Etravirine in CSF is highly protein bound

Anh Nguyen, Steven Rossi, David Croteau, Brookie M. Best, David Clifford, Ann C. Collier, Benjamin Gelman, Christina Marra, Justin Mcarthur, J. Allen Mccutchan, Susan Morgello, David Simpson, Ronald J. Ellis, Igor Grant, Edmund Capparelli, Scott Letendre, Ian Abramson, Muhammad Al-lozi, J. Hampton Atkinson, Christine Fennema-notestineAnthony C. Gamst, Robert K. Heaton, Thomas D. Marcotte, Davey M. Smith, Michael J. Taylor, Rebecca Theilmann, Florin Vaida, Steven Paul woods, Clint Cushman, Matthew Dawson, Donald Franklin, Trudy Jones, Kristen Lewis, Letty Mintz, Mengesha Teshome, Will Toperoff

Research output: Contribution to journalArticle

14 Scopus citations

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 IC. 50 in any of the specimens. Conclusions: Unbound etravirine may not achieve optimal concentrations to inhibit HIV replication in the CNS.

Original languageEnglish (US)
Article numberdks517
Pages (from-to)1161-1168
Number of pages8
JournalJournal of Antimicrobial Chemotherapy
Volume68
Issue number5
DOIs
StatePublished - May 2013

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Keywords

  • Antiretroviral therapy
  • Central nervous system
  • CNS
  • CSF
  • HIV
  • Protein binding

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Nguyen, A., Rossi, S., Croteau, D., Best, B. M., Clifford, D., Collier, A. C., Gelman, B., Marra, C., Mcarthur, J., Mccutchan, J. A., Morgello, S., Simpson, D., Ellis, R. J., Grant, I., Capparelli, E., Letendre, S., Abramson, I., Al-lozi, M., Atkinson, J. H., ... Toperoff, W. (2013). Etravirine in CSF is highly protein bound. Journal of Antimicrobial Chemotherapy, 68(5), 1161-1168. [dks517]. https://doi.org/10.1093/jac/dks517