Pharmacokinetic Analysis of Capsaicin After Topical Administration of a High-concentration Capsaicin Patch to Patients With Peripheral Neuropathic Pain

Capsaicin, a pungent compound in chili peppers, is a highly selective agonist for the transient receptor potential vanilloid 1 receptor expressed in nociceptive sensory nerves. A high-concentration (640 μg/cm2) capsaicin patch, designated NGX-4010, is in clinical evaluation for the management of peripheral neuropathic pain. To determine systemic capsaicin exposure after single 60- or 90-minute NGX-4010 […]

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Inactivation of CYP2D6 by Methylenedioxymethamphetamine in Different Recombinant Expression Systems

Recombinantly expressed CYP450 systems (rCYPs) are often used to screen for irreversible/quasi-irreversible enzyme inhibitors during drug development. The concentration- and time-dependent inactivation of CYP2D6 by methylenedioxymethamphetamine (MDMA) was compared in three different rCYP2D6 systems (yeast microsomes, Supersomes™ and Bactosomes™) under the conditions of the most commonly used protocols in assessing mechanism-based inactivation (MBI). MDMA (2-20µM) […]

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Predictive Population Pharmacokinetic/Pharmacodynamic Model for a Novel COX-2 Inhibitor

The objectives of these analyses were to (1) develop a population pharmacokinetic/pharmacodynamic model for a novel COX-2 inhibitor (CS-706) using data from primarily Caucasian subjects, (2) predict responses in subpopulations of interest (including Japanese subjects), and (3) correlate pharmacodynamic parameters to safety outcomes. The model was developed using data from 130 healthy adults following single […]

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Implications of Mechanism-based Inhibition of CYP2D6 for the Pharmacokinetics and Toxicity of MDMA

The aim of this study was to model the in vivo kinetic consequences of mechanism-based inhibition (MBI) of CYP2D6 by 3,4 methylenedioxymethamphetamine (MDMA, ecstasy). A model with physiologically-based components of drug metabolism was developed, taking account of change in the hepatic content of active CYP2D6 due to MBI by MDMA. Based on the in vitro […]

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Development of a Predictive Pharmacokinetic Model for a Novel Cyclooxygenase-2 Inhibitor

A predictive population pharmacokinetic model was developed for a novel cyclooxygenase-2 (COX-2) inhibitor CS-706, using data from 130 subjects in 3 phase 1 trials after single or multiple doses of CS-706 (2- to 800-mg doses daily, up to 14 days) and validated using sparse data from a separate study. A 2-compartment model described the data. […]

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Therapeutic Benefit of Eletriptan Compared to Sumatriptan for the Acute Relief of Migraine Pain—Results of a Model-based Meta-analysis that Accounts for Encapsulation

A novel model-based meta-analysis was used to quantify the dose-response relationship of sumatriptan and eletriptan for the proportion of patients that achieve migraine pain relief up to 4 h after treatment. The proportion of patients that became pain free was also evaluated. This analysis includes some unique features, allowing comparison of sumatriptan and eletriptan doses […]

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The Use of Clinical Trial Simulation to Support Dose Selection: Application to Development of a New Treatment for Chronic Neuropathic Pain

Pregabalin is being evaluated for the treatment of neuropathic pain. Two phase 2 studies were simulated to determine how precisely the dose that caused a one-point reduction in the pain score could be estimated. The likelihood of demonstrating at least a one-point change for each available dose strength was also calculated. A pharmacokinetic-pharmacodynamic (PK/PD) model […]

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