Model‐Aided Adults‐to‐Children Pharmacokinetic Extrapolation and Empirical Body Size‐Based Dosing Exploration for Therapeutic Monoclonal Antibodies—Is Allometry a Reasonable Choice?

Abstract

The importance of pharmacokinetic (PK) evaluation in pediatric drug development is well recognized, and a pediatric PK study is generally recommended before pivotal trials to ensure the "right" dose in these studies. The PK of therapeutic monoclonal antibodies (mAbs) is primarily affected by body weight, where adults-to-children extrapolation may conform to allometry. Therefore, PK behavior of mAbs in pediatrics, particularly for those with linear PK, is expected to be predictable based on data in adults. To test this hypothesis, we reviewed published population PK reports of marketed mAbs and assessed model-aided PK extrapolation of mAbs to children (2-17 years) through 5 case studies. For each case study, population PK models were developed based on adult data, with allometric exponents of weight on clearance and volume of distribution fixed as standard values (ie, 0.75 for clearance; 1.0 for volume of distribution), approach 1, or coming from adult model estimates, approach 2. Simulated pediatric PK using these 2 approaches was compared with PK observations in pediatric trials to assess the accuracy in model predictions. For pediatrics 6-17 years, model performance was generally comparable with the 2 approaches. For children < 6 years, no definite conclusion could be made, as only 1 case study enrolled children 2-5 years. Our work supports that PK in children 6-17 years is readily predictable for mAbs with linear PK based on adult data and considering weight effect (allometry). Empirical dosing calculations based on PK simulations with allometry are proposed to convert adult doses to equivalent pediatric doses with exposure matching for mAbs in children 2-17 years.

Pediatric Dose Selection for Therapeutic Proteins

“…The consequence is that terminal elimination half‐life can be the similar between adults and children, but overall concentrations are lower for an intravenously administered therapeutic protein with weight‐normalized dosing. These observations are in agreement with similar results reported specifically for mAbs 45 . A consistent pattern of exposure was observed for all therapeutic proteins in this study, regardless of size or affinity for the neonatal Fc receptor (FcRn).…”

“…Deviating from conventional allometry, our review finds that exponents between 0.7 and 1.0 are most frequently applied for describing the effect of body weight on volume of distribution for therapeutic proteins in children (median, 0.81). Similarly, but specific to mAbs, a recent review also noted allometric exponents between 0.7 and 0.9 in 20 popPK models for children, although the authors cautioned that their results may have been confounded by poor sampling schemes 45 . The allometric exponent of 0.8 for volume of distribution has physiologic relevance, as it reflects that young children have higher extracellular water fractions than adults 57,58 .…”

“…One case study, for example, describes how allometry was used to guide the first‐in‐pediatric dose for domagrozumab in children 6 to 10 years of age 6 . Several objective evaluations of conventional allometry for children >4 years of age suggest that predictions for therapeutic protein concentrations fell within a 1.5‐ to 2‐fold error in the majority of the model extrapolations 45,56 . However, there was considerable variability in accuracy when multiple adult popPK models were scaled for one drug (infliximab), with the poorest model making predictions within 2‐fold error for only 47% of the observed concentrations 56 .…”

Methods Used for Pediatric Dose Selection in Drug Development Programs Submitted to the US FDA 2012‐2020

“…Allometric scaling is an old but powerful tool for scaling doses for pediatric patients 17 . While early investigations in the pediatric population suggested that older pediatric populations were more appropriate for scaling doses from adults, 18 more recent evaluations have suggested that allometric scaling can be used for neonates and infants, 19–21 for obese pediatric patients, 22 and for therapeutic protein doses in pediatric patients 23,24 …”

Progress in Drug Development–Pediatric Dose Selection: Workshop Summary

“…Information on dosing in obese pediatric patients is not available in FDA‐approved labels, 42 and yet allometry may provide a method of estimating drug clearance in obesity 43 . Therapeutic monoclonal antibodies that are approved for pediatric use have widely divergent dosing recommendations, 44 but allometry has been suggested as being a reasonable approach for dosing in older children 45 . The use of allometry to predict DDI 46 and to predict drug clearance in extremely low‐birth‐weight infants 47 are additional applications that have been proposed for drug development.…”