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

TitleDarunavir is predominantly unbound to protein in cerebrospinal fluid and concentrations exceed the wild-type HIV-1 median 90% inhibitory concentration.
Publication TypeJournal Article
Year of Publication2013
AuthorsCroteau, D, Rossi, SS, Best, BM, Capparelli, E, Ellis, RJ, Clifford, DB, Collier, AC, Gelman, BB, Marra, CM, McArthur, J, J McCutchan, A, Morgello, S, Simpson, DM, Grant, I, Letendre, S
Corporate AuthorsCHARTER Group
JournalJ Antimicrob Chemother
Volume68
Issue3
Pagination684-9
Date Published2013 Mar
ISSN1460-2091
KeywordsAnti-HIV Agents, Cerebrospinal Fluid, Chromatography, High Pressure Liquid, Chromatography, Liquid, Female, HIV Infections, Humans, Male, Middle Aged, Plasma, Protein Binding, Proteins, Specimen Handling, Sulfonamides, Tandem Mass Spectrometry, Ultrafiltration
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.

DOI10.1093/jac/dks441
Alternate JournalJ. Antimicrob. Chemother.
PubMed ID23143899
PubMed Central IDPMC3566670
Grant ListK24 MH097673 / MH / NIMH NIH HHS / United States
N01 MH22005 / MH / NIMH NIH HHS / United States