1. Academic Validation
  2. Pharmacokinetics-pharmacodynamics of a respiratory syncytial virus fusion inhibitor in the cotton rat model

Pharmacokinetics-pharmacodynamics of a respiratory syncytial virus fusion inhibitor in the cotton rat model

  • Antimicrob Agents Chemother. 2010 Nov;54(11):4534-9. doi: 10.1128/AAC.00643-10.
Marie-Claude Rouan 1 Tom Gevers Dirk Roymans Loeckie de Zwart David Nauwelaers Marc De Meulder Pieter van Remoortere Marc Vanstockem Anil Koul Kenny Simmen Koen Andries
Affiliations

Affiliation

  • 1 Tibotec BVBA, Johnson & Johnson, Generaal De Wittelaan L11B3, Mechelen, Belgium.
Abstract

Human respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in infants, young children, elderly persons, and severely immunocompromised patients. Effective postinfection treatments are not widely available, and currently there is no approved vaccine. TMC353121 is a potent RSV fusion inhibitor in vitro, and its ability to reduce viral loads in vivo was demonstrated in cotton rats following prophylactic intravenous administration. Here, the pharmacokinetics of TMC353121 in the cotton rat, which is semipermissive for RSV replication, were further explored to build a pharmacokinetic-pharmacodynamic (PK-PD) model and to estimate the plasma drug levels needed for significant Antiviral efficacy. TMC353121 reduced the viral titers in bronchoalveolar lavage fluid in a dose-dependent manner after a single subcutaneous administration and intranasal RSV inoculation 24 h after compound administration. The viral titer reduction and plasma TMC353121 concentration at the time of RSV inoculation were well described using a simple E(max) model with a maximal viral titer reduction (E(max)) of 1.5 log(10). The plasma drug level required to achieve 50% of the E(max) (200 ng/ml) was much higher than the 50% inhibitory concentration observed in vitro in HeLaM cells (0.07 ng/ml). In conclusion, this simple PK-PD approach may be useful in predicting efficacious exposure levels for future RSV inhibitors.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-11097
    ≥98.0%, RSV抑制剂
    RSV