Therapeutic amprenavir concentrations in cerebrospinal fluid

David Croteau, Scott Letendre, Brookie M. Best, Steven S. Rossi, Ronald J. Ellis, David B. Clifford, Ann C. Collier, Benjamin B. Gelman, Christina M. Marra, Justin McArthur, J. Allen McCutchan, Susan Morgello, David M. Simpson, Lauren Way, Edmund Capparelli, Igor Grant

Research output: Contribution to journalArticle

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 (IC 50) 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 IC 50 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.

Original languageEnglish (US)
Pages (from-to)1985-1989
Number of pages5
JournalAntimicrobial agents and chemotherapy
Volume56
Issue number4
DOIs
StatePublished - Apr 1 2012

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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    Croteau, D., Letendre, S., Best, B. M., Rossi, S. S., Ellis, R. J., Clifford, D. B., Collier, A. C., Gelman, B. B., Marra, C. M., McArthur, J., McCutchan, J. A., Morgello, S., Simpson, D. M., Way, L., Capparelli, E., & Grant, I. (2012). Therapeutic amprenavir concentrations in cerebrospinal fluid. Antimicrobial agents and chemotherapy, 56(4), 1985-1989. https://doi.org/10.1128/AAC.05098-11