The efficacy and pharmacokinetics of brincidofovir for the treatment of lethal rabbitpox virus infection: a model of smallpox disease.
Brincidofovir (BCV) has broad-spectrum in vitro activity against dsDNA viruses, including smallpox, and is being developed as a treatment for smallpox as well as infections caused by other dsDNA viruses. BCV has previously been shown to be active in multiple animal models of smallpox. Here we present the results of a randomized, blinded, placebo-controlled study of the efficacy and pharmacokinetics of a novel, "humanized" regimen of BCV for treatment of New Zealand White rabbits infected with a highly lethal inoculum of rabbitpox virus, a well characterized model of smallpox. Compared with placebo, a dose-dependent increase in survival was observed in all BCV-treatment groups. Concentrations of cidofovir diphosphate (CDV-PP), the active antiviral, in rabbit peripheral blood mononuclear cells (PBMCs) were determined for comparison to those produced in humans at the dose proposed for treatment of smallpox. CDV-PP exposure in PBMCs from rabbits given BCV scaled to human exposures at the dose proposed for treatment of smallpox, which is also currently under evaluation for other indications. The results of this study demonstrate the activity of BCV in the rabbitpox model of smallpox and the feasibility of scaling doses efficacious in the model to a proposed human dose and regimen for treatment of smallpox.
Chimerix, Inc., 2505 Meridian Pkwy, STE 340, Durham, NC 27713, USA. Electronic address: ltrost@chimerix.com.
Lawrence C
LC
Trost
Chimerix, Inc., 2505 Meridian Pkwy, STE 340, Durham, NC 27713, USA.
Michelle L
ML
Rose
Chimerix, Inc., 2505 Meridian Pkwy, STE 340, Durham, NC 27713, USA.
Jody
J
Khouri
Chimerix, Inc., 2505 Meridian Pkwy, STE 340, Durham, NC 27713, USA.
Laurie
L
Keilholz
MRIGlobal, 425 Volker Boulevard, Kansas City, MO 64110-2241, USA(1).
James
J
Long
United Therapeutics Corp., 55 T W Alexander Dr, Research Triangle Park, NC 27709, USA(1).
Stephen J
SJ
Godin
Chimerix, Inc., 2505 Meridian Pkwy, STE 340, Durham, NC 27713, USA.
Scott A
SA
Foster
D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood; D000914:Antibodies, Viral / Q000097:blood; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D000077404:Cidofovir; D003596:Cytosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D006801:Humans; D007271:Injections, Intradermal; D063065:Organophosphonates / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D011817:Rabbits; D011897:Random Allocation; D012899:Smallpox / Q000188:drug therapy*; D014615:Vaccinia / Q000188:drug therapy* / Q000821:virology; D014616:Vaccinia virus / Q000187:drug effects* / Q000254:growth & development; D012901:Variola virus / Q000187:drug effects / Q000254:growth & development
D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D000998:Antiviral Agents; D063065:Organophosphonates; C525733:brincidofovir; D003596:Cytosine; D000077404:Cidofovir
Animal rule; Brincidofovir; Cidofovir; Rabbitpox; Smallpox; Variola