title: Pharmacokinetics and Safety of Single Intravenous Doses of JNJ-54452840, an Anti-β1-Adrenergic Receptor Antibody Cyclopeptide, in Healthy Male Japanese and Caucasian Participants.
abstract: OBJECTIVE
  To evaluate the pharmacokinetics and safety of single intravenous doses of JNJ-54452840 infused over 1 minute in healthy male Japanese and Caucasian participants. JNJ-54452840 is a novel peptide for the treatment of chronic heart failure, with a proposed mechanism of action of binding interference and decreased production of anti-β1-adrenergic receptor (anti-β1-AR) antibodies, which stimulate the cardiac β1-AR.
  
  
  METHODS
  In this randomized, single-centre, double-blind, placebo-controlled, four-way crossover study, 32 male Japanese and Caucasian participants (16 in each group) received single intravenous doses of JNJ-54452840 20, 80 and 240 mg, and placebo, each separated by a ≥7-day washout period. Pharmacokinetics and safety were assessed predose and at specified timepoints for 24 h. Anti-β1-AR antibodies were monitored.
  
  
  RESULTS
  The mean JNJ-54452840 maximum observed plasma concentration (C max) and area under the concentration-time curve from time zero to infinity with extrapolation of the terminal phase (AUCinf) values increased linearly with dose, with rapid elimination in both groups. Dose proportionality criteria were not met between the 20 and 240 mg doses for both study cohorts. The median time to reach C max (T max) ranged from 1 to 5 minutes. The mean total systemic clearance after intravenous administration (CL), volume of distribution at steady state (V ss), mean residence time (MRT) and terminal half-life (T ½) values were similar for both groups. The mean T ½ values ranged from 5.9 to 26.1 min in a dose-dependent manner. The overall prevalence of antibodies was 9.4 % at baseline; antibodies not present at baseline developed in five Caucasians (15.6 %) but not in Japanese participants. One participant in each group experienced a serious thromboembolic event (pulmonary embolism, ischaemic stroke).
  
  
  CONCLUSIONS
  JNJ-54452840 demonstrated similar pharmacokinetics in both groups. JNJ-54452840 was possibly immunogenic, and two participants reported thromboembolic serious adverse events. The relationship between these events and antibody formation is not known.
authors.affiliation: Biologics Clinical Pharmacology, Janssen Research & Development, LLC, 1400 McKean Road, PO Box 776, Spring House, PA, 19477, USA.
authors.forename: Ivo P
authors.initials: IP
authors.lastname: Nnane
authors.affiliation: Janssen Research & Development, LLC, Raritan, NJ, USA.
authors.forename: Alexei H
authors.initials: AH
authors.lastname: Plotnikov
authors.affiliation: Cardiovascular, Metabolic, Medical Office, Janssen Research & Development, LLC, 1400 McKean Road, PO Box 776, Spring House, PA, 19477, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Peters
authors.affiliation: Janssen Research & Development, LLC, Raritan, NJ, USA.
authors.forename: Maureen
authors.initials: M
authors.lastname: Johnson
authors.affiliation: Janssen Research & Development, LLC, Raritan, NJ, USA.
authors.forename: Clare
authors.initials: C
authors.lastname: Kojak
authors.affiliation: WCCT Global, LLC, Cypress, CA, USA.
authors.forename: Apinya
authors.initials: A
authors.lastname: Vutikullird
authors.affiliation: Janssen Research & Development, LLC, Raritan, NJ, USA.
authors.forename: Jay
authors.initials: J
authors.lastname: Ariyawansa
authors.affiliation: Janssen Research & Development, Beerse, Belgium.
authors.forename: Ronald
authors.initials: R
authors.lastname: De Vries
authors.affiliation: Biologics Clinical Pharmacology, Janssen Research & Development, LLC, 1400 McKean Road, PO Box 776, Spring House, PA, 19477, USA. bdavies5@its.jnj.com.
authors.forename: Brian E
authors.initials: BE
authors.lastname: Davies
mesh_terms: D061605:Administration, Intravenous; D000328:Adult; D000906:Antibodies / Q000097:blood; D044466:Asian People; D018592:Cross-Over Studies; D004311:Double-Blind Method; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D018342:Receptors, Adrenergic, beta-1 / Q000276:immunology; D044465:White People; D055815:Young Adult
chemical_list: D000906:Antibodies; C000611983:JNJ-54452840; D010456:Peptides, Cyclic; D018342:Receptors, Adrenergic, beta-1