title: 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.
abstract: OBJECTIVE
  Nociceptive 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.
  
  
  METHODS
  In 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.
  
  
  RESULTS
  JNJ-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.
  
  
  CONCLUSIONS
  JNJ-38893777 was tolerated at single doses up to 500 mg (fed) and is suitable for further clinical development.
authors.affiliation: Janssen Research & Development, LLC, 920 Rt 202, Raritan, 08869, NJ, USA, PManitpi@its.jnj.com.
authors.forename: Prasarn
authors.initials: P
authors.lastname: Manitpisitkul
authors.forename: Arthur
authors.initials: A
authors.lastname: Mayorga
authors.forename: Kevin
authors.initials: K
authors.lastname: Shalayda
authors.forename: Marc
authors.initials: M
authors.lastname: De Meulder
authors.forename: Gary
authors.initials: G
authors.lastname: Romano
authors.forename: Chen
authors.initials: C
authors.lastname: Jun
authors.forename: John A
authors.initials: JA
authors.lastname: Moyer
mesh_terms: D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D001381:Azepines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002626:Chemistry, Pharmaceutical; D004311:Double-Blind Method; D006801:Humans; D008297:Male; D008875:Middle Aged; D010880:Piperidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors*; D013607:Tablets; D053719:Tandem Mass Spectrometry; D055815:Young Adult
chemical_list: D001381:Azepines; C000609031:JNJ-38893777; D010880:Piperidines; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D013607:Tablets