title: Application of a physiologically based pharmacokinetic model for the evaluation of single-point plasma phenotyping method of CYP2D6.
abstract: OBJECTIVE
  Determining metabolic ratio from single-point plasma is potentially a good phenotyping method of CYP2D6 to reduce the required time interval and increase the reliability of data. It is difficult to conduct large sample size clinical trials to evaluate this phenotyping method for multiple plasma points. A physiologically based pharmacokinetic (PBPK) model can be developed to do simulations based on the large virtual Chinese population and evaluate single-point plasma phenotyping method of CYP2D6.
  
  
  METHODS
  Pharmacokinetic data of dextromethorphan (DM) and its metabolite dextrorphan (DX) after oral administration were used for model development. The SimCYP® model incorporating Chinese demographic, physiological, and enzyme data was used to simulate DM and DX pharmacokinetics in different phenotype groups.
  
  
  RESULTS
  The ratios of the simulated to the observed mean AUC and Cmax of DM were 1.01 and 0.81 for extensive metabolizers (EMs), 0.90 and 0.81 for intermediate metabolizers (IMs), and 1.12 and 0.84 for poor metabolizers (PMs). The ratios of the simulated to the observed mean AUC and Cmax of DX were 1.12 and 0.89 for EMs, 0.66 and 0.62 for IMs. All ratios were within the predefined criterion of 0.5-2. The simulations of DM and DX pharmacokinetic profiles in 1000 virtual Chinese subjects with reported frequencies of different phenotypes indicated that statistically significant correlations were found between metabolic ratio of DM to DX (MRDM/DX) from AUC and from single-point plasma from 1 to 30h (all p-values <0.001).
  
  
  CONCLUSIONS
  MRDM/DX from single-point plasma from 1 to 30h after the administration of 30mg controlled-release DM could predict the MRDM/DX from AUC well and could be used as the phenotyping method of CYP2D6 for EMs, IMs, and PMs.
authors.affiliation: Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Beijing, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Chen
authors.affiliation: Manchester Pharmacy School, University of Manchester, Manchester, UK; Simcyp Limited (a Certara Company), Blades Enterprise Centre, Sheffield, UK.
authors.forename: Amin
authors.initials: A
authors.lastname: Rostami-Hodjegan
authors.affiliation: Cardiology Department, Beijing Tsinghua Chang Gung Hospital, Beijing, China.
authors.forename: Haotian
authors.initials: H
authors.lastname: Wang
authors.affiliation: Manchester Pharmacy School, University of Manchester, Manchester, UK.
authors.forename: David
authors.initials: D
authors.lastname: Berk
authors.affiliation: Roche Innovation Center Shanghai, Shanghai, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Shi
authors.affiliation: Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Beijing, China. Electronic address: peihu_pumc@126.com.
authors.forename: Pei
authors.initials: P
authors.lastname: Hu
mesh_terms: D000328:Adult; D000996:Antitussive Agents / Q000097:blood / Q000493:pharmacokinetics; D019540:Area Under Curve; D044466:Asian People; D003198:Computer Simulation; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D003915:Dextromethorphan / Q000097:blood / Q000493:pharmacokinetics*; D003917:Dextrorphan / Q000097:blood; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010641:Phenotype; D055815:Young Adult
chemical_list: D000996:Antitussive Agents; D003917:Dextrorphan; D003915:Dextromethorphan; D019389:Cytochrome P-450 CYP2D6
keywords: CYP2D6; Phenotyping method; Physiologically based pharmacokinetic model; Virtual population