Anakinra pharmacokinetics in children and adolescents with systemic-onset juvenile idiopathic arthritis and autoinflammatory syndromes

BMC Pharmacol Toxicol. 2013 Aug 5;14:40. doi: 10.1186/2050-6511-14-40.

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.

Publication types

  • Clinical Trial, Phase II

MeSH terms

  • Adolescent
  • Algorithms
  • Arthritis, Juvenile / drug therapy*
  • Arthritis, Juvenile / metabolism
  • C-Reactive Protein / metabolism
  • Child
  • Child, Preschool
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Female
  • Hereditary Autoinflammatory Diseases / drug therapy*
  • Hereditary Autoinflammatory Diseases / metabolism
  • Humans
  • Infant
  • Injections, Subcutaneous
  • Interleukin 1 Receptor Antagonist Protein / pharmacokinetics*
  • Interleukin 1 Receptor Antagonist Protein / therapeutic use
  • Male
  • Metabolic Clearance Rate
  • Models, Biological*
  • Prospective Studies
  • Syndrome
  • Tissue Distribution
  • Treatment Outcome
  • Young Adult

Substances

  • Interleukin 1 Receptor Antagonist Protein
  • C-Reactive Protein