PMID- 29202215 OWN - NLM STAT- MEDLINE DCOM- 20180806 LR - 20220330 IS - 2567-689X (Electronic) IS - 0340-6245 (Linking) VI - 117 IP - 11 DP - 2017 Nov TI - Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of Dabigatran Etexilate Oral Liquid Formulation in Infants with Venous Thromboembolism. PG - 2168-2175 LID - 10.1160/TH17-06-0429 [doi] AB - 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. CI - Schattauer GmbH Stuttgart. FAU - Halton, Jacqueline M L AU - Halton JML AD - Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada. FAU - Picard, Anne-Caroline AU - Picard AC AD - Boehringer Ingelheim, Reims CEDEX, France. FAU - Harper, Ruth AU - Harper R AD - Clinical Operations, Boehringer Ingelheim Ltd, Bracknell, United Kingdom. FAU - Huang, Fenglei AU - Huang F AD - Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, United States. FAU - Brueckmann, Martina AU - Brueckmann M AD - Clinical Development and Medical Affairs, Boehringer Ingelheim Pharma, Ingelheim, Germany. AD - Faculty of Medicine Mannheim, University of Heidelberg, Mannheim, Germany. FAU - Gropper, Savion AU - Gropper S AD - Clinical Development and Medical Affairs, Boehringer Ingelheim Pharma, Ingelheim, Germany. FAU - Maas, Hugo AU - Maas H AD - Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma, Biberach, Germany. FAU - Tartakovsky, Igor AU - Tartakovsky I AD - Clinical Development and Medical Affairs, Boehringer Ingelheim Pharma, Ingelheim, Germany. FAU - Nurmeev, Ildar AU - Nurmeev I AD - Kazan Medical University, Children's Hospital, Kazan, Tatarstan Republic, Russian Federation. FAU - Mitchell, Lesley G AU - Mitchell LG AD - University of Alberta, Edmonton, Alberta, Canada. FAU - Brandao, Leonardo R AU - Brandao LR AD - Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada. FAU - Chalmers, Elizabeth AU - Chalmers E AD - Royal Hospital for Children, Glasgow, United Kingdom. FAU - Albisetti, Manuela AU - Albisetti M AD - Hematology Department, University Children's Hospital, Zurich, Switzerland. LA - eng PT - Clinical Trial, Phase II PT - Journal Article PT - Multicenter Study PT - Research Support, Non-U.S. Gov't DEP - 20171130 PL - Germany TA - Thromb Haemost JT - Thrombosis and haemostasis JID - 7608063 RN - 0 (Antithrombins) RN - 0 (Pharmaceutical Solutions) RN - I0VM4M70GC (Dabigatran) SB - IM MH - Administration, Oral MH - Age Factors MH - Antithrombins/*administration & dosage/adverse effects/blood/*pharmacokinetics MH - Blood Coagulation/*drug effects MH - Blood Coagulation Tests MH - Dabigatran/*administration & dosage/adverse effects/blood/*pharmacokinetics MH - Drug Compounding MH - Drug Monitoring/methods MH - Female MH - France MH - Hemorrhage/chemically induced MH - Humans MH - Infant MH - Linear Models MH - Male MH - Nonlinear Dynamics MH - Ontario MH - Pharmaceutical Solutions MH - Russia MH - Treatment Outcome MH - Venous Thromboembolism/blood/diagnosis/*drug therapy COIS- Conflicts of Interest: J. M. L. H., M. A., L. G. M. and E. C. are members of a Pediatric Expert Working Group for Boehringer Ingelheim. A.-C. P., R. H., F. H., M. B., S. G., H. M. and I. T. are employees of Boehringer Ingelheim. L. G. M. is a consultant for Boehringer Ingelheim, Pfizer and Bristol-Myers Squibb. I. N. and L. R. B. are consultants for Boehringer Ingelheim. The development of the manuscript was led by the first author, in collaboration with all the authors. All the authors made the decision to submit the manuscript for publication and approved the final draft of the manuscript. Assistance with manuscript preparation, including collation of comments and revisions, was provided by a medical writer funded by the sponsor. EDAT- 2017/12/05 06:00 MHDA- 2018/08/07 06:00 CRDT- 2017/12/05 06:00 PHST- 2017/12/05 06:00 [entrez] PHST- 2017/12/05 06:00 [pubmed] PHST- 2018/08/07 06:00 [medline] AID - 10.1160/TH17-06-0429 [doi] PST - ppublish SO - Thromb Haemost. 2017 Nov;117(11):2168-2175. doi: 10.1160/TH17-06-0429. Epub 2017 Nov 30.