Brincidofovir

Breast Feeding; Lactation; Milk, Human; Anti-Infective Agents; Antiviral Agents

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

In preregistration clinical trials of brincidofovir as prevention of cytomegalovirus and adenovirus infection in adults and children after hematopoietic stem cell transplantation (HSCT), serum aminotransferase elevations were more frequent with brincidofovir (22%) than placebo (16%) treatment, the usual rate of hepatic enzyme elevations being high after HSCT. ALT elevations above 5 times the upper limit of normal (ULN) arose in 1.8% vs 1.4% , and one of 269 brincidofovir recipients discontinued therapy because of ALT elevations above 10 times ULN. The ALT and AST elevations arose early as brincidofovir was given only 2 or 3 times, on days 1 and 8 and in some trials day 21 of treatment. In the same trials mild-to-moderate elevations in serum bilirubin arose in 6.5% of those on brincidofovir vs 5.9% of placebo recipients, again reflecting the high rate of bilirubin elevations in patients after HSCT. In small studies in healthy human volunteers abnormalities of liver tests were not observed. Since approval of brincidofovir, there have been no instances of smallpox infection that qualified for its use. However, the emergence of mpox infection shortly after its approval has led to its use for this non-approved indication. Aminotransferase elevations were frequent in the mpox virus infected subjects treated with brincidofovir but were invariably asymptomatic, transient and without symptoms or concurrent bilirubin elevations. Thus, the total clinical experience with use of brincidofovir is limited. While transient serum aminotransferase elevations have been reported with its use, there have been no reports of clinically apparent liver injury linked to brincidofovir therapy.

J - Antiinfectives for systemic use

QJ - Antiinfectives for systemic use

The pharmacologically active agent resulting from brincidofovir metabolism, cidofovir diphosphate, has an exceedingly long duration of action that allows for it to be dosed once weekly. The entirety of a brincidofovir smallpox treatment consists of only two doses, on days 1 and 8, which seemingly reduces the risk of adverse reactions. Regimens involving a longer duration of administration (i.e. more than a single dose on days 1 and 8) have been shown to increase mortality compared to placebo and should therefore be avoided. Brincidofovir is considered a potential human carcinogen and has demonstrated the potential to cause infertility - as such, its use should be restricted to situations in which it is absolutely necessary.

Brincidofovir is a pro-drug comprising [cidofovir] conjugated to a lipid molecule - the lipid component mimics an endogenous lipid, lysophosphatidylcholine, which allows the molecule to hijack endogenous lipid uptake pathways to enter infected cells. Following uptake, the lipid molecule is cleaved to generate cidofovir, which is then phosphorylated to generate the active antiviral compound, cidofovir disphosphate. The antiviral effects of cidofovir diphosphate appear to be the result of two distinct mechanisms. Mechanistic studies using recombinant vaccinia DNA polymerase suggest that it inhibits orthopoxvirus DNA polymerase-mediated DNA synthesis. In addition, cidofovir is an acyclic nucleotide analogue of deoxycytidine monophosphate - cidofovir diphosphate can therefore be incorporated into the growing viral DNA chain and consequently slow the rate of viral DNA synthesis.