title: 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.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Global Clinical Pharmacology, Janssen Pharmaceutica NV, Beerse, Belgium. DHuntjes@its.jnj.com.
authors.forename: Dymphy R H
authors.initials: DRH
authors.lastname: Huntjens
authors.affiliation: Global Clinical Pharmacology, Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: Sivi
authors.initials: S
authors.lastname: Ouwerkerk-Mahadevan
authors.affiliation: Global Clinical Pharmacology, Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: Anne
authors.initials: A
authors.lastname: Brochot
authors.affiliation: Statistics and Decision Sciences, Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: Sarah
authors.initials: S
authors.lastname: Rusch
authors.affiliation: Global Clinical Development, Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: Marita
authors.initials: M
authors.lastname: Stevens
authors.affiliation: Global Clinical Development, Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: Rene
authors.initials: R
authors.lastname: Verloes
mesh_terms: D000293:Adolescent; D000328:Adult; D000998:Antiviral Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D048289:Imidazolidines / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D007211:Indoles / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D012136:Respiratory Syncytial Viruses / Q000187:drug effects; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D048289:Imidazolidines; D007211:Indoles; C000624632:JNJ-53718678