title: Population Pharmacokinetic Modeling of Tapentadol Extended Release (ER) in Healthy Subjects and Patients with Moderate or Severe Chronic Pain.
abstract: OBJECTIVE
  Tapentadol is a centrally acting analgesic with two mechanisms of action, µ-opioid receptor agonism and noradrenaline reuptake inhibition. The objectives were to describe the pharmacokinetic behavior of tapentadol after oral administration of an extended-release (ER) formulation in healthy subjects and patients with chronic pain and to evaluate covariate effects.
  
  
  METHODS
  Data were obtained from 2276 subjects enrolled in five phase I and nine phase II and III studies. Nonlinear mixed-effects modeling was conducted using NONMEM.
  
  
  RESULTS
  The population estimates of apparent oral clearance and apparent central volume of distribution were 257 L/h and 1870 L, respectively. The complex absorption was described with a transit compartment for the first input. The second input function embraces saturable "binding" in the "absorption compartment", and a time-varying rate constant. Covariate evaluation demonstrated that age, aspartate aminotransferase, and health (painful diabetic neuropathy or not) had a statistically significant effect on apparent clearance, and bioavailability appeared to be dependent on body weight. The pcVPC indicted that the model provided a robust and unbiased fit to the data.
  
  
  CONCLUSIONS
  A one-compartment disposition model with two input functions and first-order elimination adequately described the pharmacokinetics of tapentadol ER. The dose-dependency in the pharmacokinetics of tapentadol ER is adequately described by the absorption model. None of the covariates were considered as clinically relevant factors that warrant dose adjustments.
authors.affiliation: Clinical Pharmacology and Pharmacometrics, Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340, Beerse, Belgium. dhuntjens@its.jnj.com.
authors.forename: Dymphy R
authors.initials: DR
authors.lastname: Huntjens
authors.affiliation: LAP&P Consultants BV, Leiden, The Netherlands.
authors.forename: Lia C
authors.initials: LC
authors.lastname: Liefaard
authors.affiliation: Clinical Pharmacology and Pharmacometrics, Janssen Research and Development, a Division of Janssen Pharmaceutica NV, Titusville, NY, USA.
authors.forename: Partha
authors.initials: P
authors.lastname: Nandy
authors.affiliation: LAP&P Consultants BV, Leiden, The Netherlands.
authors.forename: Henk-Jan
authors.initials: HJ
authors.lastname: Drenth
authors.affiliation: Clinical Pharmacology and Pharmacometrics, Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340, Beerse, Belgium.
authors.forename: An
authors.initials: A
authors.lastname: Vermeulen
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000700:Analgesics / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D059350:Chronic Pain / Q000188:drug therapy*; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D003692:Delayed-Action Preparations; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010636:Phenols / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000077432:Tapentadol; D055815:Young Adult
chemical_list: D000700:Analgesics; D003692:Delayed-Action Preparations; D010636:Phenols; D000077432:Tapentadol