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DOI: 10.1160/TH16-06-0423
Apixaban pharmacodynamic activity in umbilical cord, paediatric, and adult plasma
Publication History
Received:
01 June 2016
Accepted after major revision:
09 May 2017
Publication Date:
22 November 2017 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/201708/lookinside/thumbnails/10-1160-th16-06-0423-1.jpg)
Summary
The objective was to characterise apixaban pharmacodynamic (PD) activity in umbilical cord (UC), paediatric, and adult plasma. Plasma was obtained from blood samples from six UC donors, 70 paediatric (neonates [birth–≤1 month], infants [>1–≤6 months], toddlers [>6 months–≤2 years], young children [>2–≤6 years], children [>6–≤12 years], adolescents [>12–≤18 years]), and six adult (19–45 years) subjects. Plasma spiked with apixaban 0 (baseline), 30, or 110 ng/ml was analysed for anti-factor Xa activity, factor X levels, prothrombin time (PT), and modified PT (mPT). Apixaban had similar concentration-related effects on anti-factor Xa activity across groups (30 ng/ml: 0.223–0.295 IU/ml; 110 ng/ml: 1.212–1.474 IU/ml). Endogenous baseline factor X levels were 43%–68% lower in plasma from UC and subjects ≤6 months versus adults. Factor Xa inhibition (percentage change from baseline in apparent factor X levels) was similar for both apixaban concentrations across groups, except UC, neonate, and infant groups, which showed greater inhibition vs adults for apixaban 110 ng/ml. Baseline PT and mPT were similar across groups. Apixaban had no effect on PT at the concentrations tested. Apixaban 110 ng/ml prolonged mPT similarly across groups (44.4–53.2 s to 64.5–70.0 s); no prolongation was found with apixaban 30 ng/ml. Apixaban demonstrated consistent concentration-related effects on other PD endpoints in plasma samples from all age groups, except factor Xa inhibition.
Supplementary Material to this article is available at www.thrombosis-online.com.
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References
- 1 Andrew M, Paes B, Milner R. et al. Development of the human coagulation system in the healthy premature infant. Blood 1988; 72: 1651-1657.
- 2 Andrew M, Paes B, Milner R. et al. Development of the human coagulation system in the full-term infant. Blood 1987; 70: 165-172.
- 3 Andrew M, Vegh P, Johnston M. et al. Maturation of the hemostatic system during childhood. Blood 1992; 80: 1998-2005.
- 4 Wong PC, Crain EJ, Xin B. et al. Apixaban, an oral, direct and highly selective factor Xa inhibitor: in vitro, antithrombotic and antihemostatic studies. J Thromb Haemost 2008; 06: 820-829.
- 5 Bristol-Myers Squibb, Pfizer EEIG. Eliquis® (apixaban tablets) Summary of product characteristics. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002148/WC500107728.pdf Accessed February 25, 2016.
- 6 Bristol-Myers Squibb Company PI. Eliquis (apixaban) prescribing information. Available at: http://packageinserts.bms.com/pi/pi_eliquis.pdf Accessed February 25, 2016.
- 7 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: 476-487.
- 8 Frost C, Nepal S, Wang J. et al. Safety, pharmacokinetics and pharmacodynamics of multiple oral doses of apixaban, a factor Xa inhibitor, in healthy subjects. Br J Clin Pharmacol 2013; 76: 776-786.
- 9 Barrett YC, Wang Z, Frost C. et al. Clinical laboratory measurement of direct factor Xa inhibitors: anti-Xa assay is preferable to prothrombin time assay. Thromb Haemost 2010; 104: 1263-1271.
- 10 Barrett YC, Wang Z, Knabb RM. A novel prothrombin time assay for assessing the anticoagulant activity of oral factor Xa inhibitors. Clin Appl Thromb Hemost 2013; 19: 522-528.
- 11 Becker RC, Alexander JH, Newby LK. et al. Effect of apixaban, an oral and direct factor Xa inhibitor, on coagulation activity biomarkers following acute coronary syndrome. Thromb Haemost 2010; 104: 976-983.
