Population pharmacokinetics and pharmacodynamics of rivaroxaban in patients with non-valvular atrial fibrillation: Results from ROCKET AF

I. G. Girgis, M. R. Patel, G. R. Peters, K. T. Moore, K. W. Mahaffey, C. C. Nessel, J. L. Halperin, R. M. Califf, K. A.A. Fox, R. C. Becker

Research output: Contribution to journalArticlepeer-review

96 Scopus citations

Abstract

Two once-daily rivaroxaban dosing regimens were compared with warfarin for stroke prevention in patients with non-valvular atrial fibrillation in ROCKET AF: 20mg for patients with normal/mildly impaired renal function and 15mg for patients with moderate renal impairment. Rivaroxaban population pharmacokinetic (PK)/pharmacodynamic (PD) modeling data from ROCKET AF patients (n=161) are reported and are used to confirm established rivaroxaban PK and PK/PD models and to re-estimate values of the models' parameters for the current AF population. An oral one-compartment model with first-order absorption adequately described rivaroxaban PK. Age, renal function, and lean body mass influenced the PK model. Prothrombin time and prothrombinase-induced clotting time exhibited a near-linear relationship with rivaroxaban plasma concentration; inhibitory effects were observed through to 24hours post-dose. Rivaroxaban plasma concentration and factor Xa activity had an inhibitory maximum-effect (E max) relationship. Renal function (on prothrombin time; prothrombinase-induced clotting time) and age (on factor Xa activity) had moderate effects on PK/PD models. PK and PK/PD models were shown to be adequate for describing the current dataset. These findings confirm the modeling and empirical results that led to the selection of doses tested against warfarin in ROCKET AF.

Original languageEnglish
Pages (from-to)917-927
Number of pages11
JournalJournal of Clinical Pharmacology
Volume54
Issue number8
DOIs
StatePublished - Aug 2014
Externally publishedYes

Keywords

  • anticoagulants/administration and dosage
  • anticoagulants/pharmacokinetics
  • atrial fibrillation/drug therapy
  • humans
  • rivaroxaban PK/PD

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