Robert A. Bellantone

To develop and evaluate a PK/PD model that mechanistically describes the competitive interaction between intravenous (IV) fentanyl and intranasal (IN) naloxone at brain μ-opioid receptors (MORs) and simulates reversal of respiratory depression. A compartmental PK/PD model incorporating central, peripheral, brain and nasal compartments was parameterized sequentially using human plasma concentration, PET MOR-occupancy, and controlled isohypercapnic ventilation data, supplemented by literature-derived constraints where direct estimation was not supported. Fentanyl-MOR binding and release were modeled kinetically, whereas naloxone binding was represented by a rapid-equilibrium relationship. A 1,000-member virtual ensemble was used to propagate parameter uncertainty, and Sobol global sensitivity analysis evaluated determinants of ventilation recovery. The model reproduced the component clinical datasets used for calibration and simulated rapid ventilation recovery after IN naloxone. Simulations indicated that the apparent nasal-to-brain pathway was an important contributor to early rescue, whereas the systemic pathway contributed minimally during the first minutes after dosing. In nominal simulations, recovery began when the free brain naloxone:fentanyl molar concentration ratio reached approximately 0.063. Sobol analysis showed that fentanyl MOR affinity and brain disposition dominated very early recovery, while naloxone MOR affinity and apparent nasal-to-brain allocation became increasingly influential over the subsequent 10-15 minutes. This PK/PD framework links drug disposition, receptor competition and ventilation response in a unified model. It provides a mechanistic platform for evaluating naloxone dose, repeat-dosing, and formulation strategies while explicitly accounting for parameter uncertainty and the limitations of controlled isohypercapnic calibration data.