population predictions goodness-of-fit (GOF) plots for all patients and children <12 years of age separately. Observed FIX activity levels are higher than their respective predictions (Fig. 1A and 1B) and a clear deviation of trend lines from identity lines can be seen in all patients (Figure 1A), but especially in children <12 years of age (Figure 1B). These observations indicate structural bias (underprediction) of the published model. This is also illustrated by the median PE of -48.8% (IQR: -29.9 – -63.9) for all patients and -54.1% (IQR: -43.3 – -65.8) for children <12 years of age (Supplementary Table 2A). The RMSE is shown in Supplementary Table 2B.
Furthermore, deviations were observed in plots of conditional weighted residuals (CWRES) versus population predictions (PRED, Sup. Fig. 1A) and time after dose (TAD, Sup. Fig. 1B).
Bayesian analysis was performed to obtain individual PK parameter estimates. For children <12 years of age, Figure 2A and 2B show the deviation from the individual PK estimate from the typical population value over the weight range. For the evaluation of these graphs, it is important to realize that an adequate population model would have random inter-patient variability with an average of zero and no trend with weight. Figure 2A and 2B clearly demonstrate that children’s CL and V1 are lower than would typically be expected over the studied weight range and advocate the development of a new model.