title: Anakinra pharmacokinetics in children and adolescents with systemic-onset juvenile idiopathic arthritis and autoinflammatory syndromes.
abstract: BACKGROUND
  Anakinra pharmacokinetics and pharmacodynamics were investigated in children and adolescents treated for systemic-onset juvenile idiopathic arthritis (SJIA) and autoinflammatory syndromes.
  
  
  METHODS
  Anakinra was given subcutaneously at doses between 2 and 10 mg/kg (maximum 100 mg) per day. Anakinra concentrations were recorded in patients, as well as C-reactive protein (CRP) levels, on different occasions. The data were fitted to a pharmacokinetic-pharmacodynamic model via a population approach using Monolix.
  
  
  RESULTS
  A total of 87 children and adolescents, 8 months to 21 years old, were available for pharmacokinetic evaluation. A one compartment model with linear absorption and elimination described the pharmacokinetics. Taking into account bodyweight to explain variations in apparent clearance (CL/F) and distribution volume (V/F) significantly reduced the associated between-subject and between-occasion variabilities. The final estimates were 6.24 L/h/70 kg and 65.2 L/70 kg for CL/F and V/F respectively. A mixture pharmacodynamic model described the CRP level change during anakinra treatment for the SJIA patients with 2 subpopulations, patients with high baseline and large CRP decrease and patients with low baseline and small CRP decrease followed by a re-increase in CRP levels. There was no significant effect of the combined anti-inflammatory treatment. The proportion of patients for which the development of a resistance to treatment was significant was 62% and the corresponding time was approximately 60 days.
  
  
  CONCLUSIONS
  Based on effects in SJIA, a prospective dosage adjustment was proposed based on a 0.4 mg/L Css target in order to obtain a CRP decrease to 10 mg/L or below.
authors.forename: Saik
authors.initials: S
authors.lastname: Urien
authors.forename: Christophe
authors.initials: C
authors.lastname: Bardin
authors.forename: Brigitte
authors.initials: B
authors.lastname: Bader-Meunier
authors.forename: Richard
authors.initials: R
authors.lastname: Mouy
authors.forename: Sandrine
authors.initials: S
authors.lastname: Compeyrot-Lacassagne
authors.forename: Franz
authors.initials: F
authors.lastname: Foissac
authors.forename: Benoît
authors.initials: B
authors.lastname: Florkin
authors.forename: Carine
authors.initials: C
authors.lastname: Wouters
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Neven
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Treluyer
authors.forename: Pierre
authors.initials: P
authors.lastname: Quartier
mesh_terms: D000293:Adolescent; D000465:Algorithms; D001171:Arthritis, Juvenile / Q000188:drug therapy* / Q000378:metabolism; D002097:C-Reactive Protein / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D056660:Hereditary Autoinflammatory Diseases / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007223:Infant; D007279:Injections, Subcutaneous; D053590:Interleukin 1 Receptor Antagonist Protein / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D011446:Prospective Studies; D013577:Syndrome; D014018:Tissue Distribution; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D053590:Interleukin 1 Receptor Antagonist Protein; D002097:C-Reactive Protein
references.citation: J Exp Med. 2005 May 2;201(9):1479-86
references.pmid: 15851489
references.citation: Annu Rev Pharmacol Toxicol. 2008;48:303-32
references.pmid: 17914927
references.citation: J Pharmacokinet Pharmacodyn. 2007 Apr;34(2):229-49
references.pmid: 17211713
references.citation: Ann Rheum Dis. 2011 May;70(5):747-54
references.pmid: 21173013
references.citation: Arthritis Rheum. 2011 Feb;63(2):314-24
references.pmid: 20967858
references.citation: Arthritis Rheum. 2010 Jan;62(1):258-67
references.pmid: 20039428
references.citation: N Engl J Med. 2012 Dec 20;367(25):2396-406
references.pmid: 23252526
references.citation: Ann Rheum Dis. 2008 Mar;67(3):302-8
references.pmid: 17947302
references.citation: Comput Methods Programs Biomed. 2008 May;90(2):154-66
references.pmid: 18215437