title: Flip-flop kinetics of ropivacaine during continuous epidural infusion influences its accumulation rate.
abstract: 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.
  
  
  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(48 h)) 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.
authors.affiliation: Laboratory of Clinical Pharmacokinetics, Foundation IRCCS Policlinico San Matteo, P.le Golgi, 2, I-27100, Pavia, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Cusato
authors.affiliation: Department of Anesthesia and Intensive Care I and Pain Therapy, Foundation IRCCS Policlinico San Matteo, Pavia, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Allegri
authors.affiliation: Department of Anesthesia and Intensive Care I and Pain Therapy, Foundation IRCCS Policlinico San Matteo, Pavia, Italy.|Department of Surgical Science, Pavia University, Pavia, Italy.
authors.forename: Tekla
authors.initials: T
authors.lastname: Niebel
authors.affiliation: First Service of Anesthesia and Intensive Care, San Gerardo Hospital Monza (MI) - Department of Experimental Medicine, Milan-Bicocca University, Milan, Italy.
authors.forename: Pablo
authors.initials: P
authors.lastname: Ingelmo
authors.affiliation: Laboratory of Clinical Pharmacokinetics, Foundation IRCCS Policlinico San Matteo, P.le Golgi, 2, I-27100, Pavia, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Broglia
authors.affiliation: Department of Anesthesia and Intensive Care I and Pain Therapy, Foundation IRCCS Policlinico San Matteo, Pavia, Italy.|Department of Resuscitation and Organ Transplantation Surgery Sciences, Section of Anesthesiology and Resuscitation, University of Pavia, Pavia, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Braschi
authors.affiliation: Laboratory of Clinical Pharmacokinetics, Foundation IRCCS Policlinico San Matteo, P.le Golgi, 2, I-27100, Pavia, Italy. regazzim@smatteo.pv.it.
authors.forename: Mario
authors.initials: M
authors.lastname: Regazzi
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000577:Amides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000779:Anesthetics, Local / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D005260:Female; D006207:Half-Life; D006801:Humans; D007268:Injections, Epidural; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D000077212:Ropivacaine
chemical_list: D000577:Amides; D000779:Anesthetics, Local; D000077212:Ropivacaine