Low atazanavir concentrations in cerebrospinal fluid

Brookie M. Best, Scott L. Letendre, Eileen Brigid, David B. Clifford, Ann C. Collier, Benjamin Gelman, Justin C. McArthur, J. Allen McCutchan, David M. Simpson, Ronald Ellis, Edmund V. Capparelli, Igor Grant

Research output: Contribution to journalArticle

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Abstract

Objective: Protease inhibitors may not penetrate into the central nervous system in therapeutic concentrations, which may allow ongoing HIV replication and injury. The objective of this study was to determine atazanavir penetration into cerebrospinal fluid (CSF). Design: Single random plasma or paired plasma and CSF samples were drawn from participants enrolled in a multicenter, observational cohort study and taking atazanavir with or without ritonavir between October 2003 and October 2005. Methods: Plasma samples were assayed by high performance liquid chromatography and immunoassay; lower limit of detection was 45 ng/ml. CSF samples were assayed by immunoassay (ARK ATV-test); lower limit of detection was 5 ng/ml. Results: One hundred and seventeen participants (43 ± 7.7 years, 79% men, 81 ± 15 kg) had plasma or plasma and CSF paired samples drawn a median (interquartile range) of 10(5-17) h postdose. Median (interquartile range) plasma atazanavir concentrations with or without ritonavir were 1278 (525-2265) and 523 (283-1344) ng/ml. The median (interquartile range) CSF concentrations with or without ritonavir were 10.3 (<5-21.1) and 7.9 (6.6-22) ng/ml. Nineteen of 79 (24%) CSF samples were less than 5 ng/ml. CSF concentrations were less than 1% of plasma concentrations and near the atazanavir wild-type IC50 of 1-11 ng/ml. Conclusion: Atazanavir CSF concentrations are highly variable and 100-fold lower than plasma concentrations, even with ritonavir boosting. CSF concentrations of atazanavir do not consistently exceed the wild-type IC50 of atazanavir and may not protect against HIV replication in the CSF.

Original languageEnglish (US)
Pages (from-to)83-87
Number of pages5
JournalAIDS
Volume23
Issue number1
DOIs
StatePublished - Jan 2 2009

Fingerprint

Cerebrospinal Fluid
Ritonavir
Immunoassay
Inhibitory Concentration 50
Limit of Detection
Atazanavir Sulfate
HIV
Protease Inhibitors
Observational Studies
Cohort Studies
Central Nervous System
High Pressure Liquid Chromatography
Wounds and Injuries

Keywords

  • Atazanavir
  • Central nervous system
  • Cerebrospinal fluid
  • Pharmacology
  • Protease inhibitors

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

Cite this

Best, B. M., Letendre, S. L., Brigid, E., Clifford, D. B., Collier, A. C., Gelman, B., ... Grant, I. (2009). Low atazanavir concentrations in cerebrospinal fluid. AIDS, 23(1), 83-87. https://doi.org/10.1097/QAD.0b013e328317a702

Low atazanavir concentrations in cerebrospinal fluid. / Best, Brookie M.; Letendre, Scott L.; Brigid, Eileen; Clifford, David B.; Collier, Ann C.; Gelman, Benjamin; McArthur, Justin C.; McCutchan, J. Allen; Simpson, David M.; Ellis, Ronald; Capparelli, Edmund V.; Grant, Igor.

In: AIDS, Vol. 23, No. 1, 02.01.2009, p. 83-87.

