Download PDF
Thromb Haemost 2017; 117(11): 2168-2175
DOI: 10.1160/TH17-06-0429
Stroke, Systemic or Venous Thromboembolism
Schattauer GmbH Stuttgart

Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of Dabigatran Etexilate Oral Liquid Formulation in Infants with Venous Thromboembolism

Jacqueline M. L. Halton
,
Anne-Caroline Picard
,
Ruth Harper
,
Fenglei Huang
,
Martina Brueckmann
,
Savion Gropper
,
Hugo Maas
,
Igor Tartakovsky
,
Ildar Nurmeev
,
Lesley G. Mitchell
,
Leonardo R. Brandão
,
Elizabeth Chalmers
,
Manuela Albisetti
Further Information

Publication History

23 June 2017

13 August 2017

Publication Date:
30 November 2017 (online)

Also available at
    Permissions and Reprints

Abstract

Venous thromboembolism (VTE) is more frequent in infants than in older children. Treatment guidelines in children are adapted from adult VTE data, but do not currently include direct oral anticoagulant use. Dabigatran etexilate (DE) use in the paediatric population with VTE therefore requires verification. We investigated the pharmacokinetic/pharmacodynamic (PK/PD) relationship, safety and tolerability of DE oral liquid formulation (OLF) in infants with VTE (aged < 12 months) who had completed standard anticoagulant treatment in an open-label, phase IIa study. Patients received a single-dose of DE OLF (based on an age- and weight-adjusted nomogram) yielding an exposure comparable to 150 mg in adults. The PK end point was plasma concentration of total dabigatran; PD end points included activated partial thromboplastin time (aPTT), ecarin clotting time (ECT) and diluted thrombin time (dTT). Safety end points included incidence of all bleeding and other adverse events (AEs). Ten patients were screened; eight entered the study (age range, 41–169 days). The geometric mean (gMean) total dabigatran plasma concentrations 2 hours post-dose (around peak concentrations) were 120 ng/mL with a geometric coefficient of variation (gCV) of 62.1%. The gMean at 12 hours post-dosing was 60.4 ng/mL (gCV 30%). PK/PD relationship was linear for ECT and dTT (R 2 = 0.858 and 0.920, respectively), while total dabigatran concentration and aPTT showed a non-linear correlation. There were no deaths, treatment discontinuations or treatment-related AEs. In conclusion, DE was well tolerated without any treatment-related AEs in infants. The observed PK/PD relationships were comparable with the established profile in older patients with VTE.

Keywords

dabigatran etexilate - paediatrics - pharmacokinetics - pharmacodynamics - venous thromboembolism

Funding

The study was funded by Boehringer Ingelheim Pharma GmbH & Co. KG.


 

