Darunavir concentration in PBMCs may be a better indicator of drug exposure in HIV patients

Daisuke Nagano, Takuya Araki, Kunio Yanagisawa, Yoshiyuki Ogawa, Fumito Gohda, Hideki Uchiumi, Hiroshi Handa, Tomonori Nakamura, Koujirou Yamamoto

Research output: Contribution to journalArticle

Abstract

Purpose: The clinical efficacies of some antiretroviral drugs are known to not depend on its concentration in blood. To establish a method of dosage adjustment for darunavir (DRV) based on pharmacokinetic theory, we analyzed the correlation between DRV levels in peripheral blood mononuclear cells (PBMCs) and plasma. Methods: The concentrations of DRV and ritonavir (RTV) in plasma and PBMCs of 31 samples obtained from 19 patients were analyzed. An in vitro kinetic study using MOLT-4 cells was performed to assess the contribution of RTV to the intracellular accumulation of DRV. Results: DRV levels in PBMCs varied between 7.91 and 29.36 ng/106 cells (CV 37.5%), while those in plasma were greater. No significant correlation was found between the trough level of DRV in plasma and that in PBMCs (p = 0.575). The inter-day difference in DRV levels in PBMCs seemed smaller than that in plasma (− 41.6–23.0% vs − 83.3–109.1%). In the in vitro study, the elimination half-life of cellular efflux of DRV was 15.7 h in the absence of RTV and extended to 47.6 h in the presence of RTV. Conclusions: We found a poor correlation between intracellular DRV and plasma DRV levels in patients receiving highly active antiretroviral therapy. The efflux rate of DRV from cells was slow; therefore, the concentration of DRV in PBMCs may reflect average exposure to the drug and clinical efficacy.

Original languageEnglish
Pages (from-to)1055-1060
Number of pages6
JournalEuropean Journal of Clinical Pharmacology
Volume74
Issue number8
DOIs
Publication statusPublished - 2018 Aug 1
Externally publishedYes

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Blood Cells
HIV
Pharmaceutical Preparations
Ritonavir
Darunavir
Highly Active Antiretroviral Therapy
Half-Life
Pharmacokinetics

Keywords

  • Darunavir
  • Efflux
  • Intracellular
  • PBMC
  • Ritonavir

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Nagano, D., Araki, T., Yanagisawa, K., Ogawa, Y., Gohda, F., Uchiumi, H., ... Yamamoto, K. (2018). Darunavir concentration in PBMCs may be a better indicator of drug exposure in HIV patients. European Journal of Clinical Pharmacology, 74(8), 1055-1060. https://doi.org/10.1007/s00228-018-2464-y

Darunavir concentration in PBMCs may be a better indicator of drug exposure in HIV patients. / Nagano, Daisuke; Araki, Takuya; Yanagisawa, Kunio; Ogawa, Yoshiyuki; Gohda, Fumito; Uchiumi, Hideki; Handa, Hiroshi; Nakamura, Tomonori; Yamamoto, Koujirou.

In: European Journal of Clinical Pharmacology, Vol. 74, No. 8, 01.08.2018, p. 1055-1060.

Research output: Contribution to journalArticle

Nagano, D, Araki, T, Yanagisawa, K, Ogawa, Y, Gohda, F, Uchiumi, H, Handa, H, Nakamura, T & Yamamoto, K 2018, 'Darunavir concentration in PBMCs may be a better indicator of drug exposure in HIV patients', European Journal of Clinical Pharmacology, vol. 74, no. 8, pp. 1055-1060. https://doi.org/10.1007/s00228-018-2464-y
Nagano, Daisuke ; Araki, Takuya ; Yanagisawa, Kunio ; Ogawa, Yoshiyuki ; Gohda, Fumito ; Uchiumi, Hideki ; Handa, Hiroshi ; Nakamura, Tomonori ; Yamamoto, Koujirou. / Darunavir concentration in PBMCs may be a better indicator of drug exposure in HIV patients. In: European Journal of Clinical Pharmacology. 2018 ; Vol. 74, No. 8. pp. 1055-1060.
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abstract = "Purpose: The clinical efficacies of some antiretroviral drugs are known to not depend on its concentration in blood. To establish a method of dosage adjustment for darunavir (DRV) based on pharmacokinetic theory, we analyzed the correlation between DRV levels in peripheral blood mononuclear cells (PBMCs) and plasma. Methods: The concentrations of DRV and ritonavir (RTV) in plasma and PBMCs of 31 samples obtained from 19 patients were analyzed. An in vitro kinetic study using MOLT-4 cells was performed to assess the contribution of RTV to the intracellular accumulation of DRV. Results: DRV levels in PBMCs varied between 7.91 and 29.36 ng/106 cells (CV 37.5{\%}), while those in plasma were greater. No significant correlation was found between the trough level of DRV in plasma and that in PBMCs (p = 0.575). The inter-day difference in DRV levels in PBMCs seemed smaller than that in plasma (− 41.6–23.0{\%} vs − 83.3–109.1{\%}). In the in vitro study, the elimination half-life of cellular efflux of DRV was 15.7 h in the absence of RTV and extended to 47.6 h in the presence of RTV. Conclusions: We found a poor correlation between intracellular DRV and plasma DRV levels in patients receiving highly active antiretroviral therapy. The efflux rate of DRV from cells was slow; therefore, the concentration of DRV in PBMCs may reflect average exposure to the drug and clinical efficacy.",
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AU - Araki, Takuya

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AU - Ogawa, Yoshiyuki

AU - Gohda, Fumito

AU - Uchiumi, Hideki

AU - Handa, Hiroshi

AU - Nakamura, Tomonori

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