Mathematical modeling of herpes simplex virus-2 suppression with pritelivir predicts trial outcomes.
Sci Transl Med
; 8(324): 324ra15, 2016 Feb 03.
Article
em En
| MEDLINE
| ID: mdl-26843190
ABSTRACT
Pharmacokinetic and pharmacodynamic models estimate the potency of antiviral agents but do not capture viral and immunologic factors that drive the natural dynamics of infection. We designed a mathematical model that synthesizes pharmacokinetics, pharmacodynamics, and viral pathogenesis concepts to simulate the activity of pritelivir, a DNA helicase-primase inhibitor that targets herpes simplex virus. Our simulations recapitulate detailed viral kinetic shedding features in five dosage arms of a phase 2 clinical trial. We identify that in vitro estimates of median effective concentration (EC50) are lower than in vivo values for the drug. Nevertheless, pritelivir potently decreases shedding at appropriate doses based on its mode of action and long half-life. Although pritelivir directly inhibits replication in epithelial cells, our model indicates that pritelivir also indirectly limits downstream viral spread from neurons to genital keratinocytes, within genital ulcers, and from ulcer to new mucosal sites of infection. We validate our model based on its ability to predict outcomes in a subsequent trial with a higher dose. The model can therefore be used to optimize dose selection in clinical practice.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Antivirais
/
Piridinas
/
Tiazóis
/
Herpesvirus Humano 2
/
Modelos Biológicos
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article