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Population Pharmacokinetic Modeling of JNJ-53718678, a Novel Fusion Inhibitor for the Treatment of Respiratory Syncytial Virus: Results from a Phase I, Double-Blind, Randomized, Placebo-Controlled First-in-Human Study in Healthy Adult Subjects

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Abstract

Background

JNJ-53718678 is a potent small-molecule inhibitor of the F-glycoprotein-mediated complex membrane fusion process of the respiratory syncytial virus. Here, we report the pharmacokinetics, the population pharmacokinetic modeling, and the safety and tolerability of JNJ-53718678 from the first-in-human, double-blind, randomized, placebo-controlled phase I study.

Methods

Healthy subjects were randomized (6:3) into five single-dose groups (25–1000 mg) or three multiple-dose groups [250 mg every 24 h (q24h), 500 mg q24h, 250 mg every 12 h; fed conditions for 8 days] to receive JNJ-53718678 or placebo. Blood and urine samples were collected at several timepoints up to 72 h after intake of JNJ-53718678 and analyzed using validated liquid chromatography-mass spectrometry methods. A population pharmacokinetic model was developed and validated.

Results

Peak plasma concentrations of JNJ-53718678 increased with increasing single (159 ± 54.9 to 6702 ± 1733 ng/mL) and multiple (on day 8, 1528 ± 256 to 2655 ± 591 ng/mL) doses. Steady-state conditions were reached on day 2 of the 8-day dosing regimen. Less than 4% of JNJ-53718678 was excreted in urine across all dose groups. Mean exposure of JNJ-53718678 was 7% lower in the fed state compared with the fasted state at the same dose. A two-compartment model with first-order absorption with parallel linear and non-linear elimination best described the pharmacokinetics of JNJ-53718678. No covariate effects were observed.

Conclusions

A population pharmacokinetic model that describes the concentration data well with good precision of all parameter estimates was developed and validated. JNJ-53718678 was well tolerated at all single and multiple doses studied.

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Correspondence to Dymphy R. H. Huntjens.

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Funding

This study was funded by Janssen Pharmaceutica NV, Belgium. Dr. Siddharth Mukherjee, Trilogy Writing and Consulting GmbH, Frankfurt, Germany provided medical writing and editorial assistance and this was funded by Janssen Pharmaceutica NV, Belgium.

Conflict of interest

At the time of performing the trial, all authors were employees and shareholders of Janssen Pharmaceutica NV, Belgium.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all subjects included in the study.

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Huntjens, D.R.H., Ouwerkerk-Mahadevan, S., Brochot, A. et al. Population Pharmacokinetic Modeling of JNJ-53718678, a Novel Fusion Inhibitor for the Treatment of Respiratory Syncytial Virus: Results from a Phase I, Double-Blind, Randomized, Placebo-Controlled First-in-Human Study in Healthy Adult Subjects. Clin Pharmacokinet 56, 1331–1342 (2017). https://doi.org/10.1007/s40262-017-0522-8

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