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

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

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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Authors and Affiliations

  1. Department of Clinical Pharmacology and Therapeutics, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, 371-8511, Japan

    Daisuke Nagano, Takuya Araki, Tomonori Nakamura & Koujirou Yamamoto

  2. Department of Pharmacy, Gunma University Hospital, 3-39-15 Showa-machi, Maebashi, 371-8511, Japan

    Takuya Araki, Tomonori Nakamura & Koujirou Yamamoto

  3. Department of Hematology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, 371-8511, Japan

    Kunio Yanagisawa, Yoshiyuki Ogawa, Fumito Gohda, Hideki Uchiumi & Hiroshi Handa

Authors
  1. Daisuke Nagano
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  2. Takuya Araki
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  3. Kunio Yanagisawa
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  4. Yoshiyuki Ogawa
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  5. Fumito Gohda
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  6. Hideki Uchiumi
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  7. Hiroshi Handa
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  8. Tomonori Nakamura
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  9. Koujirou Yamamoto
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Corresponding author

Correspondence to Takuya Araki.

Ethics declarations

This study was approved by the Institutional Review Board for Clinical Trials at Gunma University Hospital and the Ethics Committee for Human Genome Analysis at Gunma University; all patients gave written informed consent prior to participating in the study.

Conflict of interest

The authors declare that they have no conflicts of interest.

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Nagano, D., Araki, T., Yanagisawa, K. et al. Darunavir concentration in PBMCs may be a better indicator of drug exposure in HIV patients. Eur J Clin Pharmacol 74, 1055–1060 (2018). https://doi.org/10.1007/s00228-018-2464-y

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  • DOI: https://doi.org/10.1007/s00228-018-2464-y

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