Quantification of darunavir and etravirine in human peripheral blood mononuclear cells using high performance liquid chromatography tandem mass spectrometry (LC-MS/MS), clinical application in a cohort of 110 HIV-1 infected patients and evidence of a potential drug-drug interaction
Copyright © 2016 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved..
OBJECTIVES: To describe the validation of a sensitive high performance liquid chromatography tandem mass spectrometry (LC-MS/MS) method allowing the simultaneous quantification of darunavir (DRV) and etravirine (ETR) in peripheral blood mononuclear cells (PBMCs) and its application in a cohort of HIV-1 infected patients.
METHODS: Blood samples were obtained from 110 patients. PMBCs were isolated using density gradient centrifugation. Drug extraction from PBMCs was performed with a 60:40 methanol-water (MeOH-H2O) solution containing deuterated IS (DRV-d9 and ETR-d8). The chromatographic separation was performed on a RP18 XBridge™ column.
RESULTS: The geometric mean (GM) of cell associated concentration ([DRV]CC) and plasmatic concentration ([DRV]plasma) were 360.5ng/mL (CI95%:294.5-441.2) and 1733ng/mL (CI95%:1486-2021), respectively. A geometric mean intracellular (IC)/plasma ratio (GMR) of 0.21 (CI95%:0.18-0.24) was calculated. Adjusted for dose/body surface area and post-intake time, a statistically significant correlation was observed between [DRV]Plasma and the eGFR (p=0.002) and between [DRV]Plasma and the concomitant use of ETR (p=0.038). For the 10 patients receiving ETR in addition to DRV, the GM of [ETR]Plasma (available for 8 out of 10 patients) and [ETR]CC were 492.3ng/mL and 2951ng/mL respectively. The GMR of ETR was 7.6 (CI95%: 3.61-13.83).
CONCLUSIONS: A handy and sensitive high performance LC-MS/MS method allowing the simultaneous quantification of DRV and ETR in PBMCs has been described and successfully applied in the largest cohort of DRV-treated patients reported to date. ETR accumulates more efficiently in PBMCs compared to DRV. We have also highlighted a possible impact of ETR on DRV plasma concentrations requiring further investigations.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2016 |
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| Erschienen: |
2016 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:49 |
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| Enthalten in: |
Clinical biochemistry - 49(2016), 7-8 vom: 25. Mai, Seite 580-6 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Belkhir, Leïla [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 14.02.2017 Date Revised 09.12.2020 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.clinbiochem.2015.12.011 |
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| funding: |
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| 100 | 1 | |a Belkhir, Leïla |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Quantification of darunavir and etravirine in human peripheral blood mononuclear cells using high performance liquid chromatography tandem mass spectrometry (LC-MS/MS), clinical application in a cohort of 110 HIV-1 infected patients and evidence of a potential drug-drug interaction |
| 264 | 1 | |c 2016 | |
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| 500 | |a Date Revised 09.12.2020 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2016 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a OBJECTIVES: To describe the validation of a sensitive high performance liquid chromatography tandem mass spectrometry (LC-MS/MS) method allowing the simultaneous quantification of darunavir (DRV) and etravirine (ETR) in peripheral blood mononuclear cells (PBMCs) and its application in a cohort of HIV-1 infected patients | ||
| 520 | |a METHODS: Blood samples were obtained from 110 patients. PMBCs were isolated using density gradient centrifugation. Drug extraction from PBMCs was performed with a 60:40 methanol-water (MeOH-H2O) solution containing deuterated IS (DRV-d9 and ETR-d8). The chromatographic separation was performed on a RP18 XBridge™ column | ||
| 520 | |a RESULTS: The geometric mean (GM) of cell associated concentration ([DRV]CC) and plasmatic concentration ([DRV]plasma) were 360.5ng/mL (CI95%:294.5-441.2) and 1733ng/mL (CI95%:1486-2021), respectively. A geometric mean intracellular (IC)/plasma ratio (GMR) of 0.21 (CI95%:0.18-0.24) was calculated. Adjusted for dose/body surface area and post-intake time, a statistically significant correlation was observed between [DRV]Plasma and the eGFR (p=0.002) and between [DRV]Plasma and the concomitant use of ETR (p=0.038). For the 10 patients receiving ETR in addition to DRV, the GM of [ETR]Plasma (available for 8 out of 10 patients) and [ETR]CC were 492.3ng/mL and 2951ng/mL respectively. The GMR of ETR was 7.6 (CI95%: 3.61-13.83) | ||
| 520 | |a CONCLUSIONS: A handy and sensitive high performance LC-MS/MS method allowing the simultaneous quantification of DRV and ETR in PBMCs has been described and successfully applied in the largest cohort of DRV-treated patients reported to date. ETR accumulates more efficiently in PBMCs compared to DRV. We have also highlighted a possible impact of ETR on DRV plasma concentrations requiring further investigations | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Anti-retroviral drugs | |
| 650 | 4 | |a Darunavir | |
| 650 | 4 | |a Drug interaction | |
| 650 | 4 | |a Etravirine | |
| 650 | 4 | |a HIV-1 | |
| 650 | 4 | |a Intracellular | |
| 650 | 4 | |a LC–MS/MS | |
| 650 | 4 | |a PBMCs | |
| 650 | 7 | |a Biomarkers |2 NLM | |
| 650 | 7 | |a HIV Protease Inhibitors |2 NLM | |
| 650 | 7 | |a Nitriles |2 NLM | |
| 650 | 7 | |a Pyridazines |2 NLM | |
| 650 | 7 | |a Pyrimidines |2 NLM | |
| 650 | 7 | |a Reverse Transcriptase Inhibitors |2 NLM | |
| 650 | 7 | |a etravirine |2 NLM | |
| 650 | 7 | |a 0C50HW4FO1 |2 NLM | |
| 650 | 7 | |a Darunavir |2 NLM | |
| 650 | 7 | |a YO603Y8113 |2 NLM | |
| 700 | 1 | |a De Laveleye, Morgane |e verfasserin |4 aut | |
| 700 | 1 | |a Vandercam, Bernard |e verfasserin |4 aut | |
| 700 | 1 | |a Zech, Francis |e verfasserin |4 aut | |
| 700 | 1 | |a Delongie, Kevin-Alexandre |e verfasserin |4 aut | |
| 700 | 1 | |a Capron, Arnaud |e verfasserin |4 aut | |
| 700 | 1 | |a Yombi, Jean |e verfasserin |4 aut | |
| 700 | 1 | |a Vincent, Anne |e verfasserin |4 aut | |
| 700 | 1 | |a Elens, Laure |e verfasserin |4 aut | |
| 700 | 1 | |a Haufroid, Vincent |e verfasserin |4 aut | |
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