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

• Published in: Clinical pharmacokinetics Vol. 56; no. 11; pp. 1331 - 1342
• Main Authors: Huntjens, Dymphy R. H., Ouwerkerk-Mahadevan, Sivi, Brochot, Anne, Rusch, Sarah, Stevens, Marita, Verloes, Rene
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.11.2017; Springer Nature B.V
• Subjects: Adolescent; Adult; Adults; Antiviral Agents - adverse effects; Antiviral Agents - blood; Antiviral Agents - pharmacokinetics; Antiviral Agents - urine; Disease; Dose-Response Relationship, Drug; Double-Blind Method; Double-blind studies; Drug dosages; Female; Healthy Volunteers; Humans; Imidazolidines - adverse effects; Imidazolidines - blood; Imidazolidines - pharmacokinetics; Imidazolidines - urine; Indoles - adverse effects; Indoles - blood; Indoles - pharmacokinetics; Indoles - urine; Infections; Internal Medicine; Male; Medicine; Medicine & Public Health; Middle Aged; Models, Biological; Monoclonal antibodies; Original Research Article; Pediatrics; Pharmacokinetics; Pharmacology/Toxicology; Pharmacotherapy; Pneumonia; Population; Respiratory syncytial virus; Respiratory Syncytial Viruses - drug effects; Systematic review; Urine; Viruses; Young Adult; Acute Lower Respiratory Tract Infection; Palivizumab; Respiratory Syncytial Virus; Population Pharmacokinetic Model; Food Effect
• ISSN: 0312-5963; 1179-1926
• DOI: 10.1007/s40262-017-0522-8

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.