Dymphy R Huntjens1, Lia C Liefaard2, Partha Nandy3, Henk-Jan Drenth2, An Vermeulen4. 1. Clinical Pharmacology and Pharmacometrics, Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340, Beerse, Belgium. dhuntjens@its.jnj.com. 2. LAP&P Consultants BV, Leiden, The Netherlands. 3. Clinical Pharmacology and Pharmacometrics, Janssen Research and Development, a Division of Janssen Pharmaceutica NV, Titusville, NY, USA. 4. Clinical Pharmacology and Pharmacometrics, Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340, Beerse, Belgium.
Abstract
BACKGROUND AND 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.
BACKGROUND AND 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.
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