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. 2013 Mar;68(3):684-9.
doi: 10.1093/jac/dks441. Epub 2012 Nov 9.

Darunavir is predominantly unbound to protein in cerebrospinal fluid and concentrations exceed the wild-type HIV-1 median 90% inhibitory concentration

David Croteau  1 , Steven S Rossi, Brookie M Best, Edmund Capparelli, Ronald J Ellis, David B Clifford, Ann C Collier, Benjamin B Gelman, Christina M Marra, Justin McArthur, J Allen McCutchan, Susan Morgello, David M Simpson, Igor Grant, Scott Letendre; CHARTER Group
Collaborators, Affiliations

Darunavir is predominantly unbound to protein in cerebrospinal fluid and concentrations exceed the wild-type HIV-1 median 90% inhibitory concentration

David Croteau et al. J Antimicrob Chemother. 2013 Mar.

Abstract

Objectives: Higher CSF antiretroviral concentrations may be associated with better control of HIV replication and neurocognitive performance, but only the unbound fraction of antiretrovirals is available to inhibit HIV. Therefore, the objective of this study was to determine total and unbound darunavir concentrations in CSF and compare findings with plasma concentrations as well as the wild-type HIV-1 90% inhibitory concentration (IC(90)).

Methods: Subjects with HIV infection were selected based on the use of darunavir-containing regimens with a twice-daily dosing schedule and availability of stored CSF and matched plasma. Total darunavir was measured by HPLC for plasma or liquid chromatography-tandem mass spectroscopy (LC/MS/MS) for CSF. Plasma unbound darunavir was measured by ultrafiltration and LC/MS/MS. CSF protein binding was determined by competitive binding exchange with radiolabelled darunavir.

Results: Twenty-nine matched CSF-plasma pairs were analysed and darunavir was detected in all CSF specimens (median total concentration 55.8 ng/mL), with a CSF unbound fraction of 93.5%. Median fractional penetrance was 1.4% of median total and 9.4% of median unbound plasma concentrations. Unbound darunavir concentrations in CSF exceeded the median IC(90) for wild-type HIV in all subjects by a median of 20.6-fold, despite the relatively low fractional penetrance. Total darunavir concentrations in CSF correlated with both total and unbound darunavir concentrations in plasma.

Conclusions: Darunavir should contribute to the control of HIV replication in the CNS as a component of effective combination antiretroviral regimens.

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Figures

Figure 1.
Figure 1.
Total and unbound plasma and CSF darunavir concentrations with post-dose sampling time. The horizontal broken line shows the median IC50 (1.78 ng/mL). The horizontal continuous line shows the median IC90 (2.43 ng/mL). The LLQs were 0.39 ng/mL (CSF) and 3.9 ng/mL (plasma).
Figure 2.
Figure 2.
Correlations between CSF and total plasma concentrations and CSF and unbound plasma concentrations in log-transformed values with linear fit (continuous lines) and 95% CIs (broken lines). Three pairs have been excluded from the graph: two plasma concentrations <100 ng/mL and corresponding CSF concentrations; and one CSF concentration below the LLQ and the corresponding plasma concentration.
See this image and copyright information in PMC

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