AbstractBackgroundThe capsaicin and heat responsive ion channel TRPV1 is expressed on trigeminal nociceptive neurons and has been implicated in the pathophysiology of migraine attacks. Here we investigate the efficacy of two TRPV1 channel antagonists in blocking trigeminal activation using two in vivo models of migraine.MethodsMale Sprague–Dawley rats were used to study the effects of the TRPV1 antagonists JNJ-38893777 and JNJ-17203212 on trigeminal activation. Expression of the immediate early gene c-fos was measured following intracisternal application of inflammatory soup. In a second model, CGRP release into the external jugular vein was determined following injection of capsaicin into the carotid artery.ResultsInflammatory up-regulation of c-fos in the trigeminal brain stem complex was dose-dependently and significantly reduced by both TRPV1 antagonists. Capsaicin-induced CGRP release was attenuated by JNJ-38893777 only in higher dosage. JNJ-17203212 was effective in all doses and fully abolished CGRP release in a time and dose-dependent manner.ConclusionOur results describe two TRPV1 antagonists that are effective in two in vivo models of migraine. These results suggest that TRPV1 may play a role in the pathophysiological mechanisms, which are relevant to migraine.

01 Jun 2015·Clinical Drug InvestigationQ4 · MEDICINE

Safety, Tolerability and Pharmacokinetic and Pharmacodynamic Learnings from a Double-Blind, Randomized, Placebo-Controlled, Sequential Group First-in-Human Study of the TRPV1 Antagonist, JNJ-38893777, in Healthy Men

Q4 · MEDICINE

Article

Author: Marc De Meulder ; Kevin Shalayda ; Arthur Mayorga ; Gary Romano ; Chen Jun ; Prasarn Manitpisitkul ; John A. Moyer

BACKGROUND AND OBJECTIVENociceptive and neuropathic pain, one of common reasons of disability and loss of quality life, are often undertreated due to safety concerns with current therapies. This study assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of JNJ-38893777, a potent and selective transient receptor potential vanilloid 1 (TRPV1) channel antagonist in healthy men.METHODSIn a single-center, double-blind, placebo-controlled, sequential group, single-ascending-dose phase 1 study, 80 healthy men (18-45 years old; body mass index 18.5 to <30 kg/m(2)), randomized to two groups, received either JNJ-38893777 (n = 6) or placebo (n = 2) in a dose-escalation manner. The study was designed in two parts: Part 1, an early tablet formulation was administered under fasting conditions at 5, 15, 45, 125, 250, or 500 mg; Part 2, a new tablet formulation was administered in a fasting state (250 mg) and a high-fat fed state (250 mg, 375 mg, or 500 mg). Serial plasma and urine samples (collected over 120 h post-dose) were analyzed using LC-MS/MS for pharmacokinetic evaluations.RESULTSJNJ-38893777 concentrations peaked from 3.0 to 5.5 h (median) post-administration, and then declined multi-exponentially with a prolonged terminal phase. Renal clearance was negligible. Maximum concentration (C max) and area under the concentration-time curve from time zero to infinity (AUC∞) of the early formulation increased with increasing doses but less than dose-proportionally over 5-500 mg (fasted) doses. The new tablet formulation showed no improvements in the fasting state but showed an 11- to 22-fold increase in JNJ-38893777 exposure; interindividual variability reduced from 73-85% to 23-24%, and a significant increase (P < 0.05) in heat pain detection threshold (~3 °C) was observed in the fed state. Mild to moderate adverse events were observed, with no evidence of exposure dependence up to 500 mg (fed). Concentration-related increases in body temperature or changes in Fridericia-corrected QT interval (QTcF) were not observed.CONCLUSIONJNJ-38893777 was tolerated at single doses up to 500 mg (fed) and is suitable for further clinical development.

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Indication	Highest Phase	Country/Location	Organization	Date
Pain	Phase 1	-	Janssen Global Services LLC	-
Pain	Phase 1	US	Janssen Research & Development LLC	-

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