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

被引：24

作者：

Siguret, Virginie ^{[1
,2
,3
]}

Abdoul, Johan ^{[1
,2
]}

Delavenne, Xavier ^{[4
,5
]}

Curis, Emmanuel ^{[2
,6
,7
]}

Carlo, Audrey ^{[8
]}

Blanchard, Anne ^{[2
,9
]}

Salem, Joe-Elie ^{[10
,11
]}

Gaussem, Pascale ^{[1
,2
,12
]}

Funck-Brentano, Christian ^{[10
,11
]}

Azizi, Michel ^{[2
,9
,13
]}

Mismetti, Patrick ^{[14
,15
]}

Loriot, Marie-Anne ^{[2
,16
,17
]}

Lecompte, Thomas ^{[18
,19
]}

Gouin-Thibault, Isabelle ^{[20
,21
]}

机构：

[1] INSERM, UMR S1140, Paris, France

[2] Univ Paris 05, Sorbonne Paris Cite, Paris, France

[3] Hop Lariboisiere, AP HP, Serv Hematol Biol, Paris, France

[4] CHU St Etienne, Lab Pharmacol Toxicol, St Etienne, France

[5] Univ Jean Monnet, Grp Rech Thrombose, St Etienne, France

[6] Fac Pharm Paris, Lab Biomath, Plateau iB2, EA 7537 BioSTM, Paris, France

[7] Hop St Louis, AP HP, Serv Biostat & Informat Med, Paris, France

[8] Diagnost Stago, Paris, France

[9] Hop Europeen Georges Pompidou, AP HP, INSERM, Ctr Invest Clin,CIC 1418, Paris, France

[10] Hop La Pitie Salpetriere, AP HP, Dept Pharmacol, Paris, France

[11] Sorbonne Univ, INSERM, Inst Cardiometab & Nutr ICAN, CIC 1421,UMR ICAN 1166, Paris, France

[12] Hop Europeen Georges Pompidou, AP HP, Serv Hematol Biol, Paris, France

[13] Hop Europeen Georges Pompidou, AP HP, Unite Hypertens Arterielle, Paris, France

[14] CHU St Etienne, Serv Med Vasc & Therapeut, St Etienne, France

[15] CHU St Etienne, Unite Rech Clin, Innovat, Pharmacol, St Etienne, France

[16] Hop Europeen Georges Pompidou, AP HP, Serv Biochim, Paris, France

[17] Ctr Univ St Peres, INSERM, UMR S1147, Paris, France

[18] Univ Geneva, HUG, Dept Med, Unite Hemostase, Geneva, Switzerland

[19] Univ Geneva, GpG, Fac Med, Geneva, Switzerland

[20] CHU Pontchaillou, Lab Hematol Biol, Rennes, France

[21] Univ Rennes, INSERM, CIC 1414, Rennes, France

来源：

JOURNAL OF THROMBOSIS AND HAEMOSTASIS | 2019年 / 17卷 / 10期

关键词：

healthy volunteers; pharmacodynamic model; rivaroxaban; thrombin generation; thrombomodulin; FACTOR XA INHIBITOR; DIRECT ORAL ANTICOAGULANTS; IN-VITRO; POPULATION PHARMACOKINETICS; AGE-DEPENDENCY; APIXABAN; DABIGATRAN; COAGULATION; GUIDELINES; EDOXABAN;

D O I：

10.1111/jth.14541

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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) (C-50) were of 284 and 33.2 ng/mL, respectively: +TM, C-50 declined to 19.4 and 13.8 ng/mL, reflecting a powerful inhibitory effect. The estimated C-50 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.

引用

页码：1670 / 1682

页数：13