Virginie Siguret1,2,3, Johan Abdoul1,2, Xavier Delavenne4,5, Emmanuel Curis2,6,7, Audrey Carlo8, Anne Blanchard2,9, Joe-Elie Salem10,11, Pascale Gaussem1,2,12, Christian Funck-Brentano10,11, Michel Azizi2,9,13, Patrick Mismetti14,15, Marie-Anne Loriot2,16,17, Thomas Lecompte18, Isabelle Gouin-Thibault19,20. 1. INSERM UMR_S1140, Paris, France. 2. Université Paris Descartes, Sorbonne Paris Cité, Paris, France. 3. Service d'Hématologie Biologique, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Lariboisière, Paris, France. 4. Laboratoire de Pharmacologie -Toxicologie, Centre Hospitalier Universitaire de Saint-Etienne, Saint-Etienne, France. 5. Groupe de Recherche sur la Thrombose, Université Jean Monnet, Saint-Etienne, France. 6. Laboratoire de biomathématiques, plateau iB2, EA 7537 BioSTM, Faculté de pharmacie de Paris, Paris, France. 7. Service de biostatistiques et informatique médicale, Hôpital Saint-Louis, AP-HP, Paris, France. 8. Diagnostica Stago, Paris, France. 9. Centre d'Investigation Clinique INSERM CIC-1418, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Européen Georges Pompidou, Paris, France. 10. Département de Pharmacologie, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Pitié-Salpêtrière, Paris, France. 11. INSERM, CIC-1421, Institut de Cardio-métabolisme et Nutrition (ICAN), UMR ICAN_1166, Sorbonne Universités, Paris, France. 12. Service d'Hématologie Biologique, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Européen Georges Pompidou, Paris, France. 13. Unité d'Hypertension Artérielle, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Européen Georges Pompidou, Paris, France. 14. Service de Médecine Vasculaire et Thérapeutique, Centre Hospitalier Universitaire de Saint Étienne, Saint Étienne, France. 15. Unité de Recherche Clinique, Innovation, Pharmacologie, Centre Hospitalier Universitaire de Saint Étienne, Saint Étienne, France. 16. Service de Biochimie, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Européen Georges Pompidou, Paris, France. 17. INSERM UMR_S1147, Centre Universitaire des Saints-Pères, Paris, France. 18. Unité d'Hémostase, Département de Médecine, Hôpitaux Universitaires de Genève (HUG) and GpG, Faculté de médecine, Université de Genève, Geneva, Switzerland. 19. Laboratoire d'Hématologie Biologique, Centre Hospitalier Universitaire Pontchaillou, Rennes, France. 20. INSERM, CIC-1414, Université de Rennes, Rennes, France.
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.
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-rivaroxabanPD variability in healthy volunteers contrasts with the substantial PK variability and deserves to be studied in different patient settings.
Authors: Patricia Gomez-Rosas; Marina Pesenti; Cristina Verzeroli; Cinzia Giaccherini; Laura Russo; Roberta Sarmiento; Giovanna Masci; Luigi Celio; Mauro Minelli; Sara Gamba; Carmen Julia Tartari; Carlo Tondini; Francesco Giuliani; Fausto Petrelli; Andrea D'Alessio; Giampietro Gasparini; Roberto Labianca; Armando Santoro; Filippo De Braud; Marina Marchetti; Anna Falanga Journal: TH Open Date: 2021-02-10
Authors: Christian Pfrepper; Michael Metze; Annelie Siegemund; Tristan Klöter; Thomas Siegemund; Sirak Petros Journal: Res Pract Thromb Haemost Date: 2020-04-23
Authors: Michael Metze; Christian Pfrepper; Tristan Klöter; Stephan Stöbe; Roland Siegemund; Thomas Siegemund; Elvira Edel; Ulrich Laufs; Sirak Petros Journal: Res Pract Thromb Haemost Date: 2020-04-23