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

• Published in: Journal of antimicrobial chemotherapy 2013-03, Vol.68 (3), p.684-689
• Main Authors: Croteau, David, Rossi, Steven S, Best, Brookie M, Capparelli, Edmund, Ellis, Ronald J, Clifford, David B, Collier, Ann C, Gelman, Benjamin B, Marra, Christina M, McArthur, Justin, McCutchan, J Allen, Morgello, Susan, Simpson, David M, Grant, Igor, Letendre, Scott
• Format: Article
• Language: English
• Subjects: Anti-HIV Agents - administration & dosage; Anti-HIV Agents - pharmacokinetics; Antiretroviral drugs; Antiviral agents; Binding sites; Body fluids; Cerebrospinal Fluid - chemistry; Chromatography, High Pressure Liquid; Chromatography, Liquid; Darunavir; Female; HIV; HIV Infections - drug therapy; Human immunodeficiency virus; Human immunodeficiency virus 1; Humans; Male; Middle Aged; Original Research; Plasma; Plasma - chemistry; Protein Binding; Proteins; Proteins - metabolism; Specimen Handling - methods; Sulfonamides - administration & dosage; Sulfonamides - pharmacokinetics; Tandem Mass Spectrometry; Ultrafiltration
• ISSN: 0305-7453; 1460-2091
• DOI: 10.1093/jac/dks441

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