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Concentration effect relationship of CYP3A inhibition by ritonavir in humans

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

Abstract

Purpose

To investigate the dose and concentration dependency of CYP3A inhibition by ritonavir using the established limited sampling strategy with midazolam for CYP3A activity.

Methods

An open, fixed-sequence study was carried out in 12 healthy subjects. Single ascending doses of ritonavir (0.1–300 mg) were evaluated for CYP3A inhibition in two cohorts using midazolam as a marker substance.

Results

Ritonavir administered as a single oral dose produced a dose-dependent CYP3A inhibition with an ID50 of 3.4 mg. Using the measured ritonavir concentrations an exposure–inhibition effect curve was established with an IC50 of 600 h pmol/L (AUC2–4). Over the ritonavir dose range studied non-linear exposure of ritonavir was observed.

Conclusions

Ritonavir shows a dose and concentration effect relationship of CYP3A inhibition. In addition, a proposed auto-inhibition of ritonavir metabolism resulted in a non-linear exposure of ritonavir with sub-proportional concentrations at low doses. A time-dependent CYP3A activity may result when inhibitors of CYP3A with short elimination half-lives are used.

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Acknowledgements

The authors are grateful for the excellent assistance of Marlies Stützle-Schnetz, RN with the study conduct, and Magdalena Longo and Monika Maurer for technical support during analytical procedures.

Competing interests

None to declare.

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Authors and Affiliations

  1. Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany

    Christine Eichbaum, Marianna Cortese, Antje Blank, Jürgen Burhenne & Gerd Mikus

  2. Department of Internal Medicine, Clinical Pharmacology and Pharmacoepidemiology, University Hospital of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany

    Gerd Mikus

Authors
  1. Christine Eichbaum
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  2. Marianna Cortese
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  3. Antje Blank
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  4. Jürgen Burhenne
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  5. Gerd Mikus
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Corresponding author

Correspondence to Gerd Mikus.

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Eichbaum, C., Cortese, M., Blank, A. et al. Concentration effect relationship of CYP3A inhibition by ritonavir in humans. Eur J Clin Pharmacol 69, 1795–1800 (2013). https://doi.org/10.1007/s00228-013-1530-8

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  • DOI: https://doi.org/10.1007/s00228-013-1530-8

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