Pharmacokinetic, Pharmacogenetic, and Other Factors Influencing CNS Penetration of Antiretrovirals

Nwogu, Jacinta N.; Ma, Qing; Babalola, Chinedum P.; Adedeji, Waheed Adeola; Morse, Gene D.; Taiwo, Babafemi

doi:10.1155/2016/2587094

Cited by 22 publications

(30 citation statements)

References 157 publications

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“…Inflammation at the blood-CSF barrier or the CSF-brain barrier could lead to altered drug distribution via opening of tight junctions, altered pH changing drug ionization, and downregulation of efflux transporters. 5 The effect of meningitis coinfection on antiretroviral CNS penetration has not previously been quantified.…”

Section: Antiretroviral Brain and Csf Concentrationsmentioning

confidence: 99%

Cerebrospinal Fluid and Brain Tissue Penetration of Tenofovir, Lamivudine, and Efavirenz in Postmortem Tissues with Cryptococcal Meningitis

Nicol

Pastick

Taylor

et al. 2019

Clinical Translational Sci

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The central nervous system (CNS) is a known HIV reservoir, yet little is known about drug exposure in the brain. Our primary objective was to quantify exposure of three common antiretrovirals in brain tissue and compare exposures to plasma and cerebrospinal fluid (CSF). We also sought to identify pockets of brain most vulnerable to inadequate drug exposures and examine the role of meningitis in drug penetration into the CNS. Tenofovir, lamivudine, and efavirenz concentrations were measured using liquid chromatography and tandem mass spectrometry in plasma and CSF from 14 individuals with HIV, 7 with cryptococcal meningitis. In four individuals (three with meningitis) drug concentrations were also measured in 13 distinct brain tissue regions. In subjects with meningitis, geometric mean ratio (95% confidence interval) of tenofovir CSF to plasma was 66% (7–598%) and 14% (6–31%) in subjects without meningitis. Lamivudine CSF penetration was 100% (25–409%) in subjects with meningitis and 30% (24–37%) in subjects without meningitis. Tenofovir brain tissue concentrations were 36% (14–124%) of plasma and 49% (1–572%) of CSF. Lamivudine brain concentrations were 37% (23–64%) of plasma and 27% (1–104%) of CSF. Efavirenz brain tissue concentrations were 128% (108–179%) of plasma. Tissues collected postmortem provide a unique opportunity to assess drug distribution in tissues difficult to sample in living subjects. CSF is a poor surrogate for drug exposure throughout the CNS. Antiretrovirals differentially penetrate into the CNS and penetration may be enhanced by meningitis.

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Section: Antiretroviral Brain and Csf Concentrationsmentioning

confidence: 99%

Cerebrospinal Fluid and Brain Tissue Penetration of Tenofovir, Lamivudine, and Efavirenz in Postmortem Tissues with Cryptococcal Meningitis

Nicol

Pastick

Taylor

et al. 2019

Clinical Translational Sci

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“…23 Appropriate use of ARVs allows for successful systemic suppression of peripheral viral load; however, eradicating HIV in the brain remains a challenge partly due to limited penetration of several ARVs. 24 Inadequate ARV concentrations in the brain may allow continuous HIV-1 replication and subsequent emergence of drug-resistant viral strains. 25 Additionally, studies have demonstrated that HIV-1-targeted brain cells such as microglia have ARV concentrations that are suboptimal to achieve efficacy.…”

Section: Introductionmentioning

confidence: 99%

Selective peroxisome proliferator‐activated receptor‐gamma modulator, INT131 exhibits anti‐inflammatory effects in an EcoHIV mouse model

et al. 2019

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Despite the use of antiretroviral therapy for the treatment of HIV‐1 infection, cognitive impairments, that is, HIV‐1‐associated neurocognitive disorders remain prevalent potentially due to persistent viral replication, production of viral proteins, associated brain inflammation or in certain instances, antiretroviral neurotoxicity. Cellular targets in the brain include microglia which in response to infection release inflammatory markers and viral proteins. Evidence suggests that PPARγ agonists exert anti‐inflammatory properties in neurological disorders. However, these agonists namely, thiazolidinediones have limited use in the clinic due to reported adverse side effects. INT131 is a novel non‐thiazolidinedione compound that belongs to a new class of drugs known as selective PPARγ modulators. INT131 is considered to have a safer profile; however, its neuroprotective role in vivo is not known.The goal of this study was to examine the effect of INT131 in the context of EcoHIV‐induced inflammation in vitro, in primary cultures of mouse glial cells and in vivo, in a mouse model of EcoHIV‐associated brain inflammation, as well as characterize its pharmacokinetic properties and brain penetration. In primary cultures of glial cells and in the in vivo mouse model, EcoHIV exposure resulted in a significant elevation of inflammatory markers such as TNFα, IL‐1β, CCL3, and C3 which were attenuated with INT131 treatment. Pharmacokinetic analyses revealed that INT131 penetrates into the brain with a brain to blood partition ratio Kp value of 8.5%. Overall, this is the first report to demonstrate that INT131 could be a potential candidate for the treatment of HIV‐1‐associated brain inflammation.

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“…Infection of the CNS is characterized by the presence of multi-nucleated giant cells, reactive astrocytes, and white matter abnormalities. CNS infection remains a major obstacle to complete eradication of HIV in infected individuals, since many antiretrovirals cannot easily penetrate the blood-brain barrier, and are therefore less effective in eliminating infected cells (Nwogu et al , 2016). …”

Section: Introductionmentioning

confidence: 99%

In vivo characterization of macrophage-tropic simian immunodeficiency virus molecular clones in rhesus macaques

et al. 2018

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Macrophages are a major target of HIV/SIV infection and play an important role in pathogenesis by serving as viral reservoirs in the central nervous system. Previously, a unique early SIVmac251 envelope (Env) variant, deSIV147 was cloned from blood of a rhesus macaque with rapid disease progression and SIV-associated encephalitis. Here, we show that infectious molecular clone deSIV147 caused systemic infection in rhesus macaques following intravenous or intrarectal exposure. Next, we inoculated deSIV147 into macaques depleted of CD4+ T cells and found that animals were SIV-positive, with high plasma and CSF viral loads. These macaques also showed SIVp17-positive macrophages in brain, lymph nodes, colon, lung, and liver. Furthermore, accumulation of perivascular macrophages, multinucleated giant cells, and microgliosis was detected. These findings suggest that the neurotropic deSIV147 clone will be useful to study macrophage infection in HIV/SIV-associated neurocognitive disorders, gain insights into myeloid cell reservoirs in brain and other anatomical sites, as well as test strategies for eradication.

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Pharmacokinetic, Pharmacogenetic, and Other Factors Influencing CNS Penetration of Antiretrovirals

Cited by 22 publications

References 157 publications

Cerebrospinal Fluid and Brain Tissue Penetration of Tenofovir, Lamivudine, and Efavirenz in Postmortem Tissues with Cryptococcal Meningitis

Cerebrospinal Fluid and Brain Tissue Penetration of Tenofovir, Lamivudine, and Efavirenz in Postmortem Tissues with Cryptococcal Meningitis

Selective peroxisome proliferator‐activated receptor‐gamma modulator, INT131 exhibits anti‐inflammatory effects in an EcoHIV mouse model

In vivo characterization of macrophage-tropic simian immunodeficiency virus molecular clones in rhesus macaques

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