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

Xenobiotica. 2019 Oct;49(10):1192-1201. doi: 10.1080/00498254.2018.1539278. Epub 2018 Dec 17.


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 < 0.02) in humanized mice than NHPs. NHP CSF concentrations were >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.

Keywords: Antiretrovirals; HIV; brain tissue; cerebrospinal fluid; efavirenz; mass-spectrometry imaging; protein binding.

MeSH terms

  • Alkynes
  • Animals
  • Anti-HIV Agents* / pharmacokinetics
  • Anti-HIV Agents* / pharmacology
  • Benzoxazines* / pharmacokinetics
  • Benzoxazines* / pharmacology
  • Brain* / metabolism
  • Brain* / pathology
  • Brain* / virology
  • Cyclopropanes
  • Drug Evaluation, Preclinical
  • Female
  • HIV Infections* / cerebrospinal fluid
  • HIV Infections* / drug therapy
  • HIV Infections* / pathology
  • HIV-1*
  • Humans
  • Macaca mulatta
  • Male
  • Mice


  • Alkynes
  • Anti-HIV Agents
  • Benzoxazines
  • Cyclopropanes
  • efavirenz