Efavirenz and Metabolites in Cerebrospinal Fluid: Relationship with CYP2B6 c.516G→T Genotype and Perturbed Blood-Brain Barrier Due to Tuberculous Meningitis

Abstract

Efavirenz (EFZ) has been associated with neuropsychiatric side effects. Recently, the 8-hydroxy-EFZ (8OH-EFZ) metabolite has been shown to be a potent neurotoxin in vitro, inducing neuronal damage at concentrations of 3.3 ng/ml. EFZ induced similar neuronal damage at concentrations of 31.6 ng/ml. We investigated the effect of genotype and blood-brain barrier integrity on EFZ metabolite concentrations in cerebrospinal fluid (CSF). We measured CSF drug concentrations in subjects from two separate study populations: 47 subjects with tuberculous meningitis (TBM) coinfection in Vietnam receiving 800 mg EFZ with standard antituberculous treatment and 25 subjects from the PARTITION study in the United Kingdom without central nervous system infection receiving 600 mg EFZ. EFZ and metabolite concentrations in CSF and plasma were measured and compared with estimates of effectiveness and neurotoxicity from available published in vitro and in vivo data. The effect of the CYP2B6 c.516G→T genotype (GG genotype, fast EFV metabolizer status; GT genotype, intermediate EFV metabolizer status; TT genotype, slow EFV metabolizer status) was examined. The mean CSF concentrations of EFZ and 8OH-EFZ in the TBM group were 60.3 and 39.3 ng/ml, respectively, and those in the no-TBM group were 15.0 and 5.9 ng/ml, respectively. Plasma EFZ and 8OH-EFZ concentrations were similar between the two groups. CSF EFZ concentrations were above the in vitro toxic concentration in 76% of samples (GG genotype, 61%; GT genotype, 90%; TT genotype, 100%) in the TBM group and 13% of samples (GG genotype, 0%; GT genotype, 18%; TT genotype, 50%) in the no-TBM group. CSF 8OH-EFZ concentrations were above the in vitro toxic concentration in 98% of the TBM group and 87% of the no-TBM group; levels were independent of genotype but correlated with the CSF/plasma albumin ratio. Potentially neurotoxic concentrations of 8OH-EFZ are frequently observed in CSF independently of the CYP2B6 genotype, particularly in those with impaired blood-brain barrier integrity.

Characterization of Nanodiamond-based anti-HIV drug Delivery to the Brain

“…In this regard, it is worth mentioning that in vitro BBB membrane also present a concentration difference of FD between upper and lower chamber of the BBB model that might influence the faster release of FD to the media at the lower chamber. In addition, previous studies have also established the unformulated EFV exposure can disrupt the integrity of BBB and possible toxicity to BBB endothelial cells 40 , 41 . This might also allow more drug to pass through the BBB in a shorter period of time.…”

“…EFV is one of the very effective NNRTIs that has been in use in present combined antiretroviral therapy (cART) for the treatment of HIV-1 infection. However, its low bioavailability, poor pharmacokinetics, and subsequent drug resistance have made it necessary to optimize therapeutic delivery agents to make EFV more targeted and effective 39 – 41 . Among the many nanocarbon materials that have been investigated for use as drug carriers, ND, is the most promising due to its many favorable properties, including, chemical inertness, biocompatibility, and easy availability compared to other nanocarbon materials 17 .…”

Derived wave of gradient driven diffusion's convective flux of efavirenz

“…It is an important and widely used drug in HIV(human immunodeficiency virus) therapy [1,2]. Efavirenz is used as part of a first-line treatment and is very effective in suppressing plasma viral load [2,3]. However, there are concerns over central nervous system (CNS) toxicity related to the drug's use [1,3].…”

“…The mechanisms responsible for the CNS toxicity of this drug are yet to be resolved. Efavirenz is metabolised by Cytochrome P450 enzymes and has a number of metabolites [2,[4][5][6]. There are two main metabolites of efavirenz, that is 7-and 8-hydroxefavirenz.…”

“…It is an important and widely used drug in HIV(human immunodeficiency virus) therapy [1,2]. Efavirenz is used as part of a first-line treatment and is very effective in suppressing plasma viral load [2,3].…”