Model‐Based Assessment of Dosing Strategies in Children for Monoclonal Antibodies Exhibiting Target‐Mediated Drug Disposition

In recent years, pediatric drug development has been encouraged by regulatory authorities in light of the insufficient number of drugs, doses and formulations available for application in children and high off-label use of adult medicines.1 The US Food and Drug Administration Safety and Innovation Act (FDASIA) 2012 requires sponsors to submit a pediatric drug development plan to the regulatory agency at the end of phase II studies2 while a Pediatric Investigation Plan (PIP) is required earlier in Europe at the end of Phase I studies.3 Although the establishment of pediatric development plans is in many cases challenging due to the lack of data and an incomplete understanding of the drug's pharmacokinetics (PK) and pharmacodynamics (PD) in children, these regulatory initiatives prompted the early use of predictive models to support pediatric drug development programs.4,5,6,7 These models frequently employ simple allometric functions to scale a PK parameter (Y), such as clearance or volume of distribution, from adults to children using a body-weight (BW)–based power function (Y = a·BWb) with a coefficient (a) and an exponent (b).8,9 Although this scaling approach has found wide application for small molecules,9 it has its limitations for capturing highly non-linear processes, such as target-mediated drug disposition (TMDD) of monoclonal antibodies (mAbs)10,11 or maturational changes in mAb disposition from birth.12 Therapeutic mAbs are cleared via multiple routes, which can be divided into mAb-specific and mAb non-specific elimination routes. Non-specific mAb elimination is primarily mediated by intracellular catabolism following fluid phase and receptor-mediated endocytosis,8 which is typically non-saturable at therapeutic doses (i.e., linear PK). Interactions between the mAb and its specific target, on the other hand, can lead to saturable and thus non-linear PK. Low mAb concentration relative to the concentration of target result in rapid elimination.13 Once mAb concentrations increase, more targets are occupied, which results in a non-linear decrease in clearance. At very high mAb concentrations, when targets are completely saturated, clearance can be considered linear again.14 As such, BW-based allometric scaling may be sufficient to scale adult doses to children for mAbs with linear kinetics except for low weight children,15,16 but may less accurately predict pediatric dosing regimens for mAbs that show non-linear kinetics, i.e., that employ TMDD. Literature adult data suggests that PK parameters for many mAbs change in a less than BW-proportional manner as respective allometric exponents for clearance and volume of distribution were estimated to range from 0.3 to 0.7 (refs. 17,18) There are only a few examples, where strong BW effects were observed as indicated by exponents greater than 0.75.17 It should be noted that allometric exponents determined for within species scaling are typically smaller than those observed for between species scaling, which is likely the result of a narrower BW range in adults for a given species (approximately two- to threefold).17 Since the respective BW range in children is wider than that in adults, further research is necessary to determine appropriate allometric exponents in children.17 For example, clearance exponents were estimated to be 0.823 (ref. 19) for canakinumab in systemic juvenile idiopathic arthritis (SJIA) patients, whereas a value of 0.75 was found appropriate for palivizumab and infliximab when scaling from adults to children.15,20 Yet, few studies systematically explored the entire range of allometric exponents to determine an optimal value for CL and Vss across mAbs. There is also limited information on whether or not BW-based dosing strategies allow to reliably predict pediatric doses that result in comparable systemic drug exposure (AUC0–infinity) in children and adults for mAbs that exhibit TMDD. The uncertainty around how to optimally scale adult doses to children for mAbs with non-linear kinetics is reflected in the lack of approved pediatric dosing regimens as compared to mAb with linear kinetics (Table 1). Table 1 Overview of approved antibody-based therapeutic proteins for application in adults and children The objective of our study was therefore to evaluate the impact of differences in target expression between adults and children on pediatric dosing for mAbs exhibiting non-linear kinetics via simulations.