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

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 93 h after a 100 mg 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 +/- A 4.8 min) followed by a much slower phase (half-life of 3.9 +/- A 0.65 h). 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 +/- A 11.5 L, IIV = 26 %) was influenced by body weight (Delta 1.49 % per kg change) whereas the absorption rate constant (slower phase) of ropivacaine was affected by age (Delta 2.25 % per year change). No covariate effects were identified for the apparent clearance of the drug (CL/F =10.8 +/- A 1.0 L/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.