Efavirenz Is Predicted To Accumulate in Brain Tissue: an In Silico , In Vitro , and In Vivo Investigation

Abstract

Adequate concentrations of efavirenz in the central nervous system (CNS) are necessary to suppress viral replication, but high concentrations may increase the likelihood of CNS adverse drug reactions. The aim of this investigation was to evaluate the efavirenz distribution in the cerebrospinal fluid (CSF) and the brain by using a physiologically based pharmacokinetic (PBPK) simulation for comparison with rodent and human data. The efavirenz CNS distribution was calculated using a permeability-limited model on a virtual cohort of 100 patients receiving efavirenz (600 mg once daily). Simulation data were then compared with human data from the literature and with rodent data. Wistar rats were administered efavirenz (10 mg kg of body weight Ϫ1 ) once daily over 5 weeks. Plasma and brain tissue were collected for analysis via liquid chromatography-tandem mass spectrometry (LC-MS/ MS). The median maximum concentrations of drug (C max ) were predicted to be 3,184 ng ml Ϫ1 (interquartile range [IQR], 2,219 to 4,851 ng ml Ϫ1 ), 49.9 ng ml Ϫ1 (IQR, 36.6 to 69.7 ng ml Ϫ1 ), and 50,343 ng ml Ϫ1 (IQR, 38,351 to 65,799 ng ml Ϫ1 ) in plasma, CSF, and brain tissue, respectively, giving a tissue-to-plasma ratio of 15.8. Following 5 weeks of oral dosing of efavirenz (10 mg kg Ϫ1 ), the median plasma and brain tissue concentrations in rats were 69.7 ng ml Ϫ1 (IQR, 44.9 to 130.6 ng ml Ϫ1 ) and 702.9 ng ml Ϫ1 (IQR, 475.5 to 1,018.0 ng ml Ϫ1 ), respectively, and the median tissue-to-plasma ratio was 9.5 (IQR, 7.0 to 10.9). Although it is useful, measurement of CSF concentrations may give an underestimation of the penetration of antiretrovirals into the brain. The limitations associated with obtaining tissue biopsy specimens and paired plasma and CSF samples from patients make PBPK modeling an attractive tool for probing drug distribution.

Predicting Efavirenz Concentrations in the Brain Tissue of HIV‐Infected Individuals and Exploring their Relationship to Neurocognitive Impairment

“…With only trough concentration data available, we made limited inferences on time-dependent EFV profile and performed PK/PD analyses with brain tissue exposure as a more stable model estimate. However, our predicted PK profile in these matrices (no distinction between maximum plasma concentration (C max ) and C24h) agrees with the relatively flat EFV PK profile in the CSF, 21 and brain tissue, 27 and highlights the utility of EFV C24h.…”

“…The model-predicted brain tissue concentrations were 267-fold higher than CSF, 4-fold higher than plasma, and 15,000-fold higher than the proteinadjusted 90% inhibitory concentration of HIV replication (IC 90 ) of 0.22 ng/mL. 26 A 2017 physiologically based pharmacokinetic model 27 predicted that EFV accumulated in the brain tissue with a steady-state concentration of 50,000 ng/ Four of the eight macaques had EFV concentrations in the CSF that were below the limit of quantification. Their concentrations were imputed as one-half of the lower limit of quantification (0.5 ng/mL).…”

EFVb-HAART Increases Mortality, Locomotor Deficits and Reduces Reproductive Capacity in Drosophila melanogaster

“…The purpose of this study was to evaluate the impact of Efavirenzbased HAART on survival, longevity, climbing ability and reproductive capacity in D. melanogaster. Medications for the treatment of HIV may cause multiple toxicities such as hepatotoxicity [6], as well as central and peripheral nervous systems inflammation [27]. Nevirapine and Efavirenz have been shown to cross the blood-brain barrier and cause significant inhibition in the activity of creatine kinase, which plays a vital role in imparting cell energy homeostasis in the brain [28].…”

Effect of Different Sampling Schedules on Results of Bioavailability and Bioequivalence Studies: Evaluation by Means of Monte Carlo Simulations

“…It was also concluded that in silico studies are useful tools in the planning of bioequivalence, bioavailability and other pharmacokinetic in vivo assays. [6][7][8][9]. The goal of this study was to evaluate the usefulness of in silico studies in the planning of blood collection on bioequivalence, bioavailability and other pharmacokinetic assays.…”