Pharmacokinetic-Pharmacodynamic Analysis’ Role in Design of Phase ⅠClinical Trials of Anticoagulant Agents: A Systematic Review

References

• Wendelboe AM, Raskob GE. Global burden of thrombosis: epidemiologic aspects. Circ Res. 2016;118(9):1340–1347.
   PubMed Web of Science ®Google Scholar
• Lippi G, Gosselin R, Favaloro EJ. Current and emerging direct oral anticoagulants: state-of-the-art. Semin Thromb Hemost. 2019;45(5):490–501.
   PubMed Web of Science ®Google Scholar
• Schäfer A, Flierl U, Berliner D, et al. Anticoagulants for stroke prevention in atrial fibrillation in elderly patients. Cardiovasc Drugs Ther. 2020. DOI:https://doi.org/10.1007/s10557-020-06981-3
   Google Scholar
• Franchini M, Liumbruno GM, Bonfanti C, et al. The evolution of anticoagulant therapy. Blood Transfus. 2016;14(2):175–184.
   PubMed Web of Science ®Google Scholar
• Lippi G, Favaloro EJ. Laboratory hemostasis: milestones in clinical chemistry and laboratory medicine. Clin Chem Lab Med. 2013;51(1):91–97.
   PubMed Web of Science ®Google Scholar
• Weitz JI, Harenberg J. New developments in anticoagulants: past, present and future. Thromb Haemost. 2017;117(7):1283–1288.
   PubMed Web of Science ®Google Scholar
• Tan CSS, Lee SWH. Warfarin and food, herbal or dietary supplement interactions: a systematic review. Br J Clin Pharmacol. 2020. DOI:https://doi.org/10.1111/bcp.14404
   Google Scholar
• Patriarcheas V, Pikoulas A, Kostis M, et al. Heparin-induced thrombocytopenia: pathophysiology, diagnosis and management. Cureus. 2020;12(3):e7385.
   PubMed Web of Science ®Google Scholar
• Dabigatran etexilate (Pradaxa)–a new oral anticoagulant. Med Lett Drugs Ther. 2010;52(1351):89–90.
   PubMed Web of Science ®Google Scholar
• Ahrens I, Bode C. Rivaroxaban for stroke prevention in atrial fibrillation and secondary prevention in patients with a recent acute coronary syndrome. Future Cardiol. 2012;8(4):533–541.
   PubMedGoogle Scholar
• Mezue K, Obiagwu C, John J, et al. Novel oral anticoagulants in atrial fibrillation: update on apixaban. Curr Cardiol Rev. 2017;13(1):41–46.
   PubMed Web of Science ®Google Scholar
• Barrios V, Escobar C. Implications of edoxaban in the prevention and treatment of thromboembolic complications in clinical practice. Future Cardiol. 2016;12(4):419–433.
   PubMed Web of Science ®Google Scholar
• Palladino M, Merli G, Thomson L. Evaluation of the oral direct factor Xa inhibitor - betrixaban. Expert Opin Investig Drugs. 2013;22(11):1465–1472.
   PubMed Web of Science ®Google Scholar
• Greinacher A, Thiele T, Selleng K. Reversal of anticoagulants: an overview of current developments. Thromb Haemost. 2015;113(5):931–942.
   PubMed Web of Science ®Google Scholar
• Hellenbart EL, Faulkenberg KD, Finks SW. Evaluation of bleeding in patients receiving direct oral anticoagulants. Vasc Health Risk Manag. 2017;13:325–342.
   PubMed Web of Science ®Google Scholar
• Jaffer IH, Stafford AR, Fredenburgh JC, et al. Dabigatran is less effective than warfarin at attenuating mechanical heart valve-induced thrombin generation. J Am Heart Assoc. 2015;4(8):e002322.
   PubMed Web of Science ®Google Scholar
• Steffel J, Verhamme P, Potpara TS, et al. The 2018 European heart rhythm association practical guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation: executive summary. Europace. 2018;20(8):1231–1242.
   PubMed Web of Science ®Google Scholar
• Group IEW. ICH harmonised tripartite guideline general considerations for clinical trials E8. In: International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use. (Ed.^(Eds); 1997.
   Google Scholar
• Gaussem P, Dubar M, le Bonniec B, et al. Dose-effect relationship for several coagulation markers during administration of the direct thrombin inhibitor S 18326 in healthy subjects. Br J Clin Pharmacol. 2002;53(2):147–154.
