Impaired Rivaroxaban Clearance in Mild Renal Insufficiency With Verapamil Coadministration

Potential Implications for Bleeding Risk and Dose Selection

David J. Greenblatt, Maulik Patel, Jerold S. Harmatz, Wayne T. Nicholson, Christopher M. Rubino, Christina R. Chow

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Pharmacokinetics and antithrombotic effects of the Factor Xa inhibitor rivaroxaban were studied in subjects with mild renal insufficiency concurrently taking the P-glycoprotein and moderate CYP3A inhibitor verapamil, a drug commonly administered to patients with hypertension, ischemic heart disease, or atrial fibrillation. Age-matched controls with normal renal function were studied concurrently. Subjects' overall mean age was 59 years. Mean creatinine clearance values in the 2 groups were 105 and 71 mL/min. After single 20-mg oral doses, rivaroxaban area under the curve (AUC) was increased by a factor of 1.11 (ratio of geometric means [RGM]) in mild renal insufficiency compared to controls. Verapamil coadministration independently increased AUC to the same extent in both the mild renal insufficiency and control groups (RGM, 1.39 and 1.43). Concurrent mild renal insufficiency and verapamil produced additive inhibition compared to controls without verapamil (RGM, 1.58). Prothrombin time (PT) prolongation and Factor Xa inhibition tracked plasma rivaroxaban, and were enhanced by verapamil. Concentration-response relationships for PT (linear) and Factor Xa inhibition (hyperbolic) were unaffected by renal function or verapamil. The absolute and relative increases in rivaroxaban AUC caused by verapamil in mild renal insufficiency subjects are potentially associated with an increased bleeding risk. Modification of recommended dosage may be required in this combination of circumstances to reduce risk to patients.

Original languageEnglish (US)
JournalJournal of Clinical Pharmacology
DOIs
StateAccepted/In press - Jan 1 2017

Fingerprint

Verapamil
Renal Insufficiency
Hemorrhage
Area Under Curve
Factor Xa
Prothrombin Time
Kidney
P-Glycoprotein
Rivaroxaban
Atrial Fibrillation
Myocardial Ischemia
Creatinine
Pharmacokinetics
Hypertension
Control Groups
Pharmaceutical Preparations

Keywords

  • Bleeding risk
  • Drug interactions
  • Factor Xa inhibitor
  • Renal insufficiency
  • Rivaroxaban
  • Verapamil

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Impaired Rivaroxaban Clearance in Mild Renal Insufficiency With Verapamil Coadministration : Potential Implications for Bleeding Risk and Dose Selection. / Greenblatt, David J.; Patel, Maulik; Harmatz, Jerold S.; Nicholson, Wayne T.; Rubino, Christopher M.; Chow, Christina R.

In: Journal of Clinical Pharmacology, 01.01.2017.

Research output: Contribution to journalArticle

Greenblatt, David J. ; Patel, Maulik ; Harmatz, Jerold S. ; Nicholson, Wayne T. ; Rubino, Christopher M. ; Chow, Christina R. / Impaired Rivaroxaban Clearance in Mild Renal Insufficiency With Verapamil Coadministration : Potential Implications for Bleeding Risk and Dose Selection. In: Journal of Clinical Pharmacology. 2017.
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