Model‐based approach for methoxy polyethylene glycol‐epoetin beta drug development in paediatric patients with anaemia of chronic kidney disease

Abstract

Aims Methoxy polyethylene glycol‐epoetin beta (continuous erythropoietin receptor activator, C.E.R.A.) is used for the treatment of anaemia in adults with chronic kidney disease (CKD). Patients treated with shorter‐acting erythropoiesis‐stimulating agents up to three times weekly can be switched to once‐monthly C.E.R.A.. Doses can be adjusted on a monthly basis based on haemoglobin (Hb) levels during the preceding period. A model‐based approach was applied to optimise C.E.R.A. development, more specifically the confirmatory trial of the paediatric plan. Methods Pharmacokinetic and pharmacodynamic data from a phase II paediatric study and phase II and III adult studies were analysed together using modelling and simulation to determine the pharmacokinetic/pharmacodynamic characteristics of C.E.R.A. in a broad population. Model‐based simulations of C.E.R.A. treatment outcomes in paediatric patients were performed, notably when administered subcutaneously and compared to clinical and real‐world data. Results Age and body weight explained differences in pharmacokinetics, while the pharmacodynamic characteristics of C.E.R.A. were similar between adult and paediatric populations. Simulated Hb levels (mean and 95% prediction interval 10.9 [10.6, 11.2] g dL−1) and C.E.R.A. doses (median and 95% prediction interval 105 [72, 159] μg) 20 weeks after switching to subcutaneous C.E.R.A. were confirmed by observed real‐world data from International Pediatric Dialysis Network registries (mean Hb was 10.8 g dL−1 and median C.E.R.A. dose was 100 μg). Conclusions These analyses have facilitated optimisation of the C.E.R.A. development programme in paediatric patients with anaemia of CKD to provide this patient population with faster access to the drug while avoiding unnecessary clinical trial exposure and related monitoring burden in children.

Clinical Pharmacology Applications of Real‐World Data and Real‐World Evidence in Drug Development and Approval–An Industry Perspective

“…Chanu et al 32 used RWD/RWE to supplement modeling based on RCTs to optimize pediatric development plan and the confirmatory trial design for Continuous Erythropoietin Receptor Activator (C.E.R.A.). The initial pediatric plan was designed as a phase II dose-finding study using C.E.R.A.…”

Use of real-world data for drug development

“…P. Chanu и соавт. (2020) использовали RWD/RWE в качестве дополнения к моделированию, основанному на рандомизированных клинических исследованиях, для оптимизации плана педиатрической разработки и дизайна исследования активатора рецепторов эритропоэтина длительного действия [17]. Первоначальный педиатрический план предполагал проведение исследования фазы II по подбору дозы внутривенного активатора рецепторов эритропоэтина длительного действия с последующим изучением как внутривенного, так и подкожного путей введения по сравнению с группой сравнения.…”

Integrating real‐world data to accelerate and guide drug development: A clinical pharmacology perspective

“…In another example, a pediatric study for continuous erythropoietin receptor activators (CERA) in patients with anemia of chronic kidney disease, RWD on CERA doses and hemoglobin levels obtained from the International Pediatric Dialysis Network registries was leveraged to validate PK/PD model simulations and supported a subcutaneous starting dose in pediatric patients similar to the intravenous dose. 10 A model‐based approach confirmed by RWD helped to optimize a pediatric drug development plan approved by health authorities, with reduced drug exposure and treatment burden for children. RWE has become increasingly accepted to inform optimal dosing regimens for clinical practice, and, in some cases, to provide complementary evidence to support regulatory decisions.…”