title: Prediction of area under the curve for a p-glycoprotein, a CYP3A4 and a CYP2C9 substrate using a single time point strategy: assessment using fexofenadine, itraconazole and losartan and metabolites.
abstract: BACKGROUND
  In the present age of polypharmacy, limited sampling strategy becomes important to verify if drug levels are within the prescribed threshold limits from efficacy and safety considerations. The need to establish reliable single time concentration dependent models to predict exposure becomes important from cost and time perspectives.
  
  
  METHODS
  A simple unweighted linear regression model was developed to describe the relationship between Cmax versus AUC for fexofenadine, losartan, EXP3174, itraconazole and hydroxyitraconazole. The fold difference, defined as the quotient of the observed and predicted AUC values, were evaluated along with statistical comparison of the predicted versus observed values.
  
  
  RESULTS
  The correlation between Cmax versus AUC was well established for all the five drugs with a correlation coefficient (r) ranging from 0.9130 to 0.9997. Majority of the predicted values for all the five drugs (77%) were contained within a narrow boundary of 0.75- to 1.5-fold difference. The r values for observed versus predicted AUC were 0.9653 (n = 145), 0.8342 (n = 76), 0.9524 (n = 88), 0.9339 (n = 89) and 0.9452 (n = 66) for fexofenadine, losartan, EXP3174, itraconazole and hydroxyitraconazole, respectively.
  
  
  CONCLUSIONS
  Cmax versus AUC relationships were established for all drugs and were amenable for limited sampling strategy for AUC prediction. However, fexofenadine, EXP3174 and hydroxyitraconazole may be most relevant for AUC prediction by a single time concentration as judged by the various criteria applied in this study.
authors.affiliation: a Suramus Bio , Bangalore , Karnataka , India.
authors.forename: Nuggehally R
authors.initials: NR
authors.lastname: Srinivas
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism / Q000493:pharmacokinetics*; D019540:Area Under Curve; D018592:Cross-Over Studies; D065729:Cytochrome P-450 CYP2C9 / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D004347:Drug Interactions; D006801:Humans; D017964:Itraconazole / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics*; D019808:Losartan / Q000378:metabolism / Q000493:pharmacokinetics*; D019338:Polypharmacy; D016593:Terfenadine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; C084794:hydroxyitraconazole; D017964:Itraconazole; D016593:Terfenadine; C093230:fexofenadine; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C066026:losartan carboxylic acid; D019808:Losartan
keywords: AUC; exposure; fexofenadine; hydroxyitraconazole; itraconazole; losartan; peak concentration; pharmacokinetics