title: Perpetrators of pharmacokinetic drug-drug interactions arising from altered cytochrome P450 activity: a criteria-based assessment.
abstract: OBJECTIVE
  To catalogue the perpetrators of CYP-mediated pharmacokinetic drug-drug interactions (PK-DDIs) using clinically relevant criteria, and to compare this with an analogous catalogue.
  
  
  METHODS
  Candidate inhibitors and inducers of CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A ('perpetrators') were evaluated using published clinical pharmacokinetic interaction studies. Studies were selected on the basis of ≥six human subjects, use of a validated in vivo probe substrate for the CYP enzyme, and clinically relevant dosing. Inhibitors were described according to the FDA classifications of strong, moderate or weak, whereas inducers were classified as major (≥twofold decrease in AUC) or weak (<twofold decrease in AUC). A catalogue of major perpetrators was constructed based on twofold changes in the clearance of probe substrates. Perpetrators in the clinical version of the Cytochromes P450 Drug Interaction Table (CDIT) were compared with the 'accepted' major perpetrators.
  
  
  RESULTS
  From a list of 216 candidate drugs (349 CYP-perpetrator pairs, CYP-PPs), 36 inhibitors and eight inducers were accepted as major perpetrators of PK-DDIs, resulting in 58 CYP-PPs. In comparison, the clinical version of the CDIT had a sensitivity of 33% and a positive predictive value of 68%. One hundred and ninety-nine CYP-PPs were rejected as major perpetrators, and 92 CYP-PPs had insufficient published human pharmacokinetic data for robust classification.
  
  
  CONCLUSIONS
  Using a criteria-based assessment, the number of drugs that are proven or likely major perpetrators of CYP-mediated PK-DDIs is relatively small. Current clinical decision support on PK-DDIs is inconsistent with the published evidence and can be improved using simple criteria.
authors.affiliation: Department of Clinical Pharmacology, Flinders University and Flinders Medical Centre, Adelaide, Australia. tom.polasek@flinders.edu.au
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Polasek
authors.forename: Frank P Y
authors.initials: FP
authors.lastname: Lin
authors.forename: John O
authors.initials: JO
authors.lastname: Miners
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Doogue
mesh_terms: D002380:Catalogs, Drug as Topic; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000502:physiology*; D004347:Drug Interactions / Q000502:physiology*; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019317:Evidence-Based Medicine / Q000379:methods; D006801:Humans
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System