Predicting efavirenz concentrations in the brain tissue of HIV‐infected individuals and exploring their relationship to neurocognitive impairment

Abstract

Sparse data exist on the penetration of antiretrovirals into brain tissue. In this work we present a framework to use efavirenz 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 efavirenz 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 efavirenz (as part of a four‐drug regimen) for ten days. Plasma was collected at eight time points over ten days and at necropsy, while 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 efavirenz, and neuropsychological test evaluations were administered across 15 domains. PK modeling was performed using ADAPT v5.0 with the iterative two stage estimation method. An 8‐compartment model best described efavirenz distribution across the plasma, CSF and brain tissue of rhesus macaques and humans. Model predicted median brain tissue concentrations in humans were 31 ng/ml and 8,000 ng/ml respectively. Model‐predicted brain tissue AUC was highly correlated with plasma AUC (rho=0.99, p<0.001) but not CSF AUC (rho=0.34, p=0.1) and did not show any relationship with neurocognitive scores (rho<0.05, p>0.05). This analysis provides an approach to estimate PK the brain tissue in order to perform pharmacokinetic‐pharmacodynamic analyses at the target site.

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