Population Pharmacokinetic Modeling of Tapentadol Extended Release (ER) in Healthy Subjects and Patients with Moderate or Severe Chronic Pain

Clinical Drug Investigation
Dymphy R HuntjensAn Vermeulen

Abstract

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. 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. 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. A one-compartment disposition model with two input func...Continue Reading

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Citations

Aug 19, 2016·European Journal of Drug Metabolism and Pharmacokinetics·Devender KodatiNarsimhareddy Yellu
Apr 25, 2017·Pain Management·Joseph V PergolizziJo Ann LeQuang
Jun 2, 2020·Biological & Pharmaceutical Bulletin·Masashi HommaKoichiro Atsuda
Mar 25, 2017·Pharmacological Reports : PR·Devender Kodati, Narsimhareddy Yellu
May 1, 2017·Pharmacological Reports : PR·Devender Kodati, Narsimhareddy Yellu

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