Darunavir is predominantly unbound to protein in cerebrospinal fluid and concentrations exceed the wild-type HIV-1 median 90% inhibitory concentration

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

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Objectives: Higher CSF antiretroviral concentrations may be associated with better control of HIV replication and neurocognitive performance, but only the unbound fraction of antiretrovirals is available to inhibit HIV. Therefore, the objective of this study was to determine total and unbound darunavir concentrations in CSF and compare findings with plasma concentrations as well as the wild-type HIV-1 90% inhibitory concentration (IC. 90). Methods: Subjects with HIV infection were selected based on the use of darunavir-containing regimens with a twice-daily dosing schedule and availability of stored CSF and matched plasma. Total darunavir was measured by HPLC for plasma or liquid chromatography-tandem mass spectroscopy (LC/MS/MS) for CSF. Plasma unbound darunavir was measured by ultrafiltration and LC/MS/MS. CSF protein binding was determined by competitive binding exchange with radiolabelled darunavir. Results: Twenty-nine matched CSF-plasma pairs were analysed and darunavir was detected in all CSF specimens (median total concentration 55.8 ng/mL), with a CSF unbound fraction of 93.5%. Median fractional penetrance was 1.4% of median total and 9.4% of median unbound plasma concentrations. Unbound darunavir concentrations in CSF exceeded the median IC. 90 for wild-type HIV in all subjects by a median of 20.6-fold, despite the relatively low fractional penetrance. Total darunavir concentrations in CSF correlated with both total and unbound darunavir concentrations in plasma. Conclusions: Darunavir should contribute to the control of HIV replication in the CNS as a component of effective combination antiretroviral regimens.

Original languageEnglish (US)
Pages (from-to)684-689
Number of pages6
JournalJournal of Antimicrobial Chemotherapy
Volume68
Issue number3
DOIs
StatePublished - Mar 2013

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Cerebrospinal Fluid Proteins
HIV-1
HIV
Penetrance
Darunavir
Competitive Binding
Ultrafiltration
Protein Binding
Liquid Chromatography
HIV Infections
Mass Spectrometry
Appointments and Schedules
High Pressure Liquid Chromatography

Keywords

  • Antiretroviral therapy
  • Central nervous system
  • HIV
  • Protein binding

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Darunavir is predominantly unbound to protein in cerebrospinal fluid and concentrations exceed the wild-type HIV-1 median 90% inhibitory concentration. / Croteau, David; Rossi, Steven S.; Best, Brookie M.; Capparelli, Edmund; Ellis, Ronald J.; Clifford, David B.; Collier, Ann C.; Gelman, Benjamin; Marra, Christina M.; Mcarthur, Justin; Mccutchan, J. Allen; Morgello, Susan; Simpson, David M.; Grant, Igor; Letendre, Scott.

In: Journal of Antimicrobial Chemotherapy, Vol. 68, No. 3, 03.2013, p. 684-689.

Research output: Contribution to journalArticle

Croteau, D, Rossi, SS, Best, BM, Capparelli, E, Ellis, RJ, Clifford, DB, Collier, AC, Gelman, B, Marra, CM, Mcarthur, J, Mccutchan, JA, Morgello, S, Simpson, DM, Grant, I & Letendre, S 2013, 'Darunavir is predominantly unbound to protein in cerebrospinal fluid and concentrations exceed the wild-type HIV-1 median 90% inhibitory concentration', Journal of Antimicrobial Chemotherapy, vol. 68, no. 3, pp. 684-689. https://doi.org/10.1093/jac/dks441
Croteau, David ; Rossi, Steven S. ; Best, Brookie M. ; Capparelli, Edmund ; Ellis, Ronald J. ; Clifford, David B. ; Collier, Ann C. ; Gelman, Benjamin ; Marra, Christina M. ; Mcarthur, Justin ; Mccutchan, J. Allen ; Morgello, Susan ; Simpson, David M. ; Grant, Igor ; Letendre, Scott. / Darunavir is predominantly unbound to protein in cerebrospinal fluid and concentrations exceed the wild-type HIV-1 median 90% inhibitory concentration. In: Journal of Antimicrobial Chemotherapy. 2013 ; Vol. 68, No. 3. pp. 684-689.
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title = "Darunavir is predominantly unbound to protein in cerebrospinal fluid and concentrations exceed the wild-type HIV-1 median 90{\%} inhibitory concentration",
abstract = "Objectives: Higher CSF antiretroviral concentrations may be associated with better control of HIV replication and neurocognitive performance, but only the unbound fraction of antiretrovirals is available to inhibit HIV. Therefore, the objective of this study was to determine total and unbound darunavir concentrations in CSF and compare findings with plasma concentrations as well as the wild-type HIV-1 90{\%} inhibitory concentration (IC. 90). Methods: Subjects with HIV infection were selected based on the use of darunavir-containing regimens with a twice-daily dosing schedule and availability of stored CSF and matched plasma. Total darunavir was measured by HPLC for plasma or liquid chromatography-tandem mass spectroscopy (LC/MS/MS) for CSF. Plasma unbound darunavir was measured by ultrafiltration and LC/MS/MS. CSF protein binding was determined by competitive binding exchange with radiolabelled darunavir. Results: Twenty-nine matched CSF-plasma pairs were analysed and darunavir was detected in all CSF specimens (median total concentration 55.8 ng/mL), with a CSF unbound fraction of 93.5{\%}. Median fractional penetrance was 1.4{\%} of median total and 9.4{\%} of median unbound plasma concentrations. Unbound darunavir concentrations in CSF exceeded the median IC. 90 for wild-type HIV in all subjects by a median of 20.6-fold, despite the relatively low fractional penetrance. Total darunavir concentrations in CSF correlated with both total and unbound darunavir concentrations in plasma. Conclusions: Darunavir should contribute to the control of HIV replication in the CNS as a component of effective combination antiretroviral regimens.",
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T1 - Darunavir is predominantly unbound to protein in cerebrospinal fluid and concentrations exceed the wild-type HIV-1 median 90% inhibitory concentration

