Pharmacokinetics and Drug–Drug Interactions of Long-Acting Intramuscular Cabotegravir and Rilpivirine

Abstract

Combined antiretroviral treatments have significantly improved the morbidity and mortality related to HIV infection, thus transforming HIV infection into a chronic disease; however, the efficacy of antiretroviral treatments is highly dependent on the ability of infected individuals to adhere to life-long drug combination therapies. A major milestone in HIV treatment is the marketing of the long-acting intramuscular antiretroviral drugs cabotegravir and rilpivirine, allowing for infrequent drug administration, with the potential to improve adherence to therapy and treatment satisfaction. Intramuscular administration of cabotegravir and rilpivirine leads to differences in pharmacokinetics and drug-drug interaction (DDI) profiles compared with oral administration. A notable difference is the long elimination half-life with intramuscular administration, which reaches 5.6-11.5 weeks for cabotegravir and 13-28 weeks for rilpivirine, compared with 41 and 45 h, respectively, with their oral administration. Cabotegravir and rilpivirine have a low potential to cause DDIs, however these drugs can be victims of DDIs. Cabotegravir is mainly metabolized by UGT1A1, and rilpivirine is mainly metabolized by CYP3A4, therefore these agents are susceptible to DDIs with inhibitors, and particularly inducers of drug-metabolizing enzymes. Intramuscular administration of cabotegravir and rilpivirine has the advantage of eliminating DDIs occurring at the gastrointestinal level, however interactions can still occur at the hepatic level. This review provides insight on the intramuscular administration of drugs and summarizes the pharmacology of long-acting cabotegravir and rilpivirine. Particular emphasis is placed on DDI profiles after oral and intramuscular administration of these antiretroviral drugs.

A new paradigm for antiretroviral delivery: long-acting cabotegravir and rilpivirine for the treatment and prevention of HIV

“…The pharmacokinetic characteristics of long-acting CAB and RPV were recently reviewed in detail [ 20 ▪ ]. Briefly, sex and BMI contribute to variable pharmacokinetics for both intramuscular CAB and RPV; however, these two factors do not account for most of the variability observed.…”

Cabotegravir and Rilpivirine: A Long-Acting Injectable Antiretroviral Treatment for Human Immunodeficiency Virus

“…27 Studies have shown that concentrations are detectable for more than 12 months after the last dose at levels that are insufficient to maintain viral suppression. 27,28 In the case of treatment discontinuation or unplanned missed injections, viral exposure to subtherapeutic levels of CAB could lead to ART resistance. More research is needed to establish the impact of suboptimal adherence.…”

Long-acting antiretrovirals: a new era for the management and prevention of HIV infection

“… 10 , 22 , 36 This nanosuspension technology increases the apparent t ½ of cabotegravir and rilpivirine, from 41 and 45 h to approximately 8.5 and 20.5 weeks, respectively, with the LAI formulation, although with substantial interindividual variability. 38 This variability in dose–exposure–response relationships could be addressed by TDM. In patients exhibiting substantially lower or higher C min , a personalized dosing schedule, shortening or extending the dosing intervals, could be implemented with benefits in terms of efficacy or costs, respectively.…”