• Dymphy R Huntjens, Lia C Liefaard, Partha Nandy, Henk-Jan Drenth, and An Vermeulen.
• Clinical Pharmacology and Pharmacometrics, Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340, Beerse, Belgium. dhuntjens@its.jnj.com.
• Clin Drug Investig. 2016 Mar 1; 36 (3): 213-23.

Background And ObjectiveTapentadol 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.MethodsData 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.ResultsThe 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.ConclusionsA 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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