   PubMed Web of Science ®Google Scholar
• Stern R, Chanoine F, Criswell K. Are coagulation times biomarkers? Data from a phase I study of the oral thrombin inhibitor LB-30057 (CI-1028). J Clin Pharmacol. 2003;43(2):118–121.
   PubMed Web of Science ®Google Scholar
• Johansson S, Wahlander K, Larson G, et al. Pharmacokinetics and anticoagulant effect of the direct thrombin inhibitor melagatran following subcutaneous administration to healthy young men. Blood Coagul Fibrinolysis. 2003;14(7):677–684.
   PubMed Web of Science ®Google Scholar
• Eriksson UG, Bredberg U, Gislen K, et al. Pharmacokinetics and pharmacodynamics of ximelagatran, a novel oral direct thrombin inhibitor, in young healthy male subjects. Eur J Clin Pharmacol. 2003;59(1):35–43.
   PubMed Web of Science ®Google Scholar
• Stangier J, Rathgen K, Stahle H, et al. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol. 2007;64(3):292–303.
   PubMed Web of Science ®Google Scholar
• Johansson S, Cullberg M, Eriksson UG, et al. Single-dose pharmacokinetics, pharmacodynamics and safety of AZD0837, a novel oral direct thrombin inhibitor, in young healthy male subjects. Int J Clin Pharmacol Ther. 2011;49(4):258–267.
   PubMed Web of Science ®Google Scholar
• Kim J, Lee SH, Boyce M, et al. Pharmacokinetics, pharmacodynamics and food effect of LB30870, a novel direct thrombin inhibitor, after single oral doses in healthy men. Xenobiotica. 2015;45(8):663–671.
   PubMed Web of Science ®Google Scholar
• Oral AZD8165 after single oral ascending doses in healthy male subjects (NCT01150812). [ Cited 2020 Feb 20]. Available from: https://www.clinicaltrials.gov/ct2/show/NCT01150812?term=NCT01150812&draw=2&rank=1
   Google Scholar
• A Study to Evaluate Safety, Tolerability, Pharmacokinetics, Immunogenicity, and Pharmacodynamics of JNJ-64179375 in Healthy Male Subjects NCT02949206. [ Cited 2020 Feb 20]. Available from: https://www.clinicaltrials.gov/ct2/show/NCT02949206?term=NCT02949206&draw=2&rank=1
   Google Scholar
• Murayama N, Tanaka M, Kunitada S, et al. Tolerability, pharmacokinetics, and pharmacodynamics of DX-9065a, a new synthetic potent anticoagulant and specific factor Xa inhibitor, in healthy male volunteers. Clin Pharmacol Ther. 1999;66(3):258–264.
   PubMed Web of Science ®Google Scholar
• Paccaly A, Ozoux ML, Chu V, et al. Pharmacodynamic markers in the early clinical assessment of otamixaban, a direct factor Xa inhibitor. Thromb Haemost. 2005;94(6):1156–1163.
   PubMed Web of Science ®Google Scholar
• Kubitza D, Becka M, Wensing G, et al. Safety, pharmacodynamics, and pharmacokinetics of BAY 59-7939–an oral, direct factor Xa inhibitor–after multiple dosing in healthy male subjects. Eur J Clin Pharmacol. 2005;61(12):873–880.
   PubMed Web of Science ®Google Scholar
• Frost C, Wang J, Nepal S, et al. Apixaban, an oral, direct factor Xa inhibitor: single dose safety, pharmacokinetics, pharmacodynamics and food effect in healthy subjects. Br J Clin Pharmacol. 2013;75(2):476–487.
   PubMed Web of Science ®Google Scholar
• Schmitt C, Pannier A, McIntyre C, et al. Crossover dose escalation study to assess safety, pharmacokinetics, and pharmacodynamics of single doses of R1663, an oral factor Xa inhibitor, in healthy male volunteers. J Clin Pharmacol. 2012;52(4):499–510.
   PubMed Web of Science ®Google Scholar
• Ogata K, Mendell-Harary J, Tachibana M, et al. Clinical safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel factor Xa inhibitor edoxaban in healthy volunteers. J Clin Pharmacol. 2010;50(7):743–753.
   PubMed Web of Science ®Google Scholar
• Kadokura T, Kashiwa M, Groenendaal D, et al. Clinical pharmacokinetics, pharmacodynamics, safety and tolerability of darexaban, an oral direct factor Xa inhibitor, in healthy Caucasian and Japanese subjects. Biopharm Drug Dispos. 2013;34(8):431–441.
