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

Belkhir, Leïla;de Laveleye, Morgane;Vandercam, Bernard;Zech, Francis;Haufroid, Vincent;et.al.
(2016) Clinical Biochemistry — Vol. 49, n° 7-8, p. 580-586 (2016)

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Authors
  • Belkhir, Leïlaorcid-logoUCLouvain
    Author
  • de Laveleye, MorganeUCLouvain
    Author
  • Vandercam, BernardUCLouvain
    Author
  • Zech, Francisorcid-logoUCLouvain
    Author
  • Delongie, Kévin-AlexandreUCLouvain
    Author
  • Capron, ArnaudUCLouvain
    Author
  • Yombi, Jean CyrUCLouvain
    Author
  • Vincent, AnneUCLouvain
    Author
  • Elens, LaureUCLouvain
    Author
  • Haufroid, Vincentorcid-logoUCLouvain
    Author
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Abstract
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.
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Belkhir, L., de Laveleye, M., Vandercam, B., Zech, F., Delongie, K.-A., Capron, A., Yombi, J. C., Vincent, A., Elens, L., & Haufroid, V. (2016). 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. Clinical Biochemistry, 49(7-8), 580-586. https://doi.org/10.1016/j.clinbiochem.2015.12.011 (Original work published 2016)