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

Abstract

In order to conduct a pediatric clinical trial, it is important to optimize pediatric dose as accurately as possible. In this study, a simple weight-based method known as ‘Salisbury Rule’ was used to predict pediatric dose for therapeutic proteins and was then compared with the observed pediatric dose. The observed dose was obtained mainly from the FDA package insert and if dosing information was not available from the FDA package insert then the observed dose was based on the dose given to an age group in a particular study. It was noted that the recommended doses of most of the therapeutic proteins were extrapolated to pediatrics from adult dose based on per kilogram (kg) body weight basis. Since it is widely believed that pediatric dose should be selected based on the pediatric clearance (CL), a CL based pediatric dose was projected from the following equation: Dose in children = Adult dose × (Observed CL in children/Observed adult CL). In this study, this dose was also considered observed pediatric dose for comparison. A ±30% prediction error (predicted vs. observed) was considered acceptable. There were 21 monoclonal antibodies, 5 polyclonal antibodies in children ≥ 2 years of age, 4 polyclonal antibodies in preterm and term neonates, and 11 therapeutic proteins (non-antibodies) in the study. In children < 30 kg body weight, the predicted doses were within 0.5–1.5-fold prediction error for 87% (monoclonal antibody), 100% (polyclonal antibody), and 92% (non-antibodies) observations. In children > 30 kg body weight, the predicted doses were within 0.5–1.5-fold prediction error for 96% (monoclonal antibody), 100% (polyclonal antibody), and 100% (non-antibodies) observations. The Salisbury Rule mimics more to CL-based dose rather than per kg body weight-based extrapolated dose from adults. The Salisbury Rule for the pediatric dose prediction can be used to select first-in-children dose in pediatric clinical trials and may be in clinical settings.