   PubMed Web of Science ®Google Scholar
• Ogata K, Shimizu T, Masumoto H, et al. Clinical safety, tolerability, pharmacokinetics and pharmacodynamics of the novel factor Xa inhibitor DY-807f in healthy volunteers. Thromb Res. 2015;135(4):594–601.
   PubMed Web of Science ®Google Scholar
• Choi HY, Choi S, Kim YH, et al. Population pharmacokinetic and pharmacodynamic modeling analysis of GCC-4401C, a novel direct factor xa inhibitor, in healthy volunteers. CPT. 2016;5(10):532–543.
   Web of Science ®Google Scholar
• Xuan D, McBride S, Wastall P, et al. Safety, pharmacokinetics, and pharmacodynamics of PD 0348292, an oral, direct factor Xa inhibitor, after single and multiple dosings in healthy subjects. Clin Pharmacol Drug Dev. 2016;5(1):13–26.
   PubMed Web of Science ®Google Scholar
• Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single Rising Oral Doses of BI 11634 Solution in Healthy Male Volunteers (NCT02214914). [ Cited 2020 Feb 20]. Available from: https://www.clinicaltrials.gov/ct2/show/NCT02214914?term=NCT02214914&draw=2&rank=1
   Google Scholar
• Phase I Study of Direct Coagulation Factor Xa Inhibitor SYHA136 Tablets in Chinese Healthy Volunteers (NCT04036656). [ Cited 2020 Feb 20]. Available from: https://www.clinicaltrials.gov/ct2/show/NCT04036656?term=NCT04036656&draw=2&rank=1
   Google Scholar
• Fujimoto T, Imaeda Y, Konishi N, et al. Discovery of a tetrahydropyrimidin-2(1H)-one derivative (TAK-442) as a potent, selective, and orally active factor Xa inhibitor. J Med Chem. 2010;53(9):3517–3531.
   PubMed Web of Science ®Google Scholar
• Agnelli G, Haas S, Ginsberg JS, et al. A phase II study of the oral factor Xa inhibitor LY517717 for the prevention of venous thromboembolism after hip or knee replacement. J Thromb Haemost. 2007;5(4):746–753.
   PubMed Web of Science ®Google Scholar
• Turpie AG, Bauer KA, Davidson BL, et al. A randomized evaluation of betrixaban, an oral factor Xa inhibitor, for prevention of thromboembolic events after total knee replacement (EXPERT). Thromb Haemost. 2009;101(1):68–76.
   PubMed Web of Science ®Google Scholar
• Albrecht D, Ellis D, Canafax DM, et al. Pharmacokinetics and pharmacodynamics of tecarfarin, a novel vitamin K antagonist oral anticoagulant. Thromb Haemost. 2017;117(4):706–717.
   PubMed Web of Science ®Google Scholar
• Dimitropoulos G, Rahim SMZ, Moss AS, et al. New anticoagulants for venous thromboembolism and atrial fibrillation: what the future holds. Expert Opin Investig Drugs. 2018;27(1):71–86.
   PubMed Web of Science ®Google Scholar
• Verhamme P, Pakola S, Jensen TJ, et al. Tolerability and pharmacokinetics of TB-402 in healthy male volunteers. Clin Ther. 2010;32(6):1205–1220.
   PubMed Web of Science ®Google Scholar
• Chow FS, Benincosa LJ, Sheth SB, et al. Pharmacokinetic and pharmacodynamic modeling of humanized anti-factor IX antibody (SB 249417) in humans. Clin Pharmacol Ther. 2002;71(4):235–245.
   PubMed Web of Science ®Google Scholar
• Dyke CK, Steinhubl SR, Kleiman NS, et al. First-in-human experience of an antidote-controlled anticoagulant using RNA aptamer technology: a phase 1a pharmacodynamic evaluation of a drug-antidote pair for the controlled regulation of factor IXa activity. Circulation. 2006;114(23):2490–2497.
   PubMed Web of Science ®Google Scholar
• Eriksson BI, Dahl OE, Lassen MR, et al. Partial factor IXa inhibition with TTP889 for prevention of venous thromboembolism: an exploratory study. J Thromb Haemost. 2008;6(3):457–463.
   PubMed Web of Science ®Google Scholar
• Perera V, Luettgen JM, Wang Z, et al. First-in-human study to assess the safety, pharmacokinetics and pharmacodynamics of BMS-962212, a direct, reversible, small molecule factor XIa inhibitor in non-Japanese and Japanese healthy subjects. Br J Clin Pharmacol. 2018;84(5):876–887.
