Details

Autor(en) / Beteiligte

• Nnane, Ivo P.
• Plotnikov, Alexei H.
• Peters, Gary
• Johnson, Maureen
• Kojak, Clare
• Vutikullird, Apinya
• Ariyawansa, Jay
• De Vries, Ronald
• Davies, Brian E.

Titel

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

Ist Teil von

• Clinical pharmacokinetics, 2016-02, Vol.55 (2), p.225-236

Ort / Verlag

Cham: Springer International Publishing

Erscheinungsjahr

2016

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 (AUC inf ) 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.