title: Concentration effect relationship of CYP3A inhibition by ritonavir in humans.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Eichbaum
authors.forename: Marianna
authors.initials: M
authors.lastname: Cortese
authors.forename: Antje
authors.initials: A
authors.lastname: Blank
authors.forename: Jürgen
authors.initials: J
authors.lastname: Burhenne
authors.forename: Gerd
authors.initials: G
authors.lastname: Mikus
mesh_terms: D000328:Adult; D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004305:Dose-Response Relationship, Drug; D005260:Female; D017320:HIV Protease Inhibitors / Q000008:administration & dosage* / Q000097:blood / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D008875:Middle Aged; D033281:Nontherapeutic Human Experimentation; D019438:Ritonavir / Q000008:administration & dosage* / Q000097:blood / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D017320:HIV Protease Inhibitors; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D019438:Ritonavir; D008874:Midazolam