Etravirine in CSF is highly protein bound.

TitleEtravirine in CSF is highly protein bound.
Publication TypeJournal Article
Year of Publication2013
AuthorsNguyen, A, Rossi, S, Croteau, D, Best, BM, Clifford, D, Collier, AC, Gelman, B, Marra, C, McArthur, J, J McCutchan, A, Morgello, S, Simpson, D, Ellis, RJ, Grant, I, Capparelli, E, Letendre, S
Corporate AuthorsCHARTER Group
JournalJ Antimicrob Chemother
Volume68
Issue5
Pagination1161-8
Date Published2013 May
ISSN1460-2091
KeywordsAdult, Anti-HIV Agents, Cerebrospinal Fluid, Chromatography, High Pressure Liquid, Cohort Studies, Female, HIV Infections, Humans, Inhibitory Concentration 50, Isotope Labeling, Male, Middle Aged, Plasma, Protein Binding, Proteins, Pyridazines, Tandem Mass Spectrometry, Ultracentrifugation
Abstract

OBJECTIVES: Etravirine has high affinity for plasma drug-binding proteins, such as albumin and α1-acid glycoprotein, which limits the amount of unbound etravirine available to enter the CNS. The objective of this study was to compare total and unbound etravirine concentrations in CSF with plasma concentrations and the in vitro median inhibitory concentration (IC50) for wild-type HIV (0.9 ng/mL).

METHODS: Total and bound etravirine concentrations were measured in 17 CSF and plasma pairs by isotope-dilution liquid chromatography tandem mass spectroscopy, radioligand displacement and ultracentrifugation. Unbound etravirine concentrations were calculated from the bound fraction. The dynamic range of the assay was 7.8-2000 (plasma) and 0.78-200 (CSF) ng/mL.

RESULTS: Subjects were mostly middle-aged (median 43 years) white (78%) men (89%). All CSF etravirine concentrations were above the limit of quantification. Total and unbound median etravirine concentrations in CSF were 9.5 (IQR 6.4, 26.4) and 0.13 (IQR 0.08, 0.27) ng/mL, respectively. Etravirine was 96% (IQR 94.5, 97.2) protein bound in plasma and 98.4% (IQR 97.8, 98.8) in CSF. Total etravirine in CSF was 4.3% (IQR 3, 5.9) of total and 101% (IQR 76, 160) of unbound etravirine in plasma. There were no significant correlations between unbound etravirine concentrations and concentrations of albumin in plasma or CSF. Unbound etravirine concentrations in CSF did not reach the wild-type IC50 in any of the specimens.

CONCLUSIONS: Unbound etravirine may not achieve optimal concentrations to inhibit HIV replication in the CNS.

DOI10.1093/jac/dks517
Alternate JournalJ. Antimicrob. Chemother.
PubMed ID23335197
PubMed Central IDPMC3625433
Grant List1R01NS074409-01A1 / NS / NINDS NIH HHS / United States
2U01NS32228 / NS / NINDS NIH HHS / United States
AI69495 / AI / NIAID NIH HHS / United States
DA022137 / DA / NIDA NIH HHS / United States
K30RR22681 / RR / NCRR NIH HHS / United States
MH058076 / MH / NIMH NIH HHS / United States
MH22005 / MH / NIMH NIH HHS / United States
MH79886 / MH / NIMH NIH HHS / United States
N01 MH22005 / MH / NIMH NIH HHS / United States
N01MH22005 / MH / NIMH NIH HHS / United States
NS072005 / NS / NINDS NIH HHS / United States
NS32228 / NS / NINDS NIH HHS / United States
P01 DA026146 / DA / NIDA NIH HHS / United States
P01 DA12065 / DA / NIDA NIH HHS / United States
P30 MH062512 / MH / NIMH NIH HHS / United States
P30 MH62512 / MH / NIMH NIH HHS / United States
P30MH62512 / MH / NIMH NIH HHS / United States
P50 DA26306 / DA / NIDA NIH HHS / United States
P50DA26306 / DA / NIDA NIH HHS / United States
R01 AG15301 / AG / NIA NIH HHS / United States
R01 MH58076 / MH / NIMH NIH HHS / United States
R01 MH78748 / MH / NIMH NIH HHS / United States
R01 MH83552 / MH / NIMH NIH HHS / United States
R01 MH92225 / MH / NIMH NIH HHS / United States
R01MH058076 / MH / NIMH NIH HHS / United States
R01MH083627 / MH / NIMH NIH HHS / United States
R01MH095621 / MH / NIMH NIH HHS / United States
R01MH83552 / MH / NIMH NIH HHS / United States
R25MH080663 / MH / NIMH NIH HHS / United States
U01 AI 68632 / AI / NIAID NIH HHS / United States
U01 AI69432 / AI / NIAID NIH HHS / United States
U01 MH83506 / MH / NIMH NIH HHS / United States
U01 NS45911-04 / NS / NINDS NIH HHS / United States
U01MH083501 / MH / NIMH NIH HHS / United States
U01MH83506 / MH / NIMH NIH HHS / United States
U13 MH81676 / MH / NIMH NIH HHS / United States
U2G PS00623 / PS / NCHHSTP CDC HHS / United States
U54 HD071600-01 / HD / NICHD NIH HHS / United States