Flip-flop kinetics of ropivacaine during continuous epidural infusion influences its accumulation rate

Background: Ropivacaine has an optimal toxicity profile for epidural anesthesia in adults, but there are currently no studies concerning its pharmacokinetics during continuous infusion. The primary objective of this study was to evaluate the pharmacokinetics and safety of ropivacaine in adults during a 48-h continuous epidural infusion. Materials and methods: We enrolled 43 adults (ASA I-II) scheduled for major abdominal or urologic surgery with postoperative continuous epidural analgesia with ropivacaine 0.2% (5 mL/h) and sufentanil 0.75 μg/mL for 48 h. Ropivacaine blood samples were collected during continuous epidural infusion before the bolus and 3, 6, 12, 24, 48, 54, 60 h after the bolus; plasma concentrations were measured on HPLC-UV. The concentration-time relationship of ropivacaine levels was analyzed using a population pharmacokinetic method based on a mixed-effect-model approach (P-PHARM software). Results: Mean plasma concentration of ropivacaine at the end of epidural infusion (C_48h) was 1.69 μg/mL (0.21-3.8 μg/mL). Mean (range) C_max was 1.82 μg/mL (0.61-4.0 μg/mL); the area under the plasma concentration curve, AUC _(0-60), was 67.48∈±∈30.60 μg•h/mL. Total plasma ropivacaine concentrations fell mainly within (84%) or below (12%) the range reported to be safe in adults (1.0-3.0 μg/mL). Only two patients (5%) reached ropivacaine plasma levels higher than 3 μg/mL, namely 3.8 and 4.0 μg/mL at 48 and 54 h, respectively. Total ropivacaine concentrations up to 4.0 μg/mL were tolerated during long-term epidural ropivacaine infusion. Mean clearance for total ropivacaine was 5.33 L/h. Age was the only covariable to significantly reduce clearance variability: CL (L/h)∈=∈15.04∈-∈0. 148∈×∈age (years). The volume of distribution (Vd) was 92.15 L. The infusion dosing period half-life (t_1/2,DP∈=∈0. 693∈×∈Vd/CL) was 10.8 h. Conclusions: Exposure to ropivacaine during epidural infusion is highly variable. The apparent infusion dosing half-life t_1/2,DP is the most appropriate parameter to predict drug accumulation upon epidural infusion since it appears to better reflect the interplay interference between volume distribution and absorption rate during the accumulation phase. Prediction of ropivacaine accumulation can be improved by considering patient age.