title: CYP3A activity: towards dose adaptation to the individual.
abstract: BACKGROUND
  Co-medication, gene polymorphisms and co-morbidity are main causes for high variability in expression and function of the CYP3A isoenzymes. Pharmacokinetic variability is a major source of interindividual variability of drug effect and response of CYP3A substrates. While CYP3A genotyping is of limited use, direct testing of enzyme function ('phenotyping') may be more promising to achieve individualized dosing of CYP3A substrates.
  
  
  METHODS
  We will discuss available phenotyping strategies for CYP3A isoenzymes and causes of intra- and interindividual variability of CYP3A. The impact of phenotyping on the dose selection and pharmacokinetics of CYP3A substrates (docetaxel, irinotecan, tyrosine kinase inhibitors, ciclosporin, tacrolimus) are reviewed. Pubmed searches were conducted during March-November 2015 to retrieve articles related to CYP3A enzyme, phenotyping, drug interactions with CYP3A probe substrates, and phenotyping-guided dosing algorithms.
  
  
  CONCLUSIONS
  While ample data is available on the choice appropriate phenotyping drugs (midazolam, alfentanil, aplrazolam, buspirone, triazolam), less clinical trial data is available concerning strategies to usefully guide dosing in the clinical practice. Implementation into the clinical routine necessitates further research to identify (1) an easy-to-use and cheap test for CYP3A activity that (2) adequately predicts drug exposure to (3) allow a sound decision on dose adaptation and hence (4) improve clinical outcome and/or reduce the intensity or frequency of adverse drug effects.
authors.affiliation: a Department of Clinical Pharmacology and Pharmacoepidemiology , University Hospital Heidelberg , Heidelberg , Germany.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Hohmann
authors.affiliation: a Department of Clinical Pharmacology and Pharmacoepidemiology , University Hospital Heidelberg , Heidelberg , Germany.
authors.forename: Walter E
authors.initials: WE
authors.lastname: Haefeli
authors.affiliation: a Department of Clinical Pharmacology and Pharmacoepidemiology , University Hospital Heidelberg , Heidelberg , Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Mikus
mesh_terms: D000465:Algorithms; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005838:Genotype; D006801:Humans; D007527:Isoenzymes; D004364:Pharmaceutical Preparations / Q000008:administration & dosage* / Q000378:metabolism; D010599:Pharmacokinetics; D010641:Phenotype; D011110:Polymorphism, Genetic; D057285:Precision Medicine
chemical_list: D007527:Isoenzymes; D004364:Pharmaceutical Preparations; D051544:Cytochrome P-450 CYP3A
keywords: Dosing strategies; TDM; microdosing; pharmacokinetics; phenotyping