Pharmacokinetic drug interactions of integrase strand transfer inhibitors

The integrase strand transfer inhibitor (INSTI)-containing regimens are currently considered as the first-line treatment of human immunodeficiency virus (HIV) infection. Although possessing a common mechanism of action to inhibit HIV integrase irreversibly to stop HIV replication cycle, the INSTIs, including raltegravir, elvitegravir, dolutegravir, and bictegravir, differ in pharmacokinetic characteristics. While raltegravir undergoes biotransformation by the UDP-glucuronosyltransferases (UGTs), elvitegravir is primarily metabolized by cytochrome P450 (CYP) 3A4 and co-formulated with cobicistat to increase its plasma exposure. The metabolism pathways of dolutegravir and bictegravir are similar, both including CYP3A and UGT1A1, and both agents are substrates to different drug transporters. Because of their differences in metabolism, INSTIs interact with other medications differently through CYP enzymes and transporters as inducers or inhibitors. These drug interactions may become an important consideration in the long-term clinical use because the life expectancy of people with HIV (PWH) approaches to that of the general population. Also, common geriatric challenges such as multimorbidity and polypharmacy have been increasingly recognized in PWH. This review provides a summary of pharmacokinetic interactions with INSTIs and future perspectives in implications of INSTI drug interactions.