Use of a physiologically based pharmacokinetic–pharmacodynamic model for initial dose prediction and escalation during a paediatric clinical trial

Abstract

Aims To build and verify a physiologically based pharmacokinetic (PBPK) model for radiprodil in adults and link this to a pharmacodynamic (PD) receptor occupancy (RO) model derived from in vitro data. Adapt this model to the paediatric population and predict starting and escalating doses in infants based on RO. Use the model to guide individualized dosing in a clinical trial in 2‐ to 14‐month‐old children with infantile spasms. Methods A PBPK model for radiprodil was developed to investigate the systemic exposure of the drug after oral administration in fasted and fed adults; this was then linked to RO via a PD model. The model was then expanded to include developmental physiology and ontogeny to predict escalating doses in infants that would result in a specific RO of 20, 40 and 60% based on average unbound concentration following a twice daily (b.i.d.) dosing regimen. Dose progression in the clinical trial was based on observed concentration–time data against PBPK predictions. Results For paediatric predictions, the elimination of radiprodil, based on experimental evidence, had no ontogeny. Predicted b.i.d. doses ranged from 0.04 mg/kg for 20% RO, 0.1 mg/kg for 40% RO to 0.21 mg/kg for 60% RO. For all infants recruited in the study, observed concentration–time data following the 0.04 mg/kg and subsequent doses were within the PBPK model predicted 5th and 95th percentiles. Conclusion To our knowledge, this is the first time a PBPK model linked to RO has been used to guide dose selection and escalation in the live phase of a paediatric clinical trial.

Physiologically Based Pharmacokinetic Models Are Effective Support for Pediatric Drug Development

“…For pediatric applications, it includes the in vitro data on age-related physiological and biochemical changes regarding the most likely ontogeny scenario. Overall, the application of PBPK to guide pediatric clinical trials is a personalized medical application ( 109 ). In all stages of pediatric drug development, PBPK models should be conducted routinely to help pediatric drug research and development ( 110 ).…”

A best practice framework for applying physiologically‐based pharmacokinetic modeling to pediatric drug development

“…Radiprodil has potential in the treatment of rare infantile spasms. A PBPK model was developed and verified in adults, 10 including a mechanistic absorption model to account for low solubility, the impact of fasted and fed luminal bile concentrations, and different formulations.…”

Physiologically Based Pharmacokinetic Modeling and Allometric Scaling in Pediatric Drug Development: Where Do We Draw the Line?

“…Radiprodil is a selective allosteric modulator of the NR2B N‐methyl‐D‐aspartate receptor that had potential in the treatment of infantile spasms, a rare disease. A PBPK model was developed and verified in adults, including a mechanistic absorption model to account for low solubility, and then expanded through understanding of the ontogeny of absorption and elimination to predict PK in the pediatric population that could benefit from radiprodil treatment, that is, from 2 to 14 months 27 . Initially, the ontogeny of the elimination pathways was unknown; this is fundamental for performing pediatric PBPK simulations.…”