(T1330-01-06) Validation of PBPK-Based Translation to Predict Monoclonal Antibody Pharmacokinetics in Pediatric Populations

Purpose: Accurate prediction of pediatric doses is a necessity before conducting a clinical trial or using a drug product in standard clinical practices. For the pediatric population, both safety and efficacy need to be considered due to ethical reasons¹. The recommended doses of most of the therapeutic proteins, including monoclonal antibodies (mAbs), are extrapolated to pediatrics from adult doses based on body weight. However, this approach does not consider physiological and biochemical differences between children and adults. Therefore, this could lead to mAbs’ underexposure, limiting its efficacy in this population. Other methods are necessary to mechanistically predict pediatric doses. For small molecules, physiologically based pharmacokinetic (PBPK) models have been long used to predict pediatric dose based on age-related changes in the physiology and enzymes/transporters ontogeny². The aim of this study is to evaluate the ability of PBPK model to predict pediatric exposure also for mAbs’.

Methods: Two immunoglobulin G1 (IgG1) mAbs were used for model development and validation: infliximab (anti-TNF-alpha) and bevacizumab (anti-VEGF). The PBPK models were built using the Biologics module within GastroPlus^©. Average concentration profiles in adult and pediatric populations were extracted from the literature. Simulations were conducted with specific doses, dose schedules, and subject demographic information matching specific clinical trials. For each mAb, the PBPK model was calibrated based on observed data in healthy adults. Then, the physiological parameters were scaled to match the pediatric physiology to predict exposure in pediatric population. Predicted plasma concentration-time courses were compared with reported observed data to assess the ability of the PBPK model to predict pediatric exposure. Accurate clinical predictions were defined as predicted error (PE) ratios within 0.8 to 1.25-fold and acceptable predictions within the range of 0.67 to 1.5-fold of the observed data.

Results: The final PBPK models in adults described well the observed plasma concentration-time courses for the two mAbs. For infliximab, the vascular and lymphatic reflection coefficients were adjusted to 0.99 and 0.60, respectively, and the elimination rate constant (Kdeg) was fitted to 1.34 E+04 (1/day). For pediatric population, Kdeg was increased by 1.87-fold to describe the observed data. For bevacizumab, the parameter values for the vascular reflection coefficient, the lymphatic reflection coefficient, and the Kdeg were 0.95, 0.2, and 0.22 E+04 (1/day), respectively. For pediatric population, Kdeg was increased using the same scaling factor as the one used for infliximab. These PBPK models then accurately predicted infliximab and bevacizumab exposure in multiple pediatric populations. PE ratios for Cmax and Ctrough at steady state for infliximab were 1.07 and 1.21 respectively, and PE ratios for Cmax and Ctrough for bevacizumab were 1.13 and 1.14, respectively.

Conclusion: PBPK models allowed an accurate prediction of the observed data in the pediatric population for two mAbs. Adjustment of the mAbs endosomal clearance parameters between adult and pediatric populations could be linked to age-related differences in the neonatal Fc receptor expression³. More case studies will be needed for other mAbs to confirm this study’s results. Nevertheless, the accurate pediatric extrapolation outcomes for these mAbs represent an important step in the validation process of the extrapolation method used to predict biologics’ exposure in this population using a PBPK model.

References: (1) Mahmood I. A Simple Method for the Prediction of Therapeutic Proteins (Monoclonal and Polyclonal Antibodies and Non-Antibody Proteins) for First-in-Pediatric Dose Selection: Application of Salisbury Rule. Antibodies. 2022;11(4):66.
(2) Johnson TN, Ke AB. Physiologically Based Pharmacokinetic Modeling and Allometric Scaling in Pediatric Drug Development: Where Do We Draw the Line? The Journal of Clinical Pharmacology. 2021;61(S1).
(3) Hardiansyah D, Ng CM. Effects of the FcRn developmental pharmacology on the pharmacokinetics of therapeutic monoclonal IgG antibody in pediatric subjects using minimal physiologically-based pharmacokinetic modelling. mAbs. Published online July 3, 2018:1-13.