Antiviral Activity of TMC353121, a Respiratory Syncytial Virus (RSV) Fusion Inhibitor, in a Non-Human Primate Model

被引:30
作者
Ispas, Gabriela [1 ]
Koul, Anil [1 ]
Verbeeck, Johan [2 ]
Sheehan, Jennifer [3 ]
Sanders-Beer, Brigitte [4 ]
Roymans, Dirk [1 ]
Andries, Koen [1 ]
Rouan, Marie-Claude [5 ]
De Jonghe, Sandra [5 ]
Bonfanti, Jean-Francois [6 ]
Vanstockem, Marc [1 ]
Simmen, Kenneth [7 ]
Verloes, Rene [1 ]
机构
[1] Janssen Infect Dis, Beerse, Belgium
[2] Janssen Res & Dev, London, England
[3] Huntingdon Life Sci, Somerset, NJ 08873 USA
[4] BIOQUAL Inc, Rockville, MD 20850 USA
[5] Janssen Res & Dev, Beerse, Belgium
[6] Janssen Res & Dev, Jan Cil France, Paris, France
[7] J&J Pharmaceut Res & Dev, Jan Cil UK, High Wycombe, Bucks, England
来源
PLOS ONE | 2015年 / 10卷 / 05期
关键词
HIGH-RISK INFANTS; CLINICAL CANDIDATE; YOUNG-CHILDREN; INFECTION; BRONCHIOLITIS; PALIVIZUMAB; SELECTION; EFFICACY; ANTIBODY; MONKEYS;
D O I
10.1371/journal.pone.0126959
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Background The study assessed the antiviral activity of TMC353121, a respiratory syncytial virus (RSV) fusion inhibitor, in a preclinical non-human primate challenge model with a viral shedding pattern similar to that seen in humans, following continuous infusion (CI). Methods African green monkeys were administered TMC353121 through CI, in 2 studies. Study 1 evaluated the prophylactic and therapeutic efficacy of TMC353121 at a target plasma level of 50 ng/mL (n= 15; Group 1: prophylactic arm [Px50], 0.033 mg/mL TMC353121, flow rate 2.5 mL/kg/h from 24 hours pre-infection to 10 days; Group 2: therapeutic arm [Tx50], 0.033mg/mL TMC353121 from 24 hours postinfection to 8 days; Group 3: control [Vh1] vehicle, 24 hours post-infection to 8 days). Study 2 evaluated the prophylactic efficacy of TMC353121 at target plasma levels of 5 and 500 ng/mL (n= 12; Group 1: prophylactic 5 arm [Px5], 0.0033 mg/mL TMC353121, flow rate 2.5 mL/kg/h from 72 hours pre-infection to 14 days; Group 2: prophylactic 500 arm [Px500], 0.33 mg/mL TMC353121; Group 3: control [Vh2] vehicle, 14 days). Bronchoalveolar lavage fluid and plasma were collected every 2 days from day 1 postinfection for pharmacokinetics and safety analysis. Findings TMC353121 showed a dose-dependent antiviral activity, varying from 1log(10) reduction of peak viral load to complete inhibition of the RSV replication. Complete inhibition of RSV shedding was observed for a relatively low plasma exposure (0.39 mu g/mL) and was associated with a dose-dependent reduction in INF gamma, IL6 and MIP1 alpha. TMC353121 administered as CI for 16 days was generally well-tolerated. Conclusion TMC353121 exerted dose-dependent antiviral effect ranging from full inhibition to absence of antiviral activity, in a preclinical model highly permissive for RSV replication. No new safety findings emerged from the study.
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页数:16
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