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. 2013 May;68(5):1161-8.
doi: 10.1093/jac/dks517. Epub 2013 Jan 20.

Etravirine in CSF is highly protein bound

Anh Nguyen  1 , 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; CHARTER Group
Collaborators, Affiliations

Etravirine in CSF is highly protein bound

Anh Nguyen et al. J Antimicrob Chemother. 2013 May.

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.

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Figures

Figure 1.
Figure 1.
Total and unbound etravirine (ETR) concentrations in plasma and CSF.
Figure 2.
Figure 2.
Relationships between unbound CSF and plasma (unbound and total) etravirine concentrations. Filled circles indicate unbound CSF etravirine and unbound plasma etravirine concentrations, while open circles represent unbound CSF etravirine and total plasma etravirine concentrations.
Figure 3.
Figure 3.
Relationship between unbound fraction and total plasma concentrations for etravirine (ETR).
See this image and copyright information in PMC

References

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