Pharmacodynamic Evaluation of Sustained Drug Release Systems

Abstract

Sustained drug release systems -- encompassing depot injections, transdermal patches, osmotic pumps, implantable reservoirs, and nanoparticle carriers -- maintain therapeutic plasma concentrations over days to months from a single administration, yet pharmacodynamic (PD) evaluation of these systems remains anchored to methodologies developed for immediate-release dosage forms that poorly capture the time-dependent, concentration-plateau pharmacological effects characteristic of sustained delivery. This study presents the Sustained Release Pharmacodynamic Assessment Framework (SRPDAF), evaluating five PD evaluation approaches -- traditional Emax modelling, mechanism-based PK/PD modelling, time-to-event analysis, longitudinal biomarker trajectory modelling, and model-informed precision dosing -- across four sustained release platforms: PLGA microsphere depots, transdermal reservoir patches, osmotic controlled-release tablets, and lipid nanoparticle carriers. Our Sustained Release PD Evaluation Score (SRPDES) integrates PD model fit, dose-response characterisation accuracy, therapeutic window maintenance prediction, inter-subject variability explanation, and clinical decision utility. Mechanism-based PK/PD modelling achieved the highest SRPDES (0.926) through semi-mechanistic models incorporating receptor binding kinetics, signal transduction cascades, and disease progression that captured the delayed and prolonged PD effects of sustained release formulations with prediction error below 8%, while longitudinal biomarker modelling achieved the highest inter-subject variability explanation (R-squared = 0.86) through mixed-effects models that partition formulation, patient, and disease contributions to PD response variability.