Abstract
Physiologically based pharmacokinetic (PBPK) models are increasingly used to support pediatric dose selection for small molecule drugs. In contrast, only a few pediatric PBPK models for therapeutic antibodies have been published recently, and the knowledge on the maturation of the processes relevant for antibody pharmacokinetics (PK) is limited compared to small molecules. The aim of this study was, thus, to evaluate predictions from antibody PBPK models for children which were scaled from PBPK models for adults in order to identify respective knowledge gaps. For this, we used the generic PBPK model implemented in PK-Sim without further modifications. Focusing on general clearance and distribution mechanisms, we selected palivizumab and bevacizumab as examples for this evaluation since they show simple, linear PK which is not governed by drug-specific target mediated disposition at usual therapeutic dosages, and their PK has been studied in pediatric populations after intravenous application. The evaluation showed that the PK of palivizumab was overall reasonably well predicted, while the clearance for bevacizumab seems to be underestimated. Without implementing additional ontogeny for antibody PK-specific processes into the PBPK model, bodyweight normalized clearance increases only moderately in young children compared to adults. If growth during aging at the time of the simulation was considered, the apparent clearance is approximately 20% higher compared to simulations for which growth was not considered for newborns due to the long half-life of antibodies. To fully understand the differences and similarities in the PK of antibodies between adults and children, further research is needed. By integrating available information and data, PBPK modeling can contribute to reveal the relevance of involved processes as well as to generate and test hypothesis.
Highlights
Pediatric drug development has accelerated over the last two decades due to increased regulatory requirements in response to unmet medical needs in this special patient population (Manolis et al, 2011; Leong et al, 2012)
The pediatric physiologically based pharmacokinetic (PBPK) predictions for palivizumab were compared to the experimental data (Subramanian et al, 1998; Saez-Llorens et al, 2004) as well as the results derived from the population
PBPK models typically consist of three distinct parts: 1) drug-specific parameters characterizing the physicochemical properties of the drug, 2) system-specific parameters characterizing the functioning of the underlying system, and 3) trial design parameters
Summary
Pediatric drug development has accelerated over the last two decades due to increased regulatory requirements in response to unmet medical needs in this special patient population (Manolis et al, 2011; Leong et al, 2012). Additional maturational processes, phase I and phase II enzyme ontogeny, may have to be considered in children younger than two years of age for small molecule drugs. This has given rise to more complex approaches, including physiologically based pharmacokinetic (PBPK) models for which there is considerable experience with scaling PBPK models to pediatric populations for small molecule drugs (Leong et al, 2012; Templeton et al, 2018; Heimbach et al, 2019; Willmann et al, 2019). For therapeutic proteins like antibodies, there is currently only very limited experience with scaling PBPK models to children (Hardiansyah and Ng, 2018; Hanke et al, 2019; Malik and Edginton, 2019; Malik and Edginton, 2020), and there is currently only limited quantitative information regarding the maturation of the processes relevant for antibody PK (Shi and Derendorf, 2010; Xu et al, 2013; Edlund et al, 2015; Zhang et al, 2015; Liu et al, 2019)
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