Rivaroxaban pharmacodynamics in healthy volunteers evaluated with thrombin generation and the active protein C system modeling and assessing inter-individual variability

Virginie Siguret 1, 2, 3 Johan Abdoul 1, 3 Xavier Delavenne 4, 5 Emmanuel Curis 6, 7 Audrey Carlo 8 Anne Blanchard 9, 10 Joe-Elie Salem 11, 12, 13 Pascale Gaussem 3, 14 Christian Funck-Brentano 11, 12, 13 Michel Azizi 15, 10, 14 Patrick Mismetti 4 Marie-Anne Loriot 16, 14 Thomas Lecompte Isabelle Gouin-Thibault 17, 18
1 UPEM - Université Paris-Est Marne-la-Vallée
2 AP-HP - Hopital Saint-Louis, Assistance Publique – Hôpitaux de Paris
3 IThEM - U1140 - Innovations thérapeutiques en hémostase
4 CHU de Saint-Etienne - Centre Hospitalier Universitaire de Saint-Etienne
5 GRT (EA 3065) - Groupe de recherche sur la thrombose
6 UPD5 Pharmacie - Université Paris Descartes - Faculté de Pharmacie de Paris
7 CHU Saint Louis [APHP]
8 Diagnostica Stago
9 UPD5 Médecine - Université Paris Descartes - Faculté de Médecine
10 CIC 1418 - CIC - HEGP
11 CHU Pitié-Salpêtrière [APHP]
12 CIC Paris Est
13 ICAN - Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition
14 HEGP - Hôpital Européen Georges Pompidou [APHP]
15 UPD5 - Université Paris Descartes - Paris 5
16 MEPPOT - U1147 - Médecine Personnalisée, Pharmacogénomique, Optimisation Thérapeutique
17 CHU Pontchaillou [Rennes]
18 CIC - Centre d'Investigation Clinique [Rennes]
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 : rivaroxaban thrombin generation thrombomodulin pharmacodynamic model healthy volunteers
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UNIV-RENNES1 | SU-MEDECINE | UR1-UFR-SVE | USPC | UNIV-RENNES | SORBONNE-UNIVERSITE | BIOSIT | ICAN | CIC203 | CIC | UNIV-ST-ETIENNE | UPEC-UPEM | UNIV-PARIS5

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Virginie Siguret, Johan Abdoul, Xavier Delavenne, Emmanuel Curis, Audrey Carlo, et al.. Rivaroxaban pharmacodynamics in healthy volunteers evaluated with thrombin generation and the active protein C system modeling and assessing inter-individual variability. Journal of Thrombosis and Haemostasis, Wiley, In press, 17 (10), pp.1670-1682. ⟨10.1111/jth.14541⟩. ⟨hal-02179152⟩

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