Open AccessPredicting Efavirenz Concentrations in the Brain Tissue of HIV ‐Infected Individuals and Exploring their Relationship to Neurocognitive Impairment
Author(s) -
Srinivas Nithya,
Joseph Sarah Beth,
Robertson Kevin,
Kincer Laura P.,
Menezes Prema,
Adamson Lourdes,
Schauer Amanda P.,
Blake Kimberly H.,
White Nicole,
Sykes Craig,
Luciw Paul,
Eron Joseph J.,
Forrest Alan,
Price Richard W.,
Spudich Serena,
Swanstrom Ronald,
Kashuba Angela D.M.
Publication year - 2019
Publication title -
clinical and translational science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.303
H-Index - 44
eISSN - 1752-8062
pISSN - 1752-8054
DOI - 10.1111/cts.12620
Subject(s) - neurocognitive , efavirenz , cerebrospinal fluid , brain tissue , pharmacokinetics , medicine , human immunodeficiency virus (hiv) , area under the curve , neuropsychology , biobank , pathology , oncology , viral load , pharmacology , physiology , immunology , antiretroviral therapy , biology , bioinformatics , psychiatry , cognition
Sparse data exist on the penetration of antiretrovirals into brain tissue. In this work, we present a framework to use efavirenz (EFV) pharmacokinetic ( PK ) data in plasma, cerebrospinal fluid ( CSF ), and brain tissue of eight rhesus macaques to predict brain tissue concentrations in HIV ‐infected individuals. We then perform exposure‐response analysis with the model‐predicted EFV area under the concentration‐time curve ( AUC ) and neurocognitive scores collected from a group of 24 HIV ‐infected participants. Adult rhesus macaques were dosed daily with 200 mg EFV (as part of a four‐drug regimen) for 10 days. Plasma was collected at 8 time points over 10 days and at necropsy, whereas CSF and brain tissue were collected at necropsy. In the clinical study, data were obtained from one paired plasma and CSF sample of participants prescribed EFV, and neuropsychological test evaluations were administered across 15 domains. PK modeling was performed using ADAPT version 5.0 Biomedical Simulation Resource, Los Angeles, CA) with the iterative two‐stage estimation method. An eight‐compartment model best described EFV distribution across the plasma, CSF , and brain tissue of rhesus macaques and humans. Model‐predicted median brain tissue concentrations in humans were 31 and 8,000 ng/mL, respectively. Model‐predicted brain tissue AUC was highly correlated with plasma AUC (γ = 0.99, P < 0.001) but not CSF AUC (γ = 0.34, P = 0.1) and did not show any relationship with neurocognitive scores (γ < 0.05, P > 0.05). This analysis provides an approach to estimate PK the brain tissue in order to perform PK/pharmacodynamic analyses at the target site.