Clinical Pharmacokinetics and Pharmacodynamics of Etravirine: An Updated Review

Abstract

Etravirine is a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) for the treatment of human immunodeficiency virus type 1 infection. It is a potent inhibitor of HIV reverse transcriptase and retains activity against wild-type and most NNRTI-resistant HIV. The pharmacokinetic profile of etravirine and clinical data support twice-daily dosing, although oncedaily dosing has been investigated in treatment-naïve and treatment-experienced persons. Despite similar pharmacokinetic and pharmacodynamic results compared with twice-daily dosing, larger studies are needed to fully support once-daily etravirine dosing in treatment-naïve individuals. Etravirine is reserved for use in third-or fourth-line antiretroviral treatment regimens, as recommended, for example, in treatment guidelines by the US Department of Health and Human Services-Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV. Etravirine exhibits the potential for bi-directional drug-drug interactions with other antiretrovirals and concomitant medications through its interactions with cytochrome P450 (CYP) isozymes: CYP3A4, CYP2C9, and CYP2C19. This review summarizes the pharmacokinetic and pharmacodynamic parameters of etravirine, with particular attention to information on drug-drug interactions and use in special patient populations, including children/adolescents, women, persons with organ dysfunction, and during pregnancy.

Inhibition and induction of CYP enzymes in humans: an update

“…(minor effect at most) Minor effect in vitro at most 2C9? Lee et al ( 2012 ), Tseng et al ( 2017 ) Raltegravir E: major M: UGT1A, no CYPs No significant effects No in vitro/in vivo No in vitro/in vivo Okeke and Hicks ( 2011 ) Non-nucleoside reverse transcriptase inhibitors Doravirine M: 3A4 Strong 3A4 inhibitors ritonavir, ketoconazole (moderate) Strong 3A4 inducers rifampicin (strong) No in vitro/in vivo NA In vivo 3A4 (weak) Khalilieh et al ( 2019 ) Efavirenz M: 2B6 (primary), 2A6, 3A4 2B6 and 3A4-inducers and inhibitors (variable observed or predicted effects) 2C9, 2C19, 3A4 In vivo variable effects 3A4, 2B6 in vitro 2B6 autoinduction 2A6, 2B6, 2C19, 3A4 in vivo variable effects Best and Goicoechea ( 2008 ), Marzolini et al ( 2017 ), McDonagh et al ( 2015 ), Metzger et al ( 2019 ) Etravirine M: 3A4, 2C9, 2C19 Inhibitors and inducers variable effects 2C9, 2C19 In vitro variable effects 3A4 Havens et al ( 2020 ) Nevirapine M: 3A4, 2B6 Rifampicin (moderate) Fluconazole (strong) 3A4, 2B6 (both weak) Weak or no effects in vitro or in vivo 3A4, 2B6 In vivo autoinduction In vivo weak or moderate effect at most Ena et al ( 2012 ) Rilp...…”

Long‐Term Administration of Abacavir and Etravirine Impairs Semen Quality and Alters Redox System and Bone Metabolism in Growing Male Wistar Rats

“…Oxidative Medicine and Cellular Longevity depends mainly on alcohol dehydrogenase and glucuronidation [82]. Etravirine is metabolized by CYP3A and CYP2C enzymes and later undergoes glucuronidation [83]. It seems that the 16-week abacavir administration affects the liver to a greater extent than etravirine administration, which was also reflected in significantly elevated AST activity in the AB-receiving group and a higher liver index.…”

Drug Repositioning in Friedreich Ataxia

“…Using a frataxin reporter system in a cell-based assay, our group performed a screening of an FDA-approved and commercially available drugs library to search for compounds able to increase frataxin amount in cells. Among a few potentially interesting candidates, our attention was focused on etravirine, given its highly favorable safety profile and its potential to be used as a chronic treatment ( Croxtall, 2012 ; Havens et al, 2020 ). Etravirine (Intelence) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of the HIV enzyme ( Namasivayam et al, 2019 ; Zhuang et al, 2020 ).…”