Therapeutic amprenavir concentrations in cerebrospinal fluid.

TitleTherapeutic amprenavir concentrations in cerebrospinal fluid.
Publication TypeJournal Article
Year of Publication2012
AuthorsCroteau, D, Letendre, S, Best, BM, Rossi, SS, Ellis, RJ, Clifford, DB, Collier, AC, Gelman, BB, Marra, CM, McArthur, J, J McCutchan, A, Morgello, S, Simpson, DM, Way, L, Capparelli, E, Grant, I
Corporate AuthorsCHARTER Group
JournalAntimicrob Agents Chemother
Date Published2012 Apr
KeywordsAdult, Anti-HIV Agents, Antiretroviral Therapy, Highly Active, Carbamates, CD4-Positive T-Lymphocytes, CHARTER, Chromatography, High Pressure Liquid, Drug Administration Schedule, Drug Therapy, Combination, Female, HIV Infections, HIV-1, Humans, Inhibitory Concentration 50, Internal, Male, Middle Aged, Sulfonamides, Tandem Mass Spectrometry

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.

Alternate JournalAntimicrob. Agents Chemother.
PubMed ID22290964
PubMed Central IDPMC3318381
Grant ListHHSN271201000030C / MH / NIMH NIH HHS / United States
HHSN271201000030C / / PHS HHS / United States
HHSN271201000027C / / PHS HHS / United States
HHSN271201000027C / MH / NIMH NIH HHS / United States
U01 MH083545 / MH / NIMH NIH HHS / United States
UL1 RR029887 / RR / NCRR NIH HHS / United States
N01 MH022005 / MH / NIMH NIH HHS / United States