Translational PBPK Modeling of the Protein Therapeutic and CD95L Inhibitor Asunercept to Develop Dose Recommendations for Its First Use in Pediatric Glioblastoma Patients

The protein therapeutic and CD95L inhibitor asunercept is currently under clinical investigation for the treatment of glioblastoma and myelodysplastic syndrome. The purpose of this study was to predict the asunercept pharmacokinetics in children and to give dose recommendations for its first use in pediatric glioblastoma patients. A physiologically-based pharmacokinetic (PBPK) model of asunercept in healthy and diseased adults was successfully developed using the available clinical Phase I and Phase II study data. This model was then extrapolated to different pediatric populations, to predict the asunercept exposure in children and to find equivalent starting doses. Simulation of the asunercept serum concentration-time curves in children between 1–18 years of age shows that a dosing regimen based on body weight results in a similar asunercept steady-state exposure in all patients (pediatric or adult) above 12 years of age. For children between 1–12 years, higher doses per kg body weight are recommended, with the highest dose for the very young patients. Translational PBPK modeling is strongly encouraged by regulatory agencies to help with the initial dose selection for pediatric trials. To our knowledge, this is the first report of pediatric PBPK to support the dose selection of a therapeutic protein before its administration to children.

Model performance of the final model, demonstrated by comparison of predicted to observed asunercept serum concentration-time profiles of all healthy volunteers that participated in the Phase I study APG101_CD_001 and showed asunercept concentrations above the lower limit of quantification. continued...

Model Performance: Training Dataset, Phase II Study
Model performance of the final model, demonstrated by comparison of predicted to observed asunercept serum concentration-time profiles of the 19 patients that participated in the Phase II study APG101_CD_002 and were assigned to the training dataset. continued...

Model Performance: Test Dataset, Phase II Study
Model performance of the final model, demonstrated by comparison of predicted to observed asunercept serum concentration-time profiles of the 16 patients that participated in the Phase II study APG101_CD_002 and were assigned to the test dataset. continued...

Linear Pharmacokinetics of Asunercept
The mean asunercept serum concentrations per dosing group of the dose escalation Phase I study APG101_CD_001 show linear, dose proportional pharmacokinetics of asunercept for single dose intravenous administration of 0.2 mg/kg to 20.0 mg/kg asunercept to healthy volunteers. The asunercept serum concentrations of the two groups receiving lower doses of 0.008 mg/kg and 0.04 mg/kg asunercept were below the lower limit of quantification.

Sensitivity Analysis
Sensitivity of the final PBPK model to single parameters (local sensitivity analysis) was calculated, measured as relative change of the AUC at steady-state (week 15) of a 400 mg asunercept QW dosing regimen, using a sialic acid:glycan ratio of 0.64 for asunercept. Sensitivity analysis was carried out with a variation range of 0.1 and number of steps of 2. Using a variation range of 1.0 gave very similar results. Parameters were included into the analysis if they have been optimized (FcRn Kd (lysosomal), CD95L Kd, CD95L koff, ASGR clearance), if they are associated with optimized parameters or if they might have a strong impact due to calculation methods used in the model. Sensitivity to a parameter was calculated as the ratio of the relative change of the simulated AUC to the relative variation of the parameter around its value used in the final model according to:

Dose Recommendations: Predicted First Dose AUC and Cmax Values
The asunercept dose recommendations were optimized to generate the same asunercept serum concentrations-time profiles and steady-state AUC values in the pediatric age groups as have been observed in the adult reference population of study APG101_CD_002. The simulated steady-state AUC and Cmax values using either 5.2 mg/kg asunercept QW for all age groups or the recommended doses are shown in Figure 7 of the main document, the simulated first dose AUC and Cmax values using these regimens are illustrated below. Figure S6. Population predicted asunercept first dose AUC and Cmax values following administration of 5.2 mg/kg asunercept (left panel) or of the recommended doses (right panel) to children of different age groups. The boxes show population medians, 25 th and 75 th percentiles, the whiskers represent the most extreme data points not considered outliers. The dark green lines and shaded green areas illustrate the median and 25 th to 75 th percentile interval of the adult reference population of the Phase II study APG101_CD_002. Simulations were conducted using a sialic acid:glycan ratio of 0.64 for asunercept.