Pharmacokinetic modelling of interleukin-1 receptor antagonist in plasma and cerebrospinal fluid of patients following subarachnoid haemorrhage

Ivelina Gueorguieva, Simon R. Clark, Catherine J. McMahon, Sylvia Scarth, Nancy J. Rothwell, Pippa J. Tyrell, Stephen J. Hopkins, Malcolm Rowland, Philippa Tyrrell

Research output: Contribution to journalArticlepeer-review


Aim: The naturally occurring interlukin-1 receptor antagonist (IL-1RA) markedly protects rodents against ischaemic, excitotoxic and traumatic brain injury, suggesting it may be of therapeutic value. The aim was to determine the pharmacokinetics of IL-1RA in cerebrospinal fluid (CSF) of patients, to allow modelling that would aid development of therapeutic regimens. Methods: When administered intravenously to patients soon after stroke, IL-1RA is safe and reduces the peripheral inflammatory response. However, IL-1RA is a large protein (17 kDa), which may limit brain penetration, thereby limiting its potential utility in brain injury. In seven patients with subarchnoid haemorrhage (SAH), IL-1RA was administered by intravenous bolus, then infusion for 24 h, and both blood and CSF, via external ventricular drains, were sampled during and after stopping the infusion. Results: Plasma steady-state concentrations were rapidly attained and maintained throughout the infusion, whereas CSF concentrations rose slowly towards a plateau during the 24-h infusion, reaching at best only 4% of that in plasma. Plasma kinetic parameters were within the literature range. Modelling of the combined data yielded rate constants entering and leaving the CSF of 0.0019 h-1 [relative standard error (RSE) = 19%] and 0.1 h-1 (RSE = 19%), respectively. Conclusions: Peripherally administered IL-1RA crosses slowly into and out of the CSF of patients with SAH. However, there is a large concentration gradient of IL-1RA between plasma and CSF. These CSF:plasma data are consistent with very low permeation of IL-1RA into the CSF and elimination kinetics from it controlled by the volumetric turnover of CSF. © 2007 The Authors.
Original languageEnglish
Pages (from-to)317-325
Number of pages8
JournalBritish Journal of Clinical Pharmacology
Issue number3
Publication statusPublished - Mar 2008


  • CSF
  • Interleukin-1 receptor antagonist
  • Ischemia
  • Modelling
  • Patients
  • Pharmacokinetics
  • Subarachnoid haemmorage


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