J Crohns Colitis. 2022 May 8:jjac066. doi: 10.1093/ecco-jcc/jjac066. Online ahead of print.
ABSTRACT
BACKGROUND AND AIMS: The Phase 3 study ENVISION I demonstrated efficacy and safety of adalimumab in pediatric patients with moderate to severe ulcerative colitis. The protocol-specified high dose adalimumab regimen was numerically more efficacious than the standard dose regimen. The objective of this work was to bridge a fixed dosing regimen to the protocol-specified high induction/high maintenance body weight-based dosing regimen studied in ENVISION I, using a pharmacometrics modeling and simulation approach.
METHODS: A stepwise strategy was implemented, including developing an adalimumab pediatric population pharmacokinetic model; using this model to determine a fixed dosing regimen in pediatric ulcerative colitis patients that achieves similar concentrations to those observed in ENVISION I patients; determining adalimumab exposure-response relationship using population pharmacokinetic/pharmacodynamic model and data from ENVISION I; simulating clinical remission rate in pediatric ulcerative colitis patients using the Markov exposure-response model and the dosing regimen determined to provide similar efficacy to that observed in ENVISION I.
RESULTS: Both developed population pharmacokinetic and pharmacokinetic/pharmacodynamic models adequately described the observed data. Adalimumab exposure was identified as a significant predictor of clinical remission at Week 8 based on logistic regression (p <0.01). Simulated efficacy suggested that the fixed dosing regimen performs similarly to the more efficacious dosing regimen used in ENVISION I by providing comparable clinical remission per Partial Mayo Score response rates over time. No relationship between adalimumab exposure and adverse events was identified.
CONCLUSIONS: The population pharmacokinetic/pharmacodynamic model supports the appropriateness of the use of fixed dosing regimen in the pediatric ulcerative colitis population.
PMID:35526272 | DOI:10.1093/ecco-jcc/jjac066
