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Minimal Physiologically Based Pharmacokinetic and Drug‐Drug‐Disease Interaction Model of Rivaroxaban and Verapamil in Healthy and Renally Impaired Subjects
Author(s) -
Ismail Mohamed,
Lee Vincent H.,
Chow Christina R.,
Rubino Christopher M.
Publication year - 2018
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.1044
Subject(s) - rivaroxaban , medicine , dosing , pharmacokinetics , verapamil , concomitant , pharmacology , renal function , urology , warfarin , calcium , atrial fibrillation
Current dosing recommendations for rivaroxaban advocate dosage reduction in patients with moderate to severe renal impairment and avoidance of concomitant strong inhibitors of CYP3A or P‐glycoprotein. However, rivaroxaban dosing in patients with mild renal impairment taking concomitant moderate inhibitors of CYP3A and P‐glycoprotein is not addressed. To quantify the impacts of concomitant verapamil administration and renal impairment on rivaroxaban pharmacokinetics, a minimal physiologically based pharmacokinetic model system was developed and used to evaluate potential increases in rivaroxaban exposure and the consequent increase in risk of major bleeding. Data from a phase 1, drug‐drug interaction study were used to qualify the minimal physiologically based pharmacokinetic model system. Model‐based simulations indicate that coadministration of rivaroxaban with verapamil substantially increases rivaroxaban exposure across all renal function categories, resulting in an exponential increase in bleeding risk. Reduction of the daily rivaroxaban dose to 10 to 15 mg reduces the major bleeding risk below the designated 4.5% threshold in the majority of patients with normal or mildly impaired renal function. A reduction to 10 mg daily in patients with moderate to severe renal impairment provides additional risk reduction so that 90% of those patients fall below the 4.5% threshold. A risk threshold of 4.5% was selected because it is the median predicted risk in patients treated concomitantly with ketoconazole, which is contraindicated for use with rivaroxaban. Patients taking both rivaroxaban and verapamil should take a reduced daily dose of rivaroxaban to minimize bleeding risk.

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