title: Therapeutic amprenavir concentrations in cerebrospinal fluid.
abstract: Antiretrovirals that reach higher concentrations in cerebrospinal fluid (CSF) are associated with better control of HIV in CSF and possibly better neurocognitive performance. The objective of this study was to determine whether amprenavir (APV) concentrations in CSF are in the therapeutic range. Individuals were selected based on the use of regimens that included fosamprenavir (FPV), a prodrug of APV, and the availability of stored CSF and matched plasma. Total APV was measured in 119 matched CSF-plasma pairs from 75 subjects by high-performance liquid chromatography (HPLC) (plasma) or liquid chromatography tandem mass spectrometry (LC/MS/MS) (CSF). Concentrations were compared to the 50% inhibitory concentration (IC₅₀) for wild-type HIV (5.6 ng/ml). Subjects were predominantly middle-aged (median 44 years) white (57%) men (78%) with AIDS (77%). APV was detected in all but 4 CSF specimens, with a median concentration of 24.8 ng/ml (interquartile range [IQR], 16.2 to 44.0). The median CSF-to-plasma ratio was 0.012 (IQR, 0.008 to 0.018). CSF concentrations correlated with plasma concentrations (rho = 0.61; P < 0.0001) and with postdose sampling interval (rho = -0.29; P = 0.0019). APV concentrations in CSF exceeded the median IC₅₀ for wild-type HIV in more than 97% of CSF specimens with detectable APV by a median of 4.4-fold (IQR, 2.9 to 7.9). We conclude that administration of fosamprenavir should contribute to control of HIV replication in the central nervous system (CNS) as a component of effective antiretroviral regimens.
authors.affiliation: Department of Neurosciences, University of California, San Diego, San Diego, California, USA. dcroteau@ucsd.edu
authors.forename: David
authors.initials: D
authors.lastname: Croteau
authors.forename: Scott
authors.initials: S
authors.lastname: Letendre
authors.forename: Brookie M
authors.initials: BM
authors.lastname: Best
authors.forename: Steven S
authors.initials: SS
authors.lastname: Rossi
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: Lauren
authors.initials: L
authors.lastname: Way
authors.forename: Edmund
authors.initials: E
authors.lastname: Capparelli
authors.forename: Igor
authors.initials: I
authors.lastname: Grant
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000134:cerebrospinal fluid* / Q000493:pharmacokinetics; D023241:Antiretroviral Therapy, Highly Active; D015496:CD4-Positive T-Lymphocytes; D002219:Carbamates / Q000008:administration & dosage / Q000134:cerebrospinal fluid* / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D005663:Furans; D015658:HIV Infections / Q000097:blood / Q000134:cerebrospinal fluid; D015497:HIV-1; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D008875:Middle Aged; D013449:Sulfonamides / Q000008:administration & dosage / Q000134:cerebrospinal fluid* / Q000493:pharmacokinetics; D053719:Tandem Mass Spectrometry
chemical_list: D019380:Anti-HIV Agents; D002219:Carbamates; D005663:Furans; D013449:Sulfonamides; C095108:amprenavir