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Semisimultaneous Midazolam Administration to Evaluate the Time Course of CYP3A Activation by a Single Oral Dose of Efavirenz
Author(s) -
Mikus Gerd,
Heinrich Tilman,
Bödigheimer Julia,
Röder Claudia,
Matthee AnneKathrin,
Weiss Johanna,
Burhenne Jürgen,
Haefeli Walter E.
Publication year - 2017
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.879
Subject(s) - midazolam , cyp3a , efavirenz , oral administration , pharmacokinetics , pharmacology , medicine , in vivo , anesthesia , biology , immunology , cytochrome p450 , human immunodeficiency virus (hiv) , microbiology and biotechnology , metabolism , sedation , antiretroviral therapy , viral load
This study aimed to assess whether a single oral dose of the nonnucleoside reverse transcriptase inhibitor efavirenz can alter CYP3A in vivo. In 12 healthy participants individual CYP3A activity was quantified using a semisimultaneous methodology (midazolam orally and 6 hours later intravenously) both alone and during a period of 22 days after a single oral dose of 400 mg efavirenz. Twelve hours after efavirenz administration, midazolam apparent oral clearance was significantly increased by 70%, and midazolam systemic clearance after intravenous administration was significantly increased by 27%. Similar effects were still present on day 6, after which midazolam clearances slowly returned to baseline on day 22. At least on day 1, the midazolam clearance increase is consistent with the in vitro observed CYP3A activation. The onset of an efavirenz treatment will almost immediately result in enhanced elimination of CYP3A substrates.