Mathematical modeling of herpes simplex virus-2 suppression with pritelivir predicts trial outcomes

Abstract

Pharmacokinetic and pharmacodynamicmodels estimate the potency of antiviral agents but do not capture viral and immunologic factors that drive the natural dynamics of infection. Wedesigned amathematicalmodel 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 ofmedian 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 newmucosal sites of infection. We validate ourmodel based on its ability to predict outcomes in a subsequent trialwith a higher dose. Themodel can therefore be used to optimize dose selection in clinical practice.