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 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

15 Citations (Scopus)

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 2012

Fingerprint

Cerebrospinal Fluid
Therapeutics
HIV
amprenavir
Prodrugs
Tandem Mass Spectrometry
Liquid Chromatography
Inhibitory Concentration 50
Acquired Immunodeficiency Syndrome
Central Nervous System
High Pressure Liquid Chromatography

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology
  • Infectious Diseases

Cite this

Croteau, D., Letendre, S., Best, B. M., Rossi, S. S., Ellis, R. J., Clifford, D. B., ... 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

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

In: Antimicrobial Agents and Chemotherapy, Vol. 56, No. 4, 04.2012, p. 1985-1989.

Research output: Contribution to journalArticle

Croteau, D, Letendre, S, Best, BM, Rossi, SS, Ellis, RJ, Clifford, DB, Collier, AC, Gelman, B, Marra, CM, McArthur, J, McCutchan, JA, Morgello, S, Simpson, DM, Way, L, Capparelli, E & Grant, I 2012, 'Therapeutic amprenavir concentrations in cerebrospinal fluid', Antimicrobial Agents and Chemotherapy, vol. 56, no. 4, pp. 1985-1989. https://doi.org/10.1128/AAC.05098-11
Croteau D, Letendre S, Best BM, Rossi SS, Ellis RJ, Clifford DB et al. Therapeutic amprenavir concentrations in cerebrospinal fluid. Antimicrobial Agents and Chemotherapy. 2012 Apr;56(4):1985-1989. https://doi.org/10.1128/AAC.05098-11
Croteau, David ; Letendre, Scott ; Best, Brookie M. ; Rossi, Steven S. ; Ellis, Ronald J. ; Clifford, David B. ; Collier, Ann C. ; Gelman, Benjamin ; Marra, Christina M. ; McArthur, Justin ; McCutchan, J. Allen ; Morgello, Susan ; Simpson, David M. ; Way, Lauren ; Capparelli, Edmund ; Grant, Igor. / Therapeutic amprenavir concentrations in cerebrospinal fluid. In: Antimicrobial Agents and Chemotherapy. 2012 ; Vol. 56, No. 4. pp. 1985-1989.
@article{a2450628ef9a4ab5b0efe9e9d72df2f1,
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 (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.",
author = "David Croteau and Scott Letendre and Best, {Brookie M.} and Rossi, {Steven S.} and Ellis, {Ronald J.} and Clifford, {David B.} and Collier, {Ann C.} and Benjamin Gelman and Marra, {Christina M.} and Justin McArthur and McCutchan, {J. Allen} and Susan Morgello and Simpson, {David M.} and Lauren Way and Edmund Capparelli and Igor Grant",
year = "2012",
month = "4",
doi = "10.1128/AAC.05098-11",
language = "English (US)",
volume = "56",
pages = "1985--1989",
journal = "Antimicrobial Agents and Chemotherapy",
issn = "0066-4804",
publisher = "American Society for Microbiology",
number = "4",

}

TY - JOUR

T1 - Therapeutic amprenavir concentrations in cerebrospinal fluid

AU - Croteau, David

AU - Letendre, Scott

AU - Best, Brookie M.

AU - Rossi, Steven S.

AU - Ellis, Ronald J.

AU - Clifford, David B.

AU - Collier, Ann C.

AU - Gelman, Benjamin

AU - Marra, Christina M.

AU - McArthur, Justin

AU - McCutchan, J. Allen

AU - Morgello, Susan

AU - Simpson, David M.

AU - Way, Lauren

AU - Capparelli, Edmund

AU - Grant, Igor

PY - 2012/4

Y1 - 2012/4

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84858654878&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84858654878&partnerID=8YFLogxK

U2 - 10.1128/AAC.05098-11

DO - 10.1128/AAC.05098-11

M3 - Article

C2 - 22290964

AN - SCOPUS:84858654878

VL - 56

SP - 1985

EP - 1989

JO - Antimicrobial Agents and Chemotherapy

JF - Antimicrobial Agents and Chemotherapy

SN - 0066-4804

IS - 4

ER -