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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
Author(s) -
Grillo Joseph A.,
Zhao Ping,
Bullock Julie,
Booth Brian P.,
Lu Min,
RobieSuh Kathy,
Berglund Eva Gil,
Pang K. Sandy,
Rahman Atiqur,
Zhang Lei,
Lesko Lawrence J.,
Huang ShiewMei
Publication year - 2012
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.1771
Subject(s) - physiologically based pharmacokinetic modelling , drug , rivaroxaban , pharmacokinetics , pharmacology , medicine , drug drug interaction , clinical practice , warfarin , atrial fibrillation , family medicine
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. Copyright © 2012 John Wiley & Sons, Ltd.