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Antiretroviral concentrations and surrogate measures of efficacy in the brain tissue and CSF of preclinical species.

ABSTRACT: 1. Antiretroviral concentrations in cerebrospinal fluid (CSF) are used as surrogate for brain tissue, although sparse data support this. We quantified antiretrovirals in brain tissue across preclinical models, compared them to CSF, and calculated 90% inhibitory quotients (IQ90) for nonhuman primate (NHP) brain tissue. Spatial distribution of efavirenz was performed by mass-spectrometry imaging (MSI). 2. HIV or RT-SHIV-infected and uninfected animals from two humanized mouse models (hemopoietic-stem cell/RAG2-, n?=?36; bone marrow-liver-thymus/BLT, n?=13) and an NHP model (rhesus macaque, n?=18) were dosed with six antiretrovirals. Brain tissue, CSF (NHPs), and plasma were collected at necropsy. Drug concentrations were measured by LC-MS/MS. Rapid equilibrium dialysis determined protein binding in NHP brain. 3. Brain tissue penetration of most antiretrovirals were >10-fold lower (p?13-fold lower (p?<0.02) than brain tissue with poor agreement except for efavirenz (r?=?0.91, p?=?0.001). Despite 97% brain tissue protein binding, efavirenz achieved IQ90>1 in all animals and 2-fold greater white versus gray matter concentration. 4. Brain tissue penetration varied across animal models for all antiretrovirals except raltegravir, and extrapolating brain tissue concentrations between models should be avoided. With the exception of efavirenz, CSF is not a surrogate for brain tissue concentrations.

SUBMITTER: Srinivas N

PROVIDER: S-EPMC6579712 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Antiretroviral concentrations and surrogate measures of efficacy in the brain tissue and CSF of preclinical species.

Srinivas Nithya N Rosen Elias P EP Gilliland William M WM Kovarova Martina M Remling-Mulder Leila L De La Cruz Gabriela G White Nicole N Adamson Lourdes L Schauer Amanda P AP Sykes Craig C Luciw Paul P Garcia J Victor JV Akkina Ramesh R Kashuba Angela D M ADM

Xenobiotica; the fate of foreign compounds in biological systems 20181217 10

1. Antiretroviral concentrations in cerebrospinal fluid (CSF) are used as surrogate for brain tissue, although sparse data support this. We quantified antiretrovirals in brain tissue across preclinical models, compared them to CSF, and calculated 90% inhibitory quotients (IQ<sub>90</sub>) for nonhuman primate (NHP) brain tissue. Spatial distribution of efavirenz was performed by mass-spectrometry imaging (MSI). 2. HIV or RT-SHIV-infected and uninfected animals from two humanized mouse models (he ...[more]

PMID: 30346892

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Antiretroviral concentrations and surrogate measures of efficacy in the brain tissue and CSF of preclinical species.

Publications

Antiretroviral concentrations and surrogate measures of efficacy in the brain tissue and CSF of preclinical species.

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