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

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.

Changes in GABAA receptor properties in amygdala kindled animals: in vivo studies using [11C]flumazenil and positron emission tomography.

PURPOSE: The purpose of the present investigation was to quantify alterations in GABA(A) receptor density in vivo in rats subjected to amygdala kindling. METHODS: The GABA(A) receptor density was quantified by conducting a [(11)C]flumazenil (FMZ) positron emission tomography (PET) study according to the full saturation method, in which each animal received a single injection of FMZ to fully saturate the GABA(A) receptors. Subsequently, the concentration-time curves of FMZ in blood [using high-pressure liquid chromatography with UV detector (HPLC-UV) or high-performance liquid chromatography coupled to tandem mass spectrometry (LC/MS/MS)] and brain (with PET-scanning) were analyzed by population modeling using a pharmacokinetic model, containing expressions to describe the time course of FMZ in blood and brain. RESULTS: The GABA(A) receptor density (B(max)) in kindled rats was decreased by 36% compared with controls. This is consistent with a reduction of 28% in electroencephalography (EEG) effect of midazolam in the same animal model, suggesting that a reduced number of GABA(A) receptors underlies the decreased efficacy of midazolam. Furthermore, receptor affinity (K(D)) was not changed, but the total volume of distribution in the brain (V(Br)), is increased to 178% of control after kindling, which might indicate an alteration in the transport of FMZ across the blood-brain barrier. CONCLUSIONS: Both the GABA(A) receptor density (B(max)), and possibly also the blood-brain barrier transport of FMZ (V(Br)) are altered after kindling. Furthermore, this study indicates the feasibility of conducting PET studies for quantifying moderate changes in GABA(A) receptor density in a rat model of epilepsy in vivo.

Decreased Efficacy of GABAA-receptor modulation by midazolam in the kainate model of temporal lobe epilepsy.

PURPOSE: The objective of this investigation was to characterize quantitatively the time-dependent changes in midazolam (MDL) efficacy in the silent period after induction of status epilepticus (SE) in rats. The changes in MDL efficacy were correlated to changes in ex vivo GABA(A)-receptor expression. METHODS: MDL efficacy was quantified by pharmacokinetic-pharmacodynamic (PK-PD) modeling by using the beta-frequency of the EEG as PD end point. Two PK-PD experiments were performed in each animal: the first experiment before and the second experiment at either day 4 or day 14 after SE. SE was induced by repetitive intraperitoneal injections with kainate. GABA(A)-receptor expression was determined by ex vivo autoradiography with [(3)H]flumazenil. RESULTS: The concentration versus EEG effect relation of midazolam was successfully described by the sigmoidal E(max) model. The maximal effect on the beta-frequency of the EEG (E(max)) was reduced to 51.6 +/- 35.6% and 25.8 +/- 33.7% of the original value at 4 and 14 days after induction of SE. The ex vivo study with [(3)H]flumazenil showed that the observed reductions in E(max) were paralleled by a reduction in GABA(A)-receptor density. CONCLUSIONS: The efficacy of MDL is decreased in the silent period after SE, which can be partly accounted for by a reduction in GABA(A)-receptor density.

Population pharmacokinetic analysis for simultaneous determination of B (max) and K (D) in vivo by positron emission tomography.

PURPOSE: Changes in GABA(A)-receptor density and affinity play an important role in many forms of epilepsy. A novel approach, using positron emission tomography (PET) and [C-11]flumazenil ([C-11]FMZ), was developed for simultaneous estimation of GABA(A)-receptor properties, characterized by B (max) and K (D). PROCEDURES: Following an injection of [C-11]FMZ (dose range: 1-2,000 mug) to 21 rats, concentration time curves of FMZ in brain (using PET) and blood (using HPLC-UV) were analyzed simultaneously using a population pharmacokinetic (PK) model, containing expressions to describe the time course of the plasma concentration (including distribution to the body), the brain distribution, and the specific binding within the brain. RESULTS: Application of this method in control rats resulted in estimates of B (max) and K (D) (14.5 +/- 3.7 ng/ml and 4.68 +/- 1.5 ng/ml, respectively). CONCLUSIONS: The proposed population PK model allowed for simultaneous estimation of B (max) and K (D) for a group of animals using single injection PET experiments per animal.