Safety, tolerability and clinical pharmacology of dabigatran etexilate in adolescents

Summary

Venous thromboembolism (VTE) incidence is increasing among children owing to many factors, including improved diagnosis of VTE. There is a need for alternative treatment options. Our objective was to investigate the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of dabigatran etexilate in adolescents with VTE. Adolescents aged 12 to <18 years (n = 9) who successfully completed planned treatment for primary VTE were administered dabigatran etexilate twice daily for three days; initially 1.71 (± 10%) mg/kg (80% of a 150 mg/70 kg twice daily adult dose), followed by 2.14 (± 10%) mg/kg (target adult dose adjusted for patient’s weight), if there were no safety concerns. No bleeding events, deaths or drug-related serious adverse events (AEs) were reported; three treatment-emergent AEs, all gastrointestinal-related, occurred in two patients. In these adolescent patients with normal renal function, presumed steady-state trough plasma concentrations of dabigatran were low (geometric mean dosenormalised total dabigatran plasma concentration: 0.493 ng/ml/mg at 72 hours). Total dabigatran concentrations were well predicted by the RE-LY^® population PK model (94% of trough concentrations were within the 80% prediction interval). The relationship between total dabigatran plasma concentration, diluted thrombin time and ecarin clotting time (ECT) was linear; the relationship with activated partial thromboplastin time (aPTT) was non-linear. Adult population PK/PD models predicted the adolescent concentration–ECT and –aPTT relationships well. In conclusion, dabigatran etexilate was generally well tolerated, except for occurrence of dyspepsia in two patients, over the three-day treatment period. The dabigatran PK/PD relationship observed in adolescent patients was similar to that in adult patients.

Institution where work was performed: Main clinical study site: Children’s Hospital of Eastern Ontario, Ottawa, Ontario, Canada.

This study is registered at ClinicalTrials.gov (NCT00844415).

Keywords

Adolescent - anticoagulants - dabigatran - direct thrombin inhibitors - venous thromboembolism

