title: Semisimultaneous Midazolam Administration to Evaluate the Time Course of CYP3A Activation by a Single Oral Dose of Efavirenz.
abstract: 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.
authors.affiliation: Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Mikus
authors.affiliation: Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Tilman
authors.initials: T
authors.lastname: Heinrich
authors.affiliation: Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Bödigheimer
authors.affiliation: Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Röder
authors.affiliation: Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Anne-Kathrin
authors.initials: AK
authors.lastname: Matthee
authors.affiliation: Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Weiss
authors.affiliation: Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Burhenne
authors.affiliation: Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Walter E
authors.initials: WE
authors.lastname: Haefeli
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000480:Alkynes; D019540:Area Under Curve; D048588:Benzoxazines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D003521:Cyclopropanes; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000493:pharmacokinetics; D007275:Injections, Intravenous; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; D006993:Hypnotics and Sedatives; D018894:Reverse Transcriptase Inhibitors; C098320:efavirenz; D008874:Midazolam
keywords: CYP3A; efavirenz; enzyme activation; midazolam