title: Factors affecting intrasubject variability of PK exposure: absolute oral bioavailability and acidic nature of drugs.
abstract: OBJECTIVE
  The aim of the present study is to investigate factors affecting intrasubject variability of pharmacokinetic (PK) exposure, which affect the results of bioequivalence (BE) studies. We focused on two factors: absolute oral bioavailability (BA) and acidic nature of drugs.
  
  
  METHODS
  Intrasubject coefficient of variation (CV) for Cmax and AUC was estimated based on the 90% confidence intervals (CIs) and the number of subjects from fasting BE study results for our investigation. Relationships between the intrasubject CV and the absolute oral BA as well as the acidic nature of the drugs were investigated.
  
  
  RESULTS
  First, the relationship between absolute oral BA and intrasubject variability of PK exposure (Cmax and AUC) showed negative log-linear relationship in the BE studies following oral administration of 65 immediate-release drugs under fasted condition. Drugs with poor absolute oral BA of less than 5% showed high intrasubject CV in the range of 30-65%. In contrast, drugs with high absolute oral BA of more than 80% showed low intrasubject CV of less than 20%. Second, acidic drugs with pKa<6 had higher intrasubject CV of Cmax than AUC compared to other types of drugs. The intrasubject CV ratios of Cmax to AUC for acidic drugs with pKa<6 were significantly higher than those for other types of drugs.
  
  
  CONCLUSIONS
  Results show that absolute oral BA is one of the major factors that predict the extent of intrasubject variability of PK exposure. Acidic nature of drugs is thought to be an additional factor increasing intrasubject variability of Cmax as compared to AUC.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Sato
authors.forename: Mamoru
authors.initials: M
authors.lastname: Narukawa
mesh_terms: D000284:Administration, Oral; D019540:Area Under Curve; D001682:Biological Availability; D006801:Humans; D006863:Hydrogen-Ion Concentration; D016014:Linear Models; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism*; D012995:Solubility
chemical_list: D004364:Pharmaceutical Preparations