  • References

  • 1 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
    PubMedSearch in Google Scholar
  • 2 Sabharwal S, Passannante MR. Venous thromboembolism in children: preliminary results of a survey of POSNA members. J Pediatr Orthop 2013; 33 (08) 852-856
    CrossrefPubMedSearch in Google Scholar
  • 3 Andrew M, David M, Adams M. , et al. Venous thromboembolic complications (VTE) in children: first analyses of the Canadian Registry of VTE. Blood 1994; 83 (05) 1251-1257
    PubMedSearch in Google Scholar
  • 4 Stein PD, Kayali F, Olson RE. Incidence of venous thromboembolism in infants and children: data from the National Hospital Discharge Survey. J Pediatr 2004; 145 (04) 563-565
    CrossrefPubMedSearch in Google Scholar
  • 5 Raffini L, Huang YS, Witmer C, Feudtner C. Dramatic increase in venous thromboembolism in children's hospitals in the United States from 2001 to 2007. Pediatrics 2009; 124 (04) 1001-1008
    CrossrefPubMedSearch in Google Scholar
  • 6 Meier KA, Clark E, Tarango C, Chima RS, Shaughnessy E. Venous thromboembolism in hospitalized adolescents: an approach to risk assessment and prophylaxis. Hosp Pediatr 2015; 5 (01) 44-51
    CrossrefPubMedSearch in Google Scholar
  • 7 Chalmers E, Ganesen V, Liesner R. , et al; British Committee for Standards in Haematology. Guideline on the investigation, management and prevention of venous thrombosis in children. Br J Haematol 2011; 154 (02) 196-207
    CrossrefPubMedSearch in Google Scholar
  • 8 Male C, Chait P, Andrew M, Hanna K, Julian J, Mitchell L. ; PARKAA Investigators. Central venous line-related thrombosis in children: association with central venous line location and insertion technique. Blood 2003; 101 (11) 4273-4278
    CrossrefPubMedSearch in Google Scholar
  • 9 Goldenberg NA, Takemoto CM, Yee DL, Kittelson JM, Massicotte MP. Improving evidence on anticoagulant therapies for venous thromboembolism in children: key challenges and opportunities. Blood 2015; 126 (24) 2541-2547
    CrossrefPubMedSearch in Google Scholar
  • 10 Parasuraman S, Goldhaber SZ. Venous thromboembolism in children. Circulation 2006; 113 (02) e12-e16
    CrossrefPubMedSearch in Google Scholar
  • 11 Manco-Johnson MJ. How I treat venous thrombosis in children. Blood 2006; 107 (01) 21-29
    CrossrefPubMedSearch in Google Scholar
  • 12 Monagle P, Chan AK, Goldenberg NA. , et al. Antithrombotic therapy in neonates and children: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (2 Suppl): e737S-e801S
    CrossrefPubMedSearch in Google Scholar
  • 13 Pradaxa, European Medicines Agency (EMA). Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR-Product_Information/human/000829/WC500041059.pdf . Accessed August 19, 2016
    PubMed
  • 14 Andrew M, Paes B, Milner R. , et al. Development of the human coagulation system in the full-term infant. Blood 1987; 70 (01) 165-172
    PubMedSearch in Google Scholar
  • 15 Andrew M, Paes B, Milner R. , et al. Development of the human coagulation system in the healthy premature infant. Blood 1988; 72 (05) 1651-1657
    PubMedSearch in Google Scholar
  • 16 Schulman S, Kearon C, Kakkar AK. , et al; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009; 361 (24) 2342-2352
    CrossrefPubMedSearch in Google Scholar
  • 17 Schulman S, Kakkar AK, Goldhaber SZ. , et al; RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation 2014; 129 (07) 764-772
    CrossrefPubMedSearch in Google Scholar
  • 18 Schulman S, Kearon C, Kakkar AK. , et al; RE-MEDY Trial Investigators; RE-SONATE Trial Investigators. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med 2013; 368 (08) 709-718
    CrossrefPubMedSearch in Google Scholar
  • 19 Dietrich K, Stang L, van Ryn J, Mitchell LG. Assessing the anticoagulant effect of dabigatran in children: an in vitro study. Thromb Res 2015; 135 (04) 630-635
    CrossrefPubMedSearch in Google Scholar
  • 20 Halton JM, Lehr T, Cronin L. , et al. Safety, tolerability and clinical pharmacology of dabigatran etexilate in adolescents. An open-label phase IIa study. Thromb Haemost 2016; 116 (03) 461-471
    Thieme ConnectPubMedSearch in Google Scholar
  • 21 Halton JML, Albisetti M, Luciani M. , et al. Pharmacokinetics and pharmacodynamics of single-dose oral solution of dabigatran given after standard anticoagulant therapy in children, 2–12 years old, with venous thromboembolism. J Thromb Haemost 2016; 14: 91
    PubMedSearch in Google Scholar
  • 22 Anderson BJ, Holford NH. Mechanism-based concepts of size and maturity in pharmacokinetics. Annu Rev Pharmacol Toxicol 2008; 48: 303-332
    CrossrefPubMedSearch in Google Scholar
  • 23 Hayton WL. Maturation and growth of renal function: dosing renally cleared drugs in children. AAPS PharmSci 2000; 2 (01) E3
    CrossrefPubMedSearch in Google Scholar
  • 24 Rhodin MM, Anderson BJ, Peters AM. , et al. Human renal function maturation: a quantitative description using weight and postmenstrual age. Pediatr Nephrol 2009; 24 (01) 67-76
    CrossrefPubMedSearch in Google Scholar
  • 25 Ko RH, Young G. Pharmacokinetic- and pharmacodynamic-based antithrombotic dosing recommendations in children. Expert Rev Clin Pharmacol 2012; 5 (04) 389-396
    CrossrefPubMedSearch in Google Scholar
  • 26 Halton JML, Albisetti M, Luciani M. , et al. Pharmacokinetics, pharmacodynamics, safety and tolerability of a single-dose oral solution of dabigatran given after standard anticoagulant therapy in children (two age groups: 1-<2 and 2-<12 years old), with venous thromboembolism. Blood 2016; 128: 87
    PubMedSearch in Google Scholar
  • 27 World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA 2013; 310 (20) 2191-2194
    CrossrefPubMedSearch in Google Scholar
  • 28 ICH Harmonised Tripartite Guideline. Guideline for Good Clinical Practice E6. Available at: http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R1_Guideline.pdf . Accessed December 5, 2016
    PubMed
  • 29 Mitchell LG, Goldenberg NA, Male C, Kenet G, Monagle P, Nowak-Göttl U. ; Perinatal and Paediatric Haemostasis Subcommittee of the SSC of the ISTH. Definition of clinical efficacy and safety outcomes for clinical trials in deep venous thrombosis and pulmonary embolism in children. J Thromb Haemost 2011; 9 (09) 1856-1858
    CrossrefPubMedSearch in Google Scholar
  • 30 Trocóniz IF, Tillmann C, Liesenfeld KH, Schäfer HG, Stangier J. Population pharmacokinetic analysis of the new oral thrombin inhibitor dabigatran etexilate (BIBR 1048) in patients undergoing primary elective total hip replacement surgery. J Clin Pharmacol 2007; 47 (03) 371-382
    CrossrefPubMedSearch in Google Scholar
  • 31 Liesenfeld KH, Schäfer HG, Trocóniz IF, Tillmann C, Eriksson BI, Stangier J. Effects of the direct thrombin inhibitor dabigatran on ex vivo coagulation time in orthopaedic surgery patients: a population model analysis. Br J Clin Pharmacol 2006; 62 (05) 527-537
    CrossrefPubMedSearch in Google Scholar
  • 32 Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet 2008; 47 (05) 285-295
    CrossrefPubMedSearch in Google Scholar
  • 33 Boehringer Ingelheim. A phase III, randomized, double blind, parallel-group study of the efficacy and safety of oral dabigatran etexilate (150 mg bid) compared to warfarin (INR 2.0-3.0) for 6 month treatment of acute symptomatic venous thromboembolism. RE-COVER 1160.53. 2016
    PubMedSearch in Google Scholar
  • 34 Boehringer Ingelheim. Open-label safety and tolerability study of dabigatran etexilate given for 3 days at the end of standard anticoagulant therapy in children aged 12 years to less than 18 years. 2016
    PubMedSearch in Google Scholar
  • 35 Connolly SJ, Ezekowitz MD, Yusuf S. , et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361 (12) 1139-1151
    CrossrefPubMedSearch in Google Scholar