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Use of a physiologically based pharmacokinetic–pharmacodynamic model for initial dose prediction and escalation during a paediatric clinical trial
Author(s) -
Johnson Trevor N.,
Abduljalil Khaled,
Nicolas JeanMarie,
Muglia Pierandrea,
Chanteux Hugues,
Nicolai Johan,
Gillent Eric,
Cornet Miranda,
Sciberras David
Publication year - 2021
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.14528
Subject(s) - physiologically based pharmacokinetic modelling , dosing , pharmacokinetics , pharmacodynamics , medicine , pharmacology , percentile , clinical trial , population , statistics , mathematics , environmental health
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 5 th and 95 th 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.