title: Evaluation of the Population Pharmacokinetic Properties of Lidocaine and its Metabolites After Long-Term Multiple Applications of a Lidocaine Plaster in Post-Herpetic Neuralgia Patients.
abstract: OBJECTIVE
  Lidocaine 5% medicated plaster is the first lidocaine containing product for chronic use. As no previous investigations have been conducted to evaluate the population pharmacokinetics of long-term exposure to lidocaine 5% medicated plasters, further insights into the evaluation of the pharmacokinetic properties of lidocaine and its metabolites were needed for the assessment of its safety.
  
  
  METHODS
  The population pharmacokinetic properties of lidocaine and its metabolites were evaluated after multiple applications of lidocaine 5% medicated plasters based on data collected for up to 14.5 months from two phase III clinical trials (up to 2.5 months in the first trial, and up to 12 months in a follow-up trial) in post-herpetic neuralgia patients. Modeling was performed using nonlinear mixed effects as implemented in NONMEM®(nonlinear mixed-effect modeling) v.5. A stepwise forward inclusion and backward elimination procedure were used for covariate model building.
  
  
  RESULTS
  The model provides reliable estimates of the pharmacokinetic behavior of lidocaine after medicated plaster application. It was validated using simulations and showed adequate predictive properties. Apparent Clearance was estimated to be 48 L/h after application of two or fewer plasters, whereas its value increased to 67 L/h after application of three plasters. Model-based simulations predicted no accumulation of lidocaine or any of its metabolites after long-term exposure of three simultaneous plasters up to 1 year. The variability explained by adding covariates into the model for the long-term exposures of lidocaine following one plaster or three simultaneous plaster applications was found to be very small with respect to the overall between-subject variability.
  
  
  CONCLUSIONS
  In conclusion, exposure to lidocaine after the application of the lidocaine medicated plaster was found to be primarily affected by the number of plasters simultaneously applied, i.e., it increased with the number of applied patches, but less than proportionally. No clinically relevant effect of other covariates was found to affect the exposure to lidocaine or its metabolites. As no accumulation was predicted by the model, long-term exposure to lidocaine and its metabolites is not expected to lead to any safety concerns in post-herpetic neuralgia patients.
authors.affiliation: Global Innovation Data Sciences Pharmacometrics, Grünenthal GmbH, Zieglerstraße 6, 52099, Aachen, Germany.
authors.forename: Roberta
authors.initials: R
authors.lastname: Bursi
authors.affiliation: Global Innovation Data Sciences Pharmacometrics, Grünenthal GmbH, Zieglerstraße 6, 52099, Aachen, Germany.
authors.forename: Chiara
authors.initials: C
authors.lastname: Piana
authors.affiliation: BAST Inc Ltd., Loughborough, UK.
authors.forename: Joachim
authors.initials: J
authors.lastname: Grevel
authors.affiliation: Global Clinical Pharmacology, Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340, Beerse, Belgium.
authors.forename: Dymphy
authors.initials: D
authors.lastname: Huntjens
authors.affiliation: Global Innovation - Clinical Development, Grünenthal GmbH, Zieglerstraße 6, 52099, Aachen, Germany. irmgard.boesl@grunenthal.com.
authors.forename: Irmgard
authors.initials: I
authors.lastname: Boesl
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000779:Anesthetics, Local / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008012:Lidocaine / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D051474:Neuralgia, Postherpetic / Q000188:drug therapy* / Q000378:metabolism*
chemical_list: D000779:Anesthetics, Local; D008012:Lidocaine
keywords: Herpes Zoster; Lidocaine; Medicate Plaster; Objective Function Value; Visual Predictive Check