title: Darunavir is predominantly unbound to protein in cerebrospinal fluid and concentrations exceed the wild-type HIV-1 median 90% inhibitory concentration.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Neurosciences, University of California San Diego, San Diego, 220 Dickinson Street, Suite B, San Diego, CA 92103, USA. dcroteau@ucsd.edu
authors.forename: David
authors.initials: D
authors.lastname: Croteau
authors.forename: Steven S
authors.initials: SS
authors.lastname: Rossi
authors.forename: Brookie M
authors.initials: BM
authors.lastname: Best
authors.forename: Edmund
authors.initials: E
authors.lastname: Capparelli
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Ellis
authors.forename: David B
authors.initials: DB
authors.lastname: Clifford
authors.forename: Ann C
authors.initials: AC
authors.lastname: Collier
authors.forename: Benjamin B
authors.initials: BB
authors.lastname: Gelman
authors.forename: Christina M
authors.initials: CM
authors.lastname: Marra
authors.forename: Justin
authors.initials: J
authors.lastname: McArthur
authors.forename: J Allen
authors.initials: JA
authors.lastname: McCutchan
authors.forename: Susan
authors.initials: S
authors.lastname: Morgello
authors.forename: David M
authors.initials: DM
authors.lastname: Simpson
authors.forename: Igor
authors.initials: I
authors.lastname: Grant
authors.forename: Scott
authors.initials: S
authors.lastname: Letendre
mesh_terms: D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D002555:Cerebrospinal Fluid / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D002853:Chromatography, Liquid; D000069454:Darunavir; D005260:Female; D015658:HIV Infections / Q000188:drug therapy; D006801:Humans; D008297:Male; D008875:Middle Aged; D010949:Plasma / Q000737:chemistry; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism*; D013048:Specimen Handling / Q000379:methods; D013449:Sulfonamides / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D053719:Tandem Mass Spectrometry; D014462:Ultrafiltration
chemical_list: D019380:Anti-HIV Agents; D011506:Proteins; D013449:Sulfonamides; D000069454:Darunavir