A population pharmacokinetic model for the complex systemic absorption of ropivacaine after femoral nerve block in patients undergoing knee surgery

Abstract

Because of its slow systemic absorption and flip-flop kinetics, ropivacaine's pharmacokinetics after a peripheral nerve block has never been thoroughly characterized. The purpose of this study was to develop a population pharmacokinetic model for ropivacaine after loco-regional administration and to identify patient characteristics that may influence the drug's absorption and disposition. Frequent plasma samples were taken up to 93h after a 100mg dose given as femoral block for postoperative analgesia in 15 orthopedic patients. Ropivacaine plasma concentration-time data were analyzed using a nonlinear mixed effects modeling method. A one-compartment model with parallel inverse Gaussian and time-dependent inputs best described ropivacaine plasma concentration-time curves. Ropivacaine systemic absorption was characterized by a rapid phase (mean absorption time of 25±4.8min) followed by a much slower phase (half-life of 3.9±0.65h). Interindividual variability (IIV) for these parameters, 58 and 9%, indicated that the initial absorption phase was more variable. The apparent volume of distribution (V/F=77.2±11.5L, IIV=26%) was influenced by body weight (Δ 1.49% per kg change) whereas the absorption rate constant (slower phase) of ropivacaine was affected by age (Δ 2.25% per year change). No covariate effects were identified for the apparent clearance of the drug (CL/F =10.8±1.0L/h, 34 IIV=34 %). These findings support our hypothesis that modeling a complex systemic absorption directly from plasma concentration-time curves exhibiting flip-flop kinetics is possible. Only the age-effect was considered as relevant for possible dosing adjustments.