Yoann Cazaubon1, Cédric Mauprivez2, Catherine Feliu1, Laurent Binet3, Olivier Oget3, Claire Gozalo3, Zoubir Djerada4. 1. Department of Pharmacology and Toxicology, Pharmacology and Toxicology Laboratory, Reims University Hospital, 45 rue Cognacq Jay, Reims 51092, France; Department of Pharmacology, EA3801, SFR CAP-santé, URCA Reims University, Reims 51100, France. 2. Department of Odontology, Reims University Hospitals, 45 rue Cognacq Jay, Reims 51092, France; EA4691, Biomatériaux et Inflammation en Site Osseux, URCA Reims University, 51 rue Cognacq Jay, Reims 51092, France. 3. Department of Pharmacology and Toxicology, Pharmacology and Toxicology Laboratory, Reims University Hospital, 45 rue Cognacq Jay, Reims 51092, France. 4. Department of Pharmacology and Toxicology, Pharmacology and Toxicology Laboratory, Reims University Hospital, 45 rue Cognacq Jay, Reims 51092, France; Department of Pharmacology, EA3801, SFR CAP-santé, URCA Reims University, Reims 51100, France. Electronic address: zoubir.djerada@univ-reims.fr.
Abstract
BACKGROUND AND OBJECTIVES: Articaine is more and more used in third molar surgery under local anesthesia (LA). The objectives of this analysis were to characterize the pharmacokinetics of articaine for this type of surgery and to simulate dosing regimens. METHODS: Non-linear mixed-effects modeling conducted in Monolix 4.4.0 was used to describe articaine plasma concentration-time data from 20 patients. Monte Carlo simulations were then performed to evaluate the probability of cardiotoxic target attainment (PCTA) of various dosage regimens. RESULTS: Articaine concentration data were best described by a linear one-compartment model, with an additional depot compartment for submucosal route with a zero-order transfer to central compartment. Age and gender were found to influence duration transfer (Tk0) and elimination rate constant (Ke), respectively. Simulated maximum recommended dose regimen (7mg/kg) had a PCTA of 0%. Simulated higher doses of 10mg/kg and 15mg/kg had a PCTA of 0% and about 1-4%, respectively. CONCLUSIONS: The model adequately described the articaine pharmacokinetics. This is the first PK model qualified for articaine administered by submucosal route. The simulations suggest that maximum recommended dose regimen is safe concerning the cardiotoxicity in healthy patients.
BACKGROUND AND OBJECTIVES:Articaine is more and more used in third molar surgery under local anesthesia (LA). The objectives of this analysis were to characterize the pharmacokinetics of articaine for this type of surgery and to simulate dosing regimens. METHODS: Non-linear mixed-effects modeling conducted in Monolix 4.4.0 was used to describe articaine plasma concentration-time data from 20 patients. Monte Carlo simulations were then performed to evaluate the probability of cardiotoxic target attainment (PCTA) of various dosage regimens. RESULTS:Articaine concentration data were best described by a linear one-compartment model, with an additional depot compartment for submucosal route with a zero-order transfer to central compartment. Age and gender were found to influence duration transfer (Tk0) and elimination rate constant (Ke), respectively. Simulated maximum recommended dose regimen (7mg/kg) had a PCTA of 0%. Simulated higher doses of 10mg/kg and 15mg/kg had a PCTA of 0% and about 1-4%, respectively. CONCLUSIONS: The model adequately described the articaine pharmacokinetics. This is the first PK model qualified for articaine administered by submucosal route. The simulations suggest that maximum recommended dose regimen is safe concerning the cardiotoxicity in healthy patients.