   PubMed Web of Science ®Google Scholar
• Koch AW, Schiering N, Melkko S, et al. MAA868, a novel FXI antibody with a unique binding mode, shows durable effects on markers of anticoagulation in humans. Blood. 2019;133(13):1507–1516.
   PubMed Web of Science ®Google Scholar
• Thomas D, Thelen K, Kraff S, et al. BAY 1213790, a fully human IgG1 antibody targeting coagulation factor XIa: first evaluation of safety, pharmacodynamics, and pharmacokinetics. Res Pract Thromb Haemost. 2019;3(2):242–253.
   PubMed Web of Science ®Google Scholar
• Lorentz CU, Verbout NG, Wallisch M, et al. Contact activation inhibitor and factor XI antibody, AB023, produces safe, dose-dependent anticoagulation in a phase 1 first-in-human trial. Arterioscler Thromb Vasc Biol. 2019;39(4):799–809.
   PubMed Web of Science ®Google Scholar
• Safety and tolerability study of BMS-986177 in healthy subjects (NCT02608970). [ Cited 2020 Feb 20]. Available from: https://www.clinicaltrials.gov/ct2/show/NCT02608970?term=NCT02608970&draw=2&rank=1
   Google Scholar
• Study to Evaluate Safety, PK and PD of Single and Multiple Ascending Doses of EP-7041 in Healthy Subjects (NCT02914353). [ Cited 2020 Feb 20]. Available from: https://www.clinicaltrials.gov/ct2/show/NCT02914353?term=NCT02914353&draw=2&rank=1
   Google Scholar
• A Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single and Multiple Doses of IONIS FXI-LRx in up to 84 Healthy Volunteers (NCT03582462). [ Cited 2020 Feb 20]. Available from: https://www.clinicaltrials.gov/ct2/show/NCT03582462?term=NCT03582462&draw=2&rank=1
   Google Scholar
• The PK/PD Study of SHR2285 Tablets in Healthy Subjects (NCT03769831). [ Cited 2020 Feb 20]. Available from: https://www.clinicaltrials.gov/ct2/show/NCT03769831?term=NCT03769831&draw=2&rank=1
   Google Scholar
• A Two-Part Study to Assess the Safety, Tolerability, PK and PD of ONO-7684 in Healthy Adult Volunteers (NCT03919890). [ Cited 2020 Feb 20]. Available from: https://www.clinicaltrials.gov/ct2/show/NCT03919890?term=NCT03919890&draw=2&rank=1
   Google Scholar
• Büller HR, Bethune C, Bhanot S, et al. Factor XI antisense oligonucleotide for prevention of venous thrombosis. N Engl J Med. 2015;372(3):232–240.
   PubMed Web of Science ®Google Scholar
• Cao H, Biondo M, Lioe H, et al. Antibody-mediated inhibition of FXIIa blocks downstream bradykinin generation. J Allergy Clin Immunol. 2018;142(4):1355–1358.
   PubMed Web of Science ®Google Scholar
• Pharmacodynamics, Safety and Pharmacokinetics After Oral Administration of BIBR 1048 MS in Healthy Volunteers (NCT02170116). [ Cited 2020 Feb 20]. Available from: https://www.clinicaltrials.gov/ct2/show/NCT02170116?term=NCT02170116&draw=2&rank=1
   Google Scholar
• A Phase I Study of Monoclonal Antibody TB-402 in Healthy Male Volunteers (NCT00612196). [ Cited 2020 Feb 20]. Available from: https://www.clinicaltrials.gov/ct2/show/NCT00612196?term=NCT00612196&draw=2&rank=1
   Google Scholar
• A Study to Assess Safety, Tolerability, and Pharmacokinetics of Orally Administered GCC4401C in Healthy Volunteers (NCT01651234). [ Cited 2020 Feb 20]. Available from: https://www.clinicaltrials.gov/ct2/show/NCT01651234?term=NCT01651234&draw=2&rank=1
   Google Scholar
• A Study to Access Safety, Tolerability, Pharmacokinetics(PK) and Pharmacodynamics(PD) of Orally Administered GCC-4401C in Healthy Volunteers. [ Cited 2020 Feb 20]. Available from: https://clinicaltrials.gov/ct2/show/NCT01954238?term=NCT01954238&draw=2&rank=1
   Google Scholar
• A Study to Evaluate the Safety and Tolerability of YM150 in Healthy Caucasian and Japanese Male and Female Subjects, and to Assess the Effect That Gender May Have on Its Actions in the Body (NCT01655056). [ Cited 2020 Feb 20]. Available from: https://www.clinicaltrials.gov/ct2/show/NCT01655056?term=NCT01655056&draw=2&rank=1
   Google Scholar
• A Short and Long Intravenous Infusion Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of BMS-962212 in Healthy Subjects (NCT03197779). [ Cited 2020 Feb 20]. Available from: https://www.clinicaltrials.gov/ct2/show/NCT03197779?term=NCT03197779&draw=2&rank=1
   Google Scholar
• Safety and Tolerability Study of Xisomab 3G3 in Healthy Adult Subjects (NCT03097341). [ Cited 2020 Feb 20]. Available from: https://www.clinicaltrials.gov/ct2/show/NCT03097341?term=NCT03097341&draw=2&rank=1
   Google Scholar
• Sibille M, Patat A, Caplain H, et al. A safety grading scale to support dose escalation and define stopping rules for healthy subject first-entry-into-man studies: some points to consider from the French Club Phase I working group. Br J Clin Pharmacol. 2010;70(5):736–748.
