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

• DOI: 10.1160/th17-06-0429
• Publication Date: 2017-12-20T01:56:29Z
• Authors: Jacqueline Halton; Anne-Caroline Picard; Ruth Harper; Fenglei Huang; Martina Brueckmann; Savion Gropper; Hugo Maas; Igor Tartakovsky; Ildar Nurmeev; Lesley Mitchell; Leonardo Brandão; Elizabeth Chalmers; Manuela Albisetti
• Keywords: Pharmacodynamics; Tolerability; Direct thrombin inhibitor; Thrombin time; Nomogram

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