title: UNBLOCK: an open-label, dose-finding, pharmacokinetic and safety study of bivalirudin in children with deep vein thrombosis.
abstract: BACKGROUND
  Direct thrombin inhibitors offer potential advantages over unfractionated heparin but have been poorly studied in children.
  
  
  OBJECTIVE
  To determine appropriate dosing of bivalirudin in children and adolescents and the relationship between activated partial thromboplastin time (APTT) and plasma bivalirudin concentration.
  
  
  METHODS
  The UNBLOCK (UtilizatioN of BivaLirudin On Clots in Kids) study was an open-label, single-arm, dose-finding, pharmacokinetic, safety and efficacy study of bivalirudin for the acute treatment of deep vein thrombosis (DVT) in children aged 6 months to 18 years. Drug initiation consisted of a bolus dose (0.125 mg kg(-1) ) followed by continuous infusion (0.125 mg kg h(-1) ). Dose adjustments were based on the APTT, targeting a range of 1.5-2.5 times each patient's baseline APTT. Safety was assessed by specific bleeding endpoints and efficacy by repeat imaging at 48-72 h and 25-35 days.
  
  
  RESULTS
  Eighteen patients completed the study. Following the bolus dose and the initial infusion rate, most patients' APTT values were within the target range. The infusion rate bivalirudin correlated more closely with drug concentration than the APTT. At 48-72 h, nine (50%) patients had complete or partial thrombus resolution, increasing to 16 (89%) at 25-35 days. No major and one minor bleeding event occurred.
  
  
  CONCLUSIONS
  Bivalirudin demonstrated reassuring safety and noteworthy efficacy in terms of early clot resolution in children and adolescents with DVT. Although a widely available and familiar monitoring tool, the APTT correlates poorly with plasma bivalirudin concentration, possibly limiting its utility in managing pediatric patients receiving bivalirudin for DVT.
authors.affiliation: Division of Pediatric Hematology/Oncology, Nationwide Children's Hospital/The Ohio State University, Columbus, OH, USA.
authors.forename: S H
authors.initials: SH
authors.lastname: O'Brien
authors.affiliation: Department of Pediatrics Hematology-Oncology Section, Baylor College of Medicine, Houston, TX, USA.
authors.forename: D L
authors.initials: DL
authors.lastname: Yee
authors.affiliation: Hemostasis and Thrombosis Center, Children's Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Lira
authors.affiliation: Division of Hematology, Departments of Pediatrics and Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA.|All Children's Research Institute, All Children's Hospital, Johns Hopkins Medicine, St Petersburg, FL, USA.
authors.forename: N A
authors.initials: NA
authors.lastname: Goldenberg
authors.affiliation: Hemostasis and Thrombosis Center, Children's Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Young
mesh_terms: D000293:Adolescent; D000367:Age Factors; D000991:Antithrombins / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D015415:Biomarkers; D002648:Child; D002675:Child, Preschool; D016638:Critical Illness; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced; D006629:Hirudins / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D006801:Humans; D007223:Infant; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008297:Male; D010314:Partial Thromboplastin Time; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D011446:Prospective Studies; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D020246:Venous Thrombosis / Q000188:drug therapy*
chemical_list: D000991:Antithrombins; D015415:Biomarkers; D006629:Hirudins; D010446:Peptide Fragments; D011994:Recombinant Proteins; C074619:bivalirudin
keywords: bivalirudin; deep vein thrombosis; direct thrombin inhibitors; pediatrics; safety