• References

• 1 Goldenberg NA.. Long-term outcomes of venous thrombosis in children. Curr Opin Hematol 2005; 12: 370-376.
• 2 Gibson BES, Chalmers EA, Bolton-Maggs P. et al. Thromboembolism in childhood: a prospective two-year BPSU study in the United Kingdom. February 2001–February 2003. Br J Haematol 2004; 125: 1-72.
• 3 Massicotte MP, Dix D, Monagle P. et al. Central venous catheter related thrombosis in children: analysis of the Canadian Registry of Venous Thromboembolic Complications. J Pediatr 1998; 133: 770-776.
• 4 Schmidt B, Andrew M.. Neonatal thrombosis: report of a prospective Canadian and international registry. Pediatrics 1995; 96: 939-943.
• 5 Tuckuviene R, Christensen AL, Helgestad J. et al. Pediatric venous and arterial noncerebral thromboembolism in Denmark: a nationwide population-based study. J Pediatr 2011; 159: 663-669.
• 6 Sandoval JA, Sheehan MP, Stonerock CE. et al. Incidence, risk factors, and treatment patterns for deep venous thrombosis in hospitalized children: an increasing population at risk. J Vasc Surg 2008; 47: 837-843.
• 7 Chan AK, Monagle P.. Updates in thrombosis in pediatrics: where are we after 20 years?. Hematology Am Soc Hematol Educ Program 2012; 2012: 439-443.
• 8 Raffini L, Huang YS, Witmer C. et al. Dramatic increase in venous thromboembolism in children's hospitals in the United States from 2001 to 2007. Pediatrics 2009; 124: 1001-1008.
• 9 Parasuraman S, Goldhaber SZ.. Venous thromboembolism in children. Circulation 2006; 113: e12-e16.
• 10 Weitz JI.. New oral anticoagulants in development. Thromb Haemost 2010; 103: 62-70.
• 11 Garcia DA, Baglin TP, Weitz JI. et al. Parenteral anticoagulants: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141: e24S-e43S.
• 12 Andrew M, Vegh P, Johnston M. et al. Maturation of the hemostatic system during childhood. Blood 1992; 80: 1998-2005.
• 13 Mitchell LG, Halton JM, Vegh PA. et al. Effect of disease and chemotherapy on hemostasis in children with acute lymphoid leukemia. Am J Pediatr Hematol Oncol 1994; 16: 120-126.
• 14 Andrew M, Paes B, Milner R. et al. Development of the human coagulation system in the full-term infant. Blood 1987; 70: 165-172.
• 15 Ageno W, Gallus AS, Wittkowsky A. et al. Oral anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141: e44S-e88S.
• 16 Dansirikul C, Lehr T, Liesenfeld KH. et al. A combined pharmacometric analysis of dabigatran etexilate in healthy volunteers and patients with atrial fibrillation or undergoing orthopaedic surgery. Thromb Haemost 2012; 107: 775-785.
• 17 Liesenfeld KH, Lehr T, Dansirikul C. et al. Population pharmacokinetic analysis of the oral thrombin inhibitor dabigatran etexilate in patients with non-valvular atrial fibrillation from the RE-LY trial. J Thromb Haemost 2011; 9: 2168-2175.
• 18 Hayton WL.. Maturation and growth of renal function: dosing renally cleared drugs in children. AAPS PharmSci 2000; 2: E3.
• 19 Kuhle S, Male C, Mitchell L.. Developmental hemostasis: pro- and anticoagulant systems during childhood. Semin Thromb Hemost 2003; 29: 329-338.
• 20 Dietrich K, Stang K, van Ryn J. et al. Assessing the anticoagulant effect of dabigatran in children: An in vitro study. Thrombosis Research 2015; 135: 630-635.
• 21 Stangier J.. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet 2008; 47: 285-295.
• 22 Cockcroft DW, Gault MH.. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16: 31-41.
• 23 Schäftlein A, Maas H, Reilly PA. et al. Population modeling of the relationship between the pharmacokinetics of the oral thrombin inhibitor dabigatran etexilate and coagulation biomarkers in patients with non-valvular atrial fibrillation from the RE-LY trial. Available at: www.page-meeting.org/?abstract=3101 Accessed February 19, 2015.
• 24 Stangier J, Feuring M.. Using the HEMOCLOT direct thrombin inhibitor assay to determine plasma concentrations of dabigatran. Blood Coagul Fibrinolysis 2012; 23: 138-143.
• 25 Beyer-Westendorf J, Ebertz F, Forster K. et al. Effectiveness and safety of dabigatran therapy in daily-care patients with atrial fibrillation. Results from the Dresden NOAC Registry. Thromb Haemost 2015; 113: 1247-1257.
• 26 Bytzer P, Connolly SJ, Yang S. et al. Analysis of upper gastrointestinal adverse events among patients given dabigatran in the RE-LY trial. Clin Gastroenterol Hepatol 2013; 11: 246-252.
• 27 Staerk L, Gislason GH, Lip GY. et al. Risk of gastrointestinal adverse effects of dabigatran compared with warfarin among patients with atrial fibrillation: a nationwide cohort study. Europace 2015; 17: 1215-1222.
• 28 Schulman S, Kearon C, Kakkar AK. et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009; 361: 2342-2352.
• 29 Nieuwlaat R, Healey JS, Ezekowitz M. et al. Management of dyspepsia symptoms on dabigatran during RELY-ABLE: long-term follow up study after RE-LY. Eur Heart J. 2013 34. Abstr P549.
• 30 Connolly SJ, Ezekowitz MD, Yusuf S. et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139-1151.
• 31 Dabigatran [summary of product characteristics]. Ingelheim am Rhein. Germany: Boehringer Ingelheim Pharma GmbH & Co. KG.; Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000829/WC500041059.pdf 2013
• 32 Beyer-Westendorf J, Gehrisch S. Phamacokinetics of rivaroxaban in adolescents. Hamostaseologie 2014; 34: 85-87.
• 33 Kuhle S, Massicotte P, Dinyari M. et al. Dose-finding and pharmacokinetics of therapeutic doses of tinzaparin in pediatric patients with thromboembolic events. Thromb Haemost 2005; 94: 1164-1171.
• 34 Streif W, Andrew M, Marzinotto V. et al. Analysis of warfarin therapy in pediatric patients: A prospective cohort study of 319 patients. Blood 1999; 94: 3007-3014.
• 35 Stewart CF, Hampton EM.. Effect of maturation on drug disposition in pediatric patients. Clin Pharm 1987; 6: 548-564.
• 36 van Ryn J, Stangier J, Haertter S. et al. Dabigatran etexilate--a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010; 103: 1116-1127.
• 37 Stangier J, Clemens A.. Pharmacology, pharmacokinetics, and pharmacodynamics of dabigatran etexilate, an oral direct thrombin inhibitor. Clin Appl Thromb Hemost 2009; 15 (Suppl. 01) 9S-16S.
• 38 Pollack Jr. CV, Reilly PA, Eikelboom J. et al. Idarucizumab for Dabigatran Reversal. N Engl J Med 2015; 373: 511-520.