Research output: Contribution to journalArticle

Best, BM, Letendre, SL, Brigid, E, Clifford, DB, Collier, AC, Gelman, B, McArthur, JC, McCutchan, JA, Simpson, DM, Ellis, R, Capparelli, EV & Grant, I 2009, 'Low atazanavir concentrations in cerebrospinal fluid', AIDS, vol. 23, no. 1, pp. 83-87. https://doi.org/10.1097/QAD.0b013e328317a702
Best BM, Letendre SL, Brigid E, Clifford DB, Collier AC, Gelman B et al. Low atazanavir concentrations in cerebrospinal fluid. AIDS. 2009 Jan 2;23(1):83-87. https://doi.org/10.1097/QAD.0b013e328317a702
Best, Brookie M. ; Letendre, Scott L. ; Brigid, Eileen ; Clifford, David B. ; Collier, Ann C. ; Gelman, Benjamin ; McArthur, Justin C. ; McCutchan, J. Allen ; Simpson, David M. ; Ellis, Ronald ; Capparelli, Edmund V. ; Grant, Igor. / Low atazanavir concentrations in cerebrospinal fluid. In: AIDS. 2009 ; Vol. 23, No. 1. pp. 83-87.
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abstract = "Objective: Protease inhibitors may not penetrate into the central nervous system in therapeutic concentrations, which may allow ongoing HIV replication and injury. The objective of this study was to determine atazanavir penetration into cerebrospinal fluid (CSF). Design: Single random plasma or paired plasma and CSF samples were drawn from participants enrolled in a multicenter, observational cohort study and taking atazanavir with or without ritonavir between October 2003 and October 2005. Methods: Plasma samples were assayed by high performance liquid chromatography and immunoassay; lower limit of detection was 45 ng/ml. CSF samples were assayed by immunoassay (ARK ATV-test); lower limit of detection was 5 ng/ml. Results: One hundred and seventeen participants (43 ± 7.7 years, 79{\%} men, 81 ± 15 kg) had plasma or plasma and CSF paired samples drawn a median (interquartile range) of 10(5-17) h postdose. Median (interquartile range) plasma atazanavir concentrations with or without ritonavir were 1278 (525-2265) and 523 (283-1344) ng/ml. The median (interquartile range) CSF concentrations with or without ritonavir were 10.3 (<5-21.1) and 7.9 (6.6-22) ng/ml. Nineteen of 79 (24{\%}) CSF samples were less than 5 ng/ml. CSF concentrations were less than 1{\%} of plasma concentrations and near the atazanavir wild-type IC50 of 1-11 ng/ml. Conclusion: Atazanavir CSF concentrations are highly variable and 100-fold lower than plasma concentrations, even with ritonavir boosting. CSF concentrations of atazanavir do not consistently exceed the wild-type IC50 of atazanavir and may not protect against HIV replication in the CSF.",
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AU - Letendre, Scott L.

AU - Brigid, Eileen

AU - Clifford, David B.

AU - Collier, Ann C.

AU - Gelman, Benjamin

AU - McArthur, Justin C.

AU - McCutchan, J. Allen

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N2 - Objective: Protease inhibitors may not penetrate into the central nervous system in therapeutic concentrations, which may allow ongoing HIV replication and injury. The objective of this study was to determine atazanavir penetration into cerebrospinal fluid (CSF). Design: Single random plasma or paired plasma and CSF samples were drawn from participants enrolled in a multicenter, observational cohort study and taking atazanavir with or without ritonavir between October 2003 and October 2005. Methods: Plasma samples were assayed by high performance liquid chromatography and immunoassay; lower limit of detection was 45 ng/ml. CSF samples were assayed by immunoassay (ARK ATV-test); lower limit of detection was 5 ng/ml. Results: One hundred and seventeen participants (43 ± 7.7 years, 79% men, 81 ± 15 kg) had plasma or plasma and CSF paired samples drawn a median (interquartile range) of 10(5-17) h postdose. Median (interquartile range) plasma atazanavir concentrations with or without ritonavir were 1278 (525-2265) and 523 (283-1344) ng/ml. The median (interquartile range) CSF concentrations with or without ritonavir were 10.3 (<5-21.1) and 7.9 (6.6-22) ng/ml. Nineteen of 79 (24%) CSF samples were less than 5 ng/ml. CSF concentrations were less than 1% of plasma concentrations and near the atazanavir wild-type IC50 of 1-11 ng/ml. Conclusion: Atazanavir CSF concentrations are highly variable and 100-fold lower than plasma concentrations, even with ritonavir boosting. CSF concentrations of atazanavir do not consistently exceed the wild-type IC50 of atazanavir and may not protect against HIV replication in the CSF.

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