title: Mathematical modeling of herpes simplex virus-2 suppression with pritelivir predicts trial outcomes.
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.
authors: Department of Medicine, University of Washington, Seattle, WA 98105, USA. Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. jschiffe@fredhutch.org.
authors: Joshua T
authors: JT
authors: Schiffer
authors: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors: David A
authors: DA
authors: Swan
authors: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. Department of Laboratory Medicine, University of Washington, Seattle, WA 98105, USA.
authors: Amalia
authors: A
authors: Magaret
authors: Department of Medicine, University of Washington, Seattle, WA 98105, USA. Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. Department of Laboratory Medicine, University of Washington, Seattle, WA 98105, USA.
authors: Lawrence
authors: L
authors: Corey
authors: Department of Medicine, University of Washington, Seattle, WA 98105, USA. Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. Department of Laboratory Medicine, University of Washington, Seattle, WA 98105, USA. Department of Epidemiology, University of Washington, Seattle, WA 98105, USA.
authors: Anna
authors: A
authors: Wald
authors: AiCuris, Wuppertal D-42117, Germany.
authors: Joachim
authors: J
authors: Ossig
authors: AiCuris, Wuppertal D-42117, Germany.
authors: Helga
authors: H
authors: Ruebsamen-Schaeff
authors: AiCuris, Wuppertal D-42117, Germany.
authors: Susanne
authors: S
authors: Stoelben
authors: AiCuris, Wuppertal D-42117, Germany.
authors: Burkhard
authors: B
authors: Timmler
authors: AiCuris, Wuppertal D-42117, Germany.
authors: Holger
authors: H
authors: Zimmermann
authors: Institute for Clinical Pharmacodynamics, Latham, NY 12307, USA.
authors: Murad R
authors: MR
authors: Melhem
authors: Institute for Clinical Pharmacodynamics, Latham, NY 12307, USA. School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14260, USA.
authors: Scott A
authors: SA
authors: Van Wart
authors: Institute for Clinical Pharmacodynamics, Latham, NY 12307, USA. School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14260, USA.
authors: Christopher M
authors: CM
authors: Rubino
authors: AiCuris, Wuppertal D-42117, Germany.
authors: Alexander
authors: A
authors: Birkmann
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D002986:Clinical Trials as Topic; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D018258:Herpesvirus 2, Human / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D011725:Pyridines / Q000494:pharmacology*; D013449:Sulfonamides; D013844:Thiazoles / Q000494:pharmacology*; D016896:Treatment Outcome; D017201:Virus Shedding / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D011725:Pyridines; D013449:Sulfonamides; D013844:Thiazoles; C453221:pritelivir