   PubMed Web of Science ®Google Scholar
• Emanuel EJ, Bedarida G, Macci K, et al. Quantifying the risks of non-oncology phase I research in healthy volunteers: meta-analysis of phase I studies. BMJ. 2015;350:h3271.
   PubMed Web of Science ®Google Scholar
• Johnson RA, Rid A, Emanuel E, et al. Risks of phase I research with healthy participants: a systematic review. Clin Trials. 2016;13(2):149–160.
   PubMed Web of Science ®Google Scholar
• Gueret P, Krezel C, Fuseau E, et al. EP42675, a synthetic parenteral dual-action anticoagulant: pharmacokinetics, pharmacodynamics, and absence of interactions with antiplatelet drugs. J Thromb Haemost. 2014;12(1):24–33.
   PubMed Web of Science ®Google Scholar
• Kubitza D, Becka M, Voith B, et al. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59-7939, an oral, direct factor Xa inhibitor. Clin Pharmacol Ther. 2005;78(4):412–421.
   PubMed Web of Science ®Google Scholar
• Gueret P, Combe S, Krezel C, et al. First in man study of EP217609, a new long-acting, neutralisable parenteral antithrombotic with a dual mechanism of action. Eur J Clin Pharmacol. 2016;72(9):1041–1050.
   PubMed Web of Science ®Google Scholar
• Graefe-Mody EU, Schuhly U, Rathgen K, et al. Pharmacokinetics and pharmacodynamics of BIBT 986, a novel small molecule dual inhibitor of thrombin and factor Xa. J Thromb Haemost. 2006;4(7):1502–1509.
   PubMed Web of Science ®Google Scholar
• Lin L, Zhao L, Gao N, et al. From multi-target anticoagulants to DOACs, and intrinsic coagulation factor inhibitors. Blood Rev. 2020;39:100615.
   PubMed Web of Science ®Google Scholar
• Yandrapalli S, Andries G, Gupta S, et al. Investigational drugs for the treatment of acute myocardial infarction: focus on antiplatelet and anticoagulant agents. Expert Opin Investig Drugs. 2019;28(3):223–234.
   PubMed Web of Science ®Google Scholar
• Rai V, Balters MW, Agrawal DK. Factors IX, XI, and XII: potential therapeutic targets for anticoagulant therapy in atherothrombosis. Rev Cardiovasc Med. 2019;20(4):245–253.
   PubMed Web of Science ®Google Scholar
• Goldstein S, Bates ER, Bhatt DL, et al. Phase 2 study of TAK-442, an oral factor Xa inhibitor, in patients following acute coronary syndrome. Thromb Haemost. 2014;111(6):1141–1152.
   PubMed Web of Science ®Google Scholar
• Doggrell SA. Is there evidence to support the use of direct Factor Xa inhibitors in coronary artery disease? Rev Recent Clin Trials. 2011;6(2):147–157.
   PubMedGoogle Scholar
• Astellas Pharma Inc. Discontinues development of darexaban (YM150),an oral direct factor xa inhibitor. [ Cited 2020 Mar 4]. Available from: https://www.astellas.com/en/news/13301
   Google Scholar
• DeLoughery EP, Olson SR, Puy C, et al. The safety and efficacy of novel agents targeting factors XI and XII in early phase human trials. Semin Thromb Hemost. 2019;45(5):502–508.
