title: Utility of a physiologically-based pharmacokinetic (PBPK) modeling approach to quantitatively predict a complex drug-drug-disease interaction scenario for rivaroxaban during the drug review process: implications for clinical practice.
abstract: BACKGROUND
  Rivaroxaban is an oral Factor Xa inhibitor. The primary objective of this communication was to quantitatively predict changes in rivaroxaban exposure when individuals with varying degrees of renal impairment are co-administered with another drug that is both a P-gp and a moderate CYP3A4 inhibitor.
  
  
  METHODS
  A physiologically based pharmacokinetic (PBPK) model was developed to simulate rivaroxaban pharmacokinetics in young (20-45 years) or older (55-65 years) subjects with normal renal function, mild, moderate and severe renal impairment, with or without concomitant use of the combined P-gp and moderate CYP3A4 inhibitor, erythromycin.
  
  
  RESULTS
  The simulations indicate that combined factors (i.e., renal impairment and the use of erythromycin) have a greater impact on rivaroxaban exposure than expected when the impact of these factors are considered individually. Compared with normal young subjects taking rivaroxaban, concurrent mild, moderate or severe renal impairment plus erythromycin resulted in 1.9-, 2.4- or 2.6-fold increase in exposure, respectively in young subjects; and 2.5-, 2.9- or 3.0-fold increase in exposure in older subjects.
  
  
  CONCLUSIONS
  These simulations suggest that a drug-drug-disease interaction is possible, which may significantly increase rivaroxaban exposure and increase bleeding risk. These simulations render more mechanistic insights as to the possible outcomes and allow one to reach a decision to add cautionary language to the approved product labeling for rivaroxaban.
authors.affiliation: Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Grillo
authors.forename: Ping
authors.initials: P
authors.lastname: Zhao
authors.forename: Julie
authors.initials: J
authors.lastname: Bullock
authors.forename: Brian P
authors.initials: BP
authors.lastname: Booth
authors.forename: Min
authors.initials: M
authors.lastname: Lu
authors.forename: Kathy
authors.initials: K
authors.lastname: Robie-Suh
authors.forename: Eva Gil
authors.initials: EG
authors.lastname: Berglund
authors.forename: K Sandy
authors.initials: KS
authors.lastname: Pang
authors.forename: Atiqur
authors.initials: A
authors.lastname: Rahman
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Lesko
authors.forename: Shiew-Mei
authors.initials: SM
authors.lastname: Huang
mesh_terms: D000328:Adult; D000368:Aged; D004347:Drug Interactions / Q000502:physiology; D005069:Evaluation Studies as Topic; D005544:Forecasting; D006801:Humans; D008875:Middle Aged; D008954:Models, Biological; D009025:Morpholines / Q000493:pharmacokinetics*; D010829:Physiological Phenomena / Q000502:physiology*; D000069552:Rivaroxaban; D013876:Thiophenes / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D009025:Morpholines; D013876:Thiophenes; D000069552:Rivaroxaban