Biological drugs exhibit complex and unique pharmacokinetic (PK) and pharmacodynamic (PD) properties with large inter-subject variability, which complicates the individualization of drug regimens. Despite decades of successful applications of adaptive feedback control involving sparse clinical samples and individual MAP Bayesian projections of individual PK/PD parameters to guide the dosing of narrow therapeutic index small molecule drugs, the extension of this methodology to novel macromolecules is still in its infancy. Several barriers have been implicated in the slow adoption of model-informed precision dosing for biologics, such as the perception that this approach and the typical PK/PD models of biologics are overly complicated and require advanced computational modeling skills. This presentation will introduce the clinical pharmacology of biologics and highlight key considerations such as nonlinear target-mediated disposition, major clearance mechanisms, delayed subcutaneous absorption, immunogenicity, and time-dependent clearance. This introduction will facilitate discussion of nonlinear mixed effects modeling applications to optimize and adjust the dosing regimens of novel biological modalities in adults and pediatric patients.

To date, different dosing approaches such as mg per kg, body surface area-adjusted or dose banding are applied for dosing of biologics in children. While varying dosages of the same biologic may be applied for different diseases, the dosing strategy across age for a certain disease is typically static resulting in altered exposure in certain age groups. Additionally, biomarkers like albumin are not considered when selecting the dose. Altogether, this may result in failure of therapy, development of antibodies and/or side effects in one or more age groups. In the presentation, general principles of dosing of biologics across the pediatric age, relevance of disease or biomarkers and examples of how to apply model informed precision dosing of biologics in children will be discussed.

Precision dosing of biological drugs faces complex challenges that limit its implementation in clinical practice. One of the primary obstacles is the high degree of inter- and intra-patient variability in drug pharmacokinetics and response observed across the treatment period, influenced by patient-specific factors such as disease activity, comorbidities, and age. Standard dosing regimens often fail to account for these differences, leading to suboptimal efficacy or increased risk of adverse effects in certain patient populations.
Target-mediated drug disposition models provide a mechanistic framework that captures the complex, nonlinear pharmacokinetics often seen with biologics due to their interactions with specific biological targets. By integrating patient-specific factors such as biomarkers for disease activities, model-informed precision dosing considering biological properties enables more accurate prediction and adjustment of dosing for individual patients. This approach not only addresses the high inter- and intra-patient variability and limited flexibility of standard dosing regimens but also leverages real-time dose adjustment to optimize efficacy while minimizing adverse effects.
This presentation will overview real-world case studies for eculizumab and alemtuzumab in pediatric stem cell transplantation, highlighting clinical challenges and successes through precision dosing informed by models that consider biological properties.