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.
journal_name
Sci Transl Medjournal_title
Science translational medicineauthors
Schiffer JT,Swan DA,Magaret A,Corey L,Wald A,Ossig J,Ruebsamen-Schaeff H,Stoelben S,Timmler B,Zimmermann H,Melhem MR,Van Wart SA,Rubino CM,Birkmann Adoi
10.1126/scitranslmed.aad6654subject
Has Abstractpub_date
2016-02-03 00:00:00pages
324ra15issue
324eissn
1946-6234issn
1946-6242pii
8/324/324ra15journal_volume
8pub_type
杂志文章abstract::Sleep disorders are highly prevalent in patients with traumatic brain injury (TBI) and can significantly impair cognitive rehabilitation. No proven therapies exist to mitigate the neurocognitive consequences of TBI. We show that mild brain injury in mice causes a persistent inability to maintain wakefulness and decrea...
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