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 ± 4.8 min) followed by a much slower phase (half-life of 3.9 ± 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 ± 11.5 L, 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 ± 1.0 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.
Faculty of Pharmacy, Université de Montréal, P.O. 6128, Succursale Centre-Ville, Montreal, QC, H3C 3J7, Canada.
François
F
Gaudreault
Pierre
P
Drolet
Michel
M
Fallaha
France
F
Varin
D000042:Absorption; D000368:Aged; D000577:Amides / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D000779:Anesthetics, Local / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001835:Body Weight; D005260:Female; D005267:Femoral Nerve / Q000187:drug effects*; D006801:Humans; D007717:Knee / Q000601:surgery*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009407:Nerve Block / Q000379:methods*; D011184:Postoperative Period; D000077212:Ropivacaine
D000577:Amides; D000779:Anesthetics, Local; D000077212:Ropivacaine