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Variations of CYP3A activity induced by antiretroviral treatment in HIV-1 infected patients

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

Abstract

Objective

To measure the in vivo variations of CYP3A activity induced by anti-HIV drugs in human immunodeficiency virus (HIV)1-positive patients.

Methods

A low oral dose of midazolam (MID) (0.075 mg) was given to the patients and the 30-min total 1-OH midazolam (1-OHMID)/MID ratio was determined. Patients were phenotyped either before the introduction of antiretroviral treatments (control group, 90 patients) or after a variable period of antiretroviral treatment (56 patients). Twenty-one subjects underwent multiple phenotyping tests (before and during the course of the treatment).

Results

The median MID ratio was 3.51 in the control group (range 0.20–14.6). It was 5-fold higher in the group with efavirenz (28 patients; median, range: 16.0, 3.81–367; P<0.0001), 13-fold lower with nelfinavir (18 patients; 0.27, 0.06–36.3; P<0.0001), 17-fold lower with efavirenz+ritonavir (three patients; 0.21, 0.05–0.47; P=0.006), 50-fold lower with ritonavir (four patients; 0.07, 0.06–0.17; P=0.0007), and 7-fold lower with nevirapine+(ritonavir or nelfinavir or grapefruit juice) (three patients; 0.48, 0.03–1.83; P=0.03). CYP3A activity was lower in the efavirenz+ritonavir group (P=0.01) and in the ritonavir group (P=0.04) than in the nelfinavir group, although already strongly inhibited in the latter.

Conclusion

The low-dose MID phenotyping test was successfully used to measure the in vivo variations of CYP3A activity induced by antiretroviral drugs. Efavirenz strongly induces CYP3A activity, while ritonavir almost completely inhibits it. Nelfinavir strongly decreases CYP3A activity, but to a lesser extent than ritonavir. The inhibition of CYP3A by ritonavir or nelfinavir offsets the inductive effects of efavirenz or nevirapine administered concomitantly. Finally, no induction of CYP3A activity was noticeable after long-term administration of ritonavir at low dosages (200 mg/day b.i.d.) or of nelfinavir at standard dosages (2,500 mg/day b.i.d.).

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Acknowledgements

The authors thank Prof. J. Biollaz for reviewing this manuscript, Mrs. C. Bertschi for editorial assistance, and Mrs. E. Ponce, Mrs. J. Rosselet, and Mrs. M. Gobin for bibliographic help.

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Authors and Affiliations

  1. Division of Infectious Diseases, University Hospital of Lausanne, Switzerland

    Jacques Fellay & Amalio Telenti

  2. Department of Clinical Pharmacology, University Hospital of Lausanne, Switzerland

    Catia Marzolini, Laurent Decosterd & Thierry Buclin

  3. Unit of Biochemistry and Clinical Psychopharmacology, Center of Psychiatric Neurosciences, Hôpital de Cery, University Department of Adult Psychiatry, 1008, Prilly-Lausanne, Switzerland

    Kerry Powell Golay, Pierre Baumann & Chin B. Eap

Authors
  1. Jacques Fellay
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  2. Catia Marzolini
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  3. Laurent Decosterd
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  4. Kerry Powell Golay
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  5. Pierre Baumann
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  6. Thierry Buclin
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  7. Amalio Telenti
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  8. Chin B. Eap
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Corresponding author

Correspondence to Chin B. Eap.

Additional information

This work was supported in part by the Swiss National Research Foundation (project 3345-062092.99 and project 3200-065427.01).

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Fellay, J., Marzolini, C., Decosterd, L. et al. Variations of CYP3A activity induced by antiretroviral treatment in HIV-1 infected patients. Eur J Clin Pharmacol 60, 865–873 (2005). https://doi.org/10.1007/s00228-004-0855-8

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  • DOI: https://doi.org/10.1007/s00228-004-0855-8

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