Brincidofovir, sold under the brand name Tembexa, is an antiviral drug used to treat smallpox. Brincidofovir is a prodrug of cidofovir. Conjugated to a lipid, the compound is designed to release cidofovir intracellularly, allowing for higher intracellular and lower plasma concentrations of cidofovir, effectively increasing its activity against dsDNA viruses, as well as oral bioavailability.The most common side effects include diarrhea, nausea, vomiting, and abdominal pain.Brincidofovir was approved for medical use in the United States in June 2021. Medical uses
Brincidofovir is indicated for the treatment of human smallpox disease caused by variola virus. Mechanism of Action
Brincidofovir is a pro-drug that is composed of cidofovir, conjugated with a lipid molecule. The lipid aspect of the molecule takes on the action of endogenous lysopghosphatidyl choline, which then is able to enter cells in the body which are infected with smallpox. Once the infected cell takes in the drug, the drug cleaves to generate cidofovir. Cidofovir is then consequently phosphorylated to yield Cidofovir Diphosphate, which is the active drug.Cidofovir diphosphate arises from two key mechanisms. Firstly, cidofovir diphosphate inhibits the variola viruss DNA-polymerase mediated DNA synthesis.The second mechanism is that the drug acts as an acyclic nucleotide and incorporates itself into the viral DNA chain, which then stops viral DNA synthesis. Pharmacokinetics
The oral bioavailability of Brincidofovir is 13.4% as a tablet and 16.8% in a suspension.
Brincidofovir was administered to the first patient diagnosed in the Ebola virus disease outbreak in the US in 2014. The patient was given the drug starting six days after hospital admission when he was already critically ill; he died four days later. Brincidofovir was also given to Ebola patient Ashoka Mukpo at the Nebraska Medical Center, who had developed the disease and then was pronounced Ebola-free and released from the center on 22 October 2014.In October 2014, Chimerix reported it had been given approval by the FDA to start Phase 2 trials in patients infected with ebolaviruses for brincidofovirs safety, tolerability, and efficacy. Organised by a team of scientists at the University of Oxford, including Peter Horby, Jake Dunning, Laura Merson and Trudie Lang, a trial commenced during January 2015 in Liberia, but was subsequently discontinued. Because of a lack of suitable subjects in Liberia, Oxford University and Médecins Sans Frontières planned to extend the trial to Sierra Leone, where there were still Ebola cases; but on the 30th of January 2015, the manufacturer decided to withdraw support for the trial and end discussion of future trials. Animals
In animal trials brincidofovir has shown activity against cytomegalovirus, adenoviruses, BK virus, poxviruses, and herpes simplex viruses. Brincidofovir appears to have potential for the treatment of Ebola virus disease, which is somewhat paradoxical, as ebolaviruses are RNA viruses and thus do not contain DNA as the above-mentioned viruses. References
Further reading
Kern ER, Hartline C, Harden E, Keith K, Rodriguez N, Beadle JR, Hostetler KY (April 2002).