- 12 Becker RC, Yang H, Barrett Y. et al. Chromogenic laboratory assays to measure the factor Xa-inhibiting properties of apixaban-an oral, direct and selective factor Xa inhibitor. J Thromb Thrombolysis 2011; 32: 183-187.
- 13 Byon W, Sweeney K, Frost C, Boyd R. Population pharmacokinetic analysis of apixaban in venous thromboembolism treatment patients. J Pharmacokinet Pharmacodynam 2014; 41: S65 (Abstract T-060).
- 14 Kowalski K, Nielsen J, Roy A. et al. Apixaban exposure and anti-Xa activity in nonvalvular atrial fibrillation patients: an application of population PK/PD analysis. J Pharmacokinet Pharmacodyn 2014; 41: S19 (Abstract M-027).
- 15 Wang Z, Green G, Connolly T. Assessment of apixaban plasma levels by anti-Xa activity tests: comparison of Rotachrom and STA Liquid anti-Xa assays. Am J Hematol 2014; 89: E76-E77.
- 16 Leil TA, Frost C, Wang X. et al. Model-based exposure-response analysis of apixaban to quantify bleeding risk in special populations of subjects undergoing orthopedic surgery. CPT Pharmacometrics Syst Pharmacol 2014; 03: e136.
- 17 Lassen MR, Raskob GE, Gallus A. et al. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med 2009; 361: 594-604.
- 18 Lassen MR, Raskob GE, Gallus A. et al. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet 2010; 375: 807-815.
- 19 Monagle P, Barnes C, Ignjatovic V. et al. Developmental haemostasis. Impact for clinical haemostasis laboratories. Thromb Haemost 2006; 95: 362-372.
- 20 Attard C, Monagle P, Kubitza D. et al. The in-vitro anticoagulant effect of rivaroxaban in neonates. Blood Coagul Fibrinolysis 2014; 25: 237-240.
- 21 Andrew M, Mitchell L, Vegh P. et al. Thrombin regulation in children differs from adults in the absence and presence of heparin. Thromb Haemost 1994; 72: 836-842.
- 22 Chan AK, Berry LR, Monagle PT. et al. Decreased concentrations of heparinoids are required to inhibit thrombin generation in plasma from newborns and children compared to plasma from adults due to reduced thrombin potential. Thromb Haemost 2002; 87: 606-613.
- 23 Newall F, Ignjatovic V, Summerhayes R. et al. In vivo age dependency of unfractionated heparin in infants and children. Thromb Res 2009; 123: 710-714.
- 24 Massicotte P, Leaker M, Marzinotto V. et al. Enhanced thrombin regulation during warfarin therapy in children compared to adults. Thromb Haemost 1998; 80: 570-574.
- 25 Cade JF, Hirsh J, Martin M. Placental barrier to coagulation factors: its relevance to the coagulation defect at birth and to haemorrhage in the newborn. Br Med J 1969; 02: 281-283.
- 26 Koestenberger M, Gallistl S, Cvirn G. et al. Anticoagulant action of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran, in umbilical cord and adult plasma: an in vitro examination. Thromb Res 2005; 115: 135-142.
- 27 Douxfils J, Tamigniau A, Chatelain B. et al. Measurement of non-VKA oral anticoagulants versus classic ones: the appropriate use of hemostasis assays. Thromb J 2014; 12: 24.
- 28 Frost C, Song Y, Barrett YC. et al. A randomized direct comparison of the pharmacokinetics and pharmacodynamics of apixaban and rivaroxaban. Clin Pharmacol 2014; 06: 179-187.
- 29 Clinicaltrials.gov Study to evaluate a single dose of apixaban in pediatric subjects at risk for a thrombotic disorder. Available at: http://clinicaltrials.gov/ct2/show/NCT01707394 Accessed March 23, 2016.
- 30 Clinicaltrials.gov Apixaban for the acute treatment of venous thromboembolism in children. Available at: https://clinicaltrials.gov/ct2/show/NCT02464969 Accessed March 23, 2016.