Rivaroxaban pharmacodynamics in healthy volunteers evaluated with thrombin generation and the active protein C system: Modeling and assessing interindividual variability

J Thromb Haemost. 2019 Oct;17(10):1670-1682. doi: 10.1111/jth.14541. Epub 2019 Jul 9.

Abstract

Background: Rivaroxaban is a direct factor Xa inhibitor with substantial inter-individual pharmacokinetic (PK) variability. Pharmacodynamic (PD) variability, especially assessed with thrombin generation (TG), has been less documented.

Objectives: (i) To assess TG parameter time profiles in healthy volunteers, with TG being studied under different conditions and (ii) to model the relationship between rivaroxaban concentrations and TG parameters and subsequently estimate interindividual variability.

Methods: Sixty healthy male volunteers (DRIVING-NCT01627665) received a single 40-mg rivaroxaban dose. Blood sampling was performed at baseline and 10 predefined time points over 24 h. The TG was investigated with the fully automated ST-Genesia system (Stago), using two tissue-factor (TF) concentrations, in the absence (-), or presence (+) of thrombomodulin (TM) for the lowest one. The PD models were built to characterize the relationships between plasma rivaroxaban concentrations and endogenous thrombin potential (ETP) or peak height induced by the lowest TF concentration.

Results: Thrombin generation parameter time profiles with the lowest TF concentration showed a good sensitivity to rivaroxaban, especially +TM (active protein C negative feedback). The relationship between rivaroxaban concentrations and TG parameters was modeled with a sigmoidal relation. Mean rivaroxaban concentrations halving the baseline value of ETP and peak height (-TM) (C50 ) were of 284 and 33.2 ng/mL, respectively: +TM, C50 declined to 19.4 and 13.8 ng/mL, reflecting a powerful inhibitory effect. The estimated C50 population coefficients of variation were of 12.2% (-TM) and 31.3% (+TM) with the peak height models, 34.8% (+TM) with the ETP model.

Conclusions: This low-rivaroxaban to moderate-rivaroxaban PD variability in healthy volunteers contrasts with the substantial PK variability and deserves to be studied in different patient settings.

Keywords: healthy volunteers; pharmacodynamic model; rivaroxaban; thrombin generation; thrombomodulin.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter 1 / genetics
  • ATP Binding Cassette Transporter 1 / metabolism
  • Adolescent
  • Adult
  • Biological Variation, Individual*
  • Blood Coagulation / drug effects*
  • Cross-Over Studies
  • Drug Monitoring
  • Enzyme Activation
  • Factor Xa Inhibitors / administration & dosage
  • Factor Xa Inhibitors / blood
  • Factor Xa Inhibitors / pharmacokinetics*
  • Genotype
  • Healthy Volunteers
  • Humans
  • Male
  • Middle Aged
  • Models, Biological*
  • Protein C / metabolism*
  • Rivaroxaban / administration & dosage
  • Rivaroxaban / blood
  • Rivaroxaban / pharmacokinetics*
  • Thrombin / metabolism*
  • Young Adult

Substances

  • ABCA1 protein, human
  • ATP Binding Cassette Transporter 1
  • Factor Xa Inhibitors
  • Protein C
  • Rivaroxaban
  • Thrombin