Population Pharmacokinetic-Pharmacodynamic Modeling of Ropivacaine in Spinal Anesthesia

Background Ropivacaine is frequently used in spinal anesthesia but the relationship between plasma concentrations and sensory block level remains unknown. Objective The aim of this study was to assess the relationship between plasma ropivacaine concentrations and effects during spinal anesthesia. Methods Sixty patients aged between 18 and 82 years were included in this study after providing written informed consent. Patients were randomly assigned to receive intrathecal administration of ropivacaine 15, 20 or 25 mg. Blood samples were drawn to determine ropivacaine concentrations, and sensory blockade was assessed using pinprick testing. Ropivacaine plasma concentrations and sensory block level were analyzed using a nonlinear mixed-effects modeling approach with Monolix 4.2.2. Uncertainty of parameters was estimated by bootstrapping. Results Overall, 216 plasma ropivacaine values and 407 sensory block-related data were available for pharmacokinetic-pharmacodynamic (PK-PD) model evaluation. A two-compartment open model connected to a spinal compartment was selected to describe the PKs of ropivacaine. Sensory block modeling was performed using a sigmoid E max model assuming an equilibration delay between the amount in the depot or spinal compartment and at the effect site. Using multiple linear regression analysis, we were able to demonstrate the importance of dose, age and weight as major predictors of sensory block-level kinetics. Conclusions This first population PK-PD model for ropivacaine in spinal anesthesia confirms the relationship between plasma ropivacaine concentrations and effect. We also clarify the relationship between the spread of sensory block level and dose, age and, for the first time, weight. Study Registration This study was approved by the Reims University Hospital Ethics Committee (protocol: PHRC-2005; registered at Agence Nationale de Sécurité du Médicament et des Produits de Santé ANSM: D60890). This was an open, prospective, monocentric study conducted in the University Hospital of Reims (France).