Open AccessReceiver Operating Characteristic Analysis and Clinical Trial Simulation to Inform Dose Titration Decisions
Author(s) -
Clements John David,
Perez Ruixo Juan Jose,
Gibbs John P.,
Doshi Sameer,
Perez Ruixo Carlos,
Melhem Murad
Publication year - 2018
Publication title -
cpt: pharmacometrics and systems pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.53
H-Index - 37
ISSN - 2163-8306
DOI - 10.1002/psp4.12354
Subject(s) - receiver operating characteristic , titration , pharmacodynamics , clinical trial , pharmacokinetics , cutoff , residual , toxicity , medicine , statistics , computer science , pharmacology , mathematics , chemistry , inorganic chemistry , physics , algorithm , quantum mechanics
Optimal dose selection in clinical trials is problematic when efficacious and toxic concentrations are close. A novel quantitative approach follows for optimizing dose titration in clinical trials. A system of pharmacokinetics ( PK ), pharmacodynamics, efficacy, and toxicity was simulated for scenarios characterized by varying degrees of different types of variability. Receiver operating characteristic ( ROC ) and clinical trial simulation ( CTS ) were used to optimize drug titration by maximizing efficacy/safety. The scenarios included were a low‐variability base scenario, and high residual (20%), interoccasion (20%), interindividual (40%), and residual plus interindividual variability scenarios, and finally a shallow toxicity slope scenario. The percentage of subjects having toxicity was reduced by 87.4% to 93.5%, and those having efficacy was increased by 52.7% to 243%. Interindividual PK variability may have less impact on optimal cutoff values than other sources of variability. ROC / CTS methods for optimizing dose titration offer an individualized approach that leverages exposure‐response relationships.