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-notestine & 16 others Anthony 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

13 Citations (Scopus)

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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etravirine
Proteins

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., ... 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

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

In: Journal of Antimicrobial Chemotherapy, Vol. 68, No. 5, dks517, 05.2013, p. 1161-1168.

Research output: Contribution to journalArticle

Nguyen, A, Rossi, S, Croteau, D, Best, BM, Clifford, D, Collier, AC, Gelman, B, Marra, C, Mcarthur, J, Mccutchan, JA, Morgello, S, Simpson, D, Ellis, RJ, Grant, I, Capparelli, E, Letendre, S, Abramson, I, Al-lozi, M, Atkinson, JH, Fennema-notestine, C, Gamst, AC, Heaton, RK, Marcotte, TD, Smith, DM, Taylor, MJ, Theilmann, R, Vaida, F, Paul woods, S, Cushman, C, Dawson, M, Franklin, D, Jones, T, Lewis, K, Mintz, L, Teshome, M & Toperoff, W 2013, 'Etravirine in CSF is highly protein bound', Journal of Antimicrobial Chemotherapy, vol. 68, no. 5, dks517, pp. 1161-1168. https://doi.org/10.1093/jac/dks517
Nguyen A, Rossi S, Croteau D, Best BM, Clifford D, Collier AC et al. Etravirine in CSF is highly protein bound. Journal of Antimicrobial Chemotherapy. 2013 May;68(5):1161-1168. dks517. https://doi.org/10.1093/jac/dks517
Nguyen, Anh ; Rossi, Steven ; Croteau, David ; Best, Brookie M. ; Clifford, David ; Collier, Ann C. ; Gelman, Benjamin ; Marra, Christina ; Mcarthur, Justin ; Mccutchan, J. Allen ; Morgello, Susan ; Simpson, David ; Ellis, Ronald J. ; Grant, Igor ; Capparelli, Edmund ; Letendre, Scott ; Abramson, Ian ; Al-lozi, Muhammad ; Atkinson, J. Hampton ; Fennema-notestine, Christine ; Gamst, Anthony C. ; Heaton, Robert K. ; Marcotte, Thomas D. ; Smith, Davey M. ; Taylor, Michael J. ; Theilmann, Rebecca ; Vaida, Florin ; Paul woods, Steven ; Cushman, Clint ; Dawson, Matthew ; Franklin, Donald ; Jones, Trudy ; Lewis, Kristen ; Mintz, Letty ; Teshome, Mengesha ; Toperoff, Will. / Etravirine in CSF is highly protein bound. In: Journal of Antimicrobial Chemotherapy. 2013 ; Vol. 68, No. 5. pp. 1161-1168.
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title = "Etravirine in CSF is highly protein bound",
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.",
keywords = "Antiretroviral therapy, Central nervous system, CNS, CSF, HIV, Protein binding",
author = "Anh Nguyen and Steven Rossi and David Croteau and Best, {Brookie M.} and David Clifford and Collier, {Ann C.} and Benjamin Gelman and Christina Marra and Justin Mcarthur and Mccutchan, {J. Allen} and Susan Morgello and David Simpson and Ellis, {Ronald J.} and Igor Grant and Edmund Capparelli and Scott Letendre and Ian Abramson and Muhammad Al-lozi and Atkinson, {J. Hampton} and Christine Fennema-notestine and Gamst, {Anthony C.} and Heaton, {Robert K.} and Marcotte, {Thomas D.} and Smith, {Davey M.} and Taylor, {Michael J.} and Rebecca Theilmann and Florin Vaida and {Paul woods}, Steven and Clint Cushman and Matthew Dawson and Donald Franklin and Trudy Jones and Kristen Lewis and Letty Mintz and Mengesha Teshome and Will Toperoff",
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TY - JOUR

T1 - Etravirine in CSF is highly protein bound

AU - Nguyen, Anh

AU - Rossi, Steven

AU - Croteau, David

AU - Best, Brookie M.

AU - Clifford, David

AU - Collier, Ann C.

AU - Gelman, Benjamin

AU - Marra, Christina

AU - Mcarthur, Justin

AU - Mccutchan, J. Allen

AU - Morgello, Susan

AU - Simpson, David

AU - Ellis, Ronald J.

AU - Grant, Igor

AU - Capparelli, Edmund

AU - Letendre, Scott

AU - Abramson, Ian

AU - Al-lozi, Muhammad

AU - Atkinson, J. Hampton

AU - Fennema-notestine, Christine

AU - Gamst, Anthony C.

AU - Heaton, Robert K.

AU - Marcotte, Thomas D.

AU - Smith, Davey M.

AU - Taylor, Michael J.

AU - Theilmann, Rebecca

AU - Vaida, Florin

AU - Paul woods, Steven

AU - Cushman, Clint

AU - Dawson, Matthew

AU - Franklin, Donald

AU - Jones, Trudy

AU - Lewis, Kristen

AU - Mintz, Letty

AU - Teshome, Mengesha

AU - Toperoff, Will

PY - 2013/5

Y1 - 2013/5

N2 - 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.

AB - 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.

KW - Antiretroviral therapy

KW - Central nervous system

KW - CNS

KW - CSF

KW - HIV

KW - Protein binding

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DO - 10.1093/jac/dks517

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JF - Journal of Antimicrobial Chemotherapy

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