   PubMed Web of Science ®Google Scholar
• Székely O, Borgi M, Lip GYH. Factor XI inhibition fulfilling the optimal expectations for ideal anticoagulation. Expert Opin Emerg Drugs. 2019;24(1):55–61.
   PubMed Web of Science ®Google Scholar
• Chan NC, Weitz JI. Antithrombotic Agents. Circ Res. 2019;124(3):426–436.
   PubMed Web of Science ®Google Scholar
• Wada S, Toyoda K, Sato S, et al. Anti-Xa activity and event risk in patients with direct factor Xa inhibitors initiated early after stroke. Circ J. 2018;82(11):2872–2879.
   PubMed Web of Science ®Google Scholar
• Sakaguchi T, Osanai H, Murase Y, et al. Monitoring of anti-Xa activity and factors related to bleeding events: a study in Japanese patients with nonvalvular atrial fibrillation receiving rivaroxaban. J Cardiol. 2017;70(3):244–249.
   PubMed Web of Science ®Google Scholar
• Purrucker JC, Rizos T, Haas K, et al. Coagulation testing in intracerebral hemorrhage related to non-vitamin K antagonist oral anticoagulants. Neurocrit Care. 2017;27(2):208–213.
   PubMed Web of Science ®Google Scholar
• Kodato K, Ishida K, Shibanuma N, et al. Prothrombin time-international normalized ratio is a useful marker for edoxaban efficacy in preventing venous thromboembolism after total knee arthroplasty. Eur J Orthop Surg Traumatol. 2018;28(1):103–108.
   PubMedGoogle Scholar
• Chan N, Sager PT, Lawrence J, et al. Is there a role for pharmacokinetic/pharmacodynamic-guided dosing for novel oral anticoagulants? Am Heart J. 2018;199:59–67.
   PubMed Web of Science ®Google Scholar
• Samuelson BT, Cuker A, Siegal DM, et al. Laboratory assessment of the anticoagulant activity of direct oral anticoagulants: a systematic review. Chest. 2017;151(1):127–138.
   PubMed Web of Science ®Google Scholar
• Gosselin RC, Adcock DM, Bates SM, et al. International council for standardization in haematology (ICSH) recommendations for laboratory measurement of direct oral anticoagulants. Thromb Haemost. 2018;118(3):437–450.
   PubMed Web of Science ®Google Scholar
• Van Blerk M, Bailleul E, Chatelain B, et al. Influence of apixaban on commonly used coagulation assays: results from the Belgian national external quality assessment scheme. Int J Lab Hematol. 2017;39(4):402–408.
   PubMed Web of Science ®Google Scholar
• Cuker A, Husseinzadeh H. Laboratory measurement of the anticoagulant activity of edoxaban: a systematic review. J Thromb Thrombolysis. 2015;39(3):288–294.
   PubMed Web of Science ®Google Scholar
• Yin OQP, Antman EM, Braunwald E, et al. Linking endogenous factor Xa activity, a biologically relevant pharmacodynamic marker, to edoxaban plasma concentrations and clinical outcomes in the ENGAGE AF-TIMI 48 trial. Circulation. 2018;138(18):1963–1973.
   PubMed Web of Science ®Google Scholar
• van Pelt LJ, Lukens MV, Testa S, et al. The DaXa-inhibition assay: a concept for a readily available, universal aXa assay that measures the direct inhibitory effect of all anti-Xa drugs. Thromb Res. 2018;168:63–66.
   PubMed Web of Science ®Google Scholar
• Frost C, Song Y, Barrett YC, et al. A randomized direct comparison of the pharmacokinetics and pharmacodynamics of apixaban and rivaroxaban. Clin Pharmacol. 2014;6:179–187.
   PubMedGoogle Scholar
• Kreutz R, Persson PB, Kubitza D, et al. Dissociation between the pharmacokinetics and pharmacodynamics of once-daily rivaroxaban and twice-daily apixaban: a randomized crossover study. J Thromb Haemost. 2017;15(10):2017–2028.
   PubMed Web of Science ®Google Scholar
• Shepshelovich D, Goldvaser H, Wang L, et al. Comparison of reporting phase I trial results in ClinicalTrials.gov and matched publications. Invest New Drugs. 2017;35(6):827–833.
   PubMed Web of Science ®Google Scholar
• Shepshelovich D, Goldvaser H, Wang L, et al. Comparison of published and unpublished phase I clinical cancer trials: an analysis of the CliniclTrials.gov database. Invest New Drugs. 2018;36(5):933–938.
   PubMed Web of Science ®Google Scholar