title: Population pharmacokinetics and pharmacodynamics of rivaroxaban in patients with non-valvular atrial fibrillation: results from ROCKET AF.
abstract: Two once-daily rivaroxaban dosing regimens were compared with warfarin for stroke prevention in patients with non-valvular atrial fibrillation in ROCKET AF: 20 mg for patients with normal/mildly impaired renal function and 15 mg 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 24 hours post-dose. Rivaroxaban plasma concentration and factor Xa activity had an inhibitory maximum-effect (Emax ) 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.
authors.affiliation: Janssen Pharmaceuticals Research & Development, Raritan, NJ, USA.
authors.forename: I G
authors.initials: IG
authors.lastname: Girgis
authors.forename: M R
authors.initials: MR
authors.lastname: Patel
authors.forename: G R
authors.initials: GR
authors.lastname: Peters
authors.forename: K T
authors.initials: KT
authors.lastname: Moore
authors.forename: K W
authors.initials: KW
authors.lastname: Mahaffey
authors.forename: C C
authors.initials: CC
authors.lastname: Nessel
authors.forename: J L
authors.initials: JL
authors.lastname: Halperin
authors.forename: R M
authors.initials: RM
authors.lastname: Califf
authors.forename: K A A
authors.initials: KA
authors.lastname: Fox
authors.forename: R C
authors.initials: RC
authors.lastname: Becker
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001281:Atrial Fibrillation / Q000378:metabolism*; D001777:Blood Coagulation / Q000187:drug effects; D004311:Double-Blind Method; D015951:Factor Xa / Q000378:metabolism; D065427:Factor Xa Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009025:Morpholines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D011517:Prothrombin Time; D051437:Renal Insufficiency / Q000378:metabolism; D000069552:Rivaroxaban; D013876:Thiophenes / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics
chemical_list: D065427:Factor Xa Inhibitors; D009025:Morpholines; D013876:Thiophenes; D000069552:Rivaroxaban; D015951:Factor Xa
keywords: anticoagulants/administration and dosage; anticoagulants/pharmacokinetics; atrial fibrillation/drug therapy; humans; rivaroxaban PK/PD