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Pharmacokinetics and Safety of Single Intravenous Doses of JNJ-54452840, an Anti-β1-Adrenergic Receptor Antibody Cyclopeptide, in Healthy Male Japanese and Caucasian Participants

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Abstract

Aim

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).

Conclusion

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.

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Acknowledgments

This study was supported by Janssen Research & Development, LLC. The sponsor also provided support for manuscript development. Ivo Nnane, Alexei Plotnikov, Gary Peters, Maureen Johnson, Clare Kojak, Jay Ariyawansa, Ronald De Vries and Brian E. Davies are employees of Janssen Research & Development, LLC, and own stock/stock options in the company. Apinya Vutikullird is an employee of WCCT Global, LLC, was the study principal investigator and declares no conflict of interest.

All authors met the International Committee of Medical Journal Editors (ICMJE) criteria for authorship, and all those who fulfilled those criteria are listed as authors. All authors had access to the study data, provided direction and comments on the manuscript, made the final decision about where to publish these data, and approved the final draft and submission to this journal. The authors acknowledge Bradford Challis (Janssen Research & Development, LLC) for assistance in preparation and editorial support of the manuscript.

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Authors and Affiliations

  1. Biologics Clinical Pharmacology, Janssen Research & Development, LLC, 1400 McKean Road, PO Box 776, Spring House, PA, 19477, USA

    Ivo P. Nnane & Brian E. Davies

  2. Janssen Research & Development, LLC, Raritan, NJ, USA

    Alexei H. Plotnikov, Maureen Johnson, Clare Kojak & Jay Ariyawansa

  3. Cardiovascular, Metabolic, Medical Office, Janssen Research & Development, LLC, 1400 McKean Road, PO Box 776, Spring House, PA, 19477, USA

    Gary Peters

  4. WCCT Global, LLC, Cypress, CA, USA

    Apinya Vutikullird

  5. Janssen Research & Development, Beerse, Belgium

    Ronald De Vries

Authors
  1. Ivo P. Nnane
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  2. Alexei H. Plotnikov
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  3. Gary Peters
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  6. Apinya Vutikullird
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  8. Ronald De Vries
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  9. Brian E. Davies
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Corresponding author

Correspondence to Brian E. Davies.

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Nnane, I.P., Plotnikov, A.H., Peters, G. et al. Pharmacokinetics and Safety of Single Intravenous Doses of JNJ-54452840, an Anti-β1-Adrenergic Receptor Antibody Cyclopeptide, in Healthy Male Japanese and Caucasian Participants. Clin Pharmacokinet 55, 225–236 (2016). https://doi.org/10.1007/s40262-015-0309-8

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  • DOI: https://doi.org/10.1007/s40262-015-0309-8

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