AU - Croteau, David

AU - Rossi, Steven S.

AU - Best, Brookie M.

AU - Capparelli, Edmund

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 - Grant, Igor

AU - Letendre, Scott

PY - 2013/3

Y1 - 2013/3

N2 - Objectives: Higher CSF antiretroviral concentrations may be associated with better control of HIV replication and neurocognitive performance, but only the unbound fraction of antiretrovirals is available to inhibit HIV. Therefore, the objective of this study was to determine total and unbound darunavir concentrations in CSF and compare findings with plasma concentrations as well as the wild-type HIV-1 90% inhibitory concentration (IC. 90). Methods: Subjects with HIV infection were selected based on the use of darunavir-containing regimens with a twice-daily dosing schedule and availability of stored CSF and matched plasma. Total darunavir was measured by HPLC for plasma or liquid chromatography-tandem mass spectroscopy (LC/MS/MS) for CSF. Plasma unbound darunavir was measured by ultrafiltration and LC/MS/MS. CSF protein binding was determined by competitive binding exchange with radiolabelled darunavir. Results: Twenty-nine matched CSF-plasma pairs were analysed and darunavir was detected in all CSF specimens (median total concentration 55.8 ng/mL), with a CSF unbound fraction of 93.5%. Median fractional penetrance was 1.4% of median total and 9.4% of median unbound plasma concentrations. Unbound darunavir concentrations in CSF exceeded the median IC. 90 for wild-type HIV in all subjects by a median of 20.6-fold, despite the relatively low fractional penetrance. Total darunavir concentrations in CSF correlated with both total and unbound darunavir concentrations in plasma. Conclusions: Darunavir should contribute to the control of HIV replication in the CNS as a component of effective combination antiretroviral regimens.

AB - Objectives: Higher CSF antiretroviral concentrations may be associated with better control of HIV replication and neurocognitive performance, but only the unbound fraction of antiretrovirals is available to inhibit HIV. Therefore, the objective of this study was to determine total and unbound darunavir concentrations in CSF and compare findings with plasma concentrations as well as the wild-type HIV-1 90% inhibitory concentration (IC. 90). Methods: Subjects with HIV infection were selected based on the use of darunavir-containing regimens with a twice-daily dosing schedule and availability of stored CSF and matched plasma. Total darunavir was measured by HPLC for plasma or liquid chromatography-tandem mass spectroscopy (LC/MS/MS) for CSF. Plasma unbound darunavir was measured by ultrafiltration and LC/MS/MS. CSF protein binding was determined by competitive binding exchange with radiolabelled darunavir. Results: Twenty-nine matched CSF-plasma pairs were analysed and darunavir was detected in all CSF specimens (median total concentration 55.8 ng/mL), with a CSF unbound fraction of 93.5%. Median fractional penetrance was 1.4% of median total and 9.4% of median unbound plasma concentrations. Unbound darunavir concentrations in CSF exceeded the median IC. 90 for wild-type HIV in all subjects by a median of 20.6-fold, despite the relatively low fractional penetrance. Total darunavir concentrations in CSF correlated with both total and unbound darunavir concentrations in plasma. Conclusions: Darunavir should contribute to the control of HIV replication in the CNS as a component of effective combination antiretroviral regimens.

KW - Antiretroviral therapy

KW - Central nervous system

KW - HIV

KW - Protein binding

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