Chemical Properties
White Solid
Definition
ChEBI: A monocarboxylic acid amide obtained by formal condensation of the carboxy group of (4R,12aS)-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]ox
zine-9-carboxylic acid with the amino group of 2,4-difluorobenzylamine. Used (as its sodium salt) for treatment of HIV-1.
Description
In August 2013, the US FDA approved dolutegravir (also referred to as S/GSK1349572) for the treatment of HIV-1 infection in adults and children ages 12 years and older in combination with other antiretroviral drugs. Dolutegravir was approved in Canada in November 2013. HIV/AIDS remains a global epidemic with 35 million people infected, including 2.3 million new infections as of 2012. Dolutegravir joins raltegravir and elvitegravir (this chapter of ARMC) as the latest of three FDA-approved HIV integrase strand transfer inhibitors (INSTIs). Dolutegravir was discovered by rational design from a literature diketo acid HIV integrase inhibitor utilizing X-ray coordinates to predict ideal bond angles between the diketone and distal benzyl group. In dolutegravir, the monocyclic component of the reported inhibitor was replaced with the tricyclic carbamoyl pyridone moiety. The researchers postulated that the appropriate arrangement of three oxygens would permit chelation with two magnesium ions in the binding site thus affording improved potency. Ultimately, this arrangement along with further modifications afforded dolutegravir, a potent inhibitor of HIV integrase (IC50=1.7 nM).
Originator
Shionogi & GlaxoSmithKline (United States)
Clinical Use
Integrase inhibitor:
Treatment of HIV
Drug interactions
Potentially hazardous interactions with other drugs
Antidepressants: concentration reduced by St John’s
wort.
Antiepileptics: concentration reduced by
carbamazepine and possibly fosphenytoin,
oxcarbazepine, phenobarbital, phenytoin and
primidone.
Antivirals: concentration reduced by efavirenz,
tipranavir, etravirine and fosamprenavir; possibly
reduced by nevirapine.
Metabolism
Dolutegravir is primarily metabolised through
glucuronidation via UGT1A1 with a minor CYP3A
component.
53% of the total oral dose is excreted unchanged in
the faeces. It is unknown if all or part of this is due to
unabsorbed active substance or biliary excretion of the
glucuronidate conjugate, which can be further degraded to
form the parent compound in the gut lumen.
