Study design and population pharmacokinetic analysis of a phase II dose-ranging study of interleukin-1 receptor antagonist.

Kayode Ogungbenro, Sharon Hulme, Nancy Rothwell, Stephen Hopkins, Pippa Tyrrell, James Galea

Research output: Contribution to journalArticlepeer-review


Interleukin-1 receptor antagonist, a naturally-occurring antagonist to the pro-inflammatory cytokine Interleukin-1, is already in clinical use. In experimental models of stroke, Interleukin-1 receptor antagonist in cerebrospinal fluid has been associated with cerebral neuroprotection and in a phase I clinical trial in patients with subarachnoid haemorrhage it crosses the blood-cerebrospinal fluid barrier. The aims of the current work were to design a dose-ranging clinical study in patients and to analyse the plasma and cerebrospinal fluid data obtained using a population pharmacokinetic modelling approach. The study was designed using prior information: a published population pharmacokinetic model and associated parameter estimates. Simulations were carried out to identify combinations of intravenous bolus and 4 h infusion doses that could achieve a concentration of 100 ng/ml in cerebrospinal fluid within approximately 30 min. The most informative time points for plasma and cerebrospinal fluid were obtained prospectively; optimisation identified five sampling time points that were included in the 15 time points in the present study design. All plasma and cerebrospinal fluid concentration data from previous and current studies were combined for updated analysis. The result of the simulations showed that a dosage regimen of 500 mg intravenous bolus and 10 mg/kg/h could achieve the target concentration, however four other regimens that represent a stepwise increase in maximum concentration were also selected. Analysis of the updated data showed improvement in parameter accuracy and predictive performance of the model; the percentage relative standard errors for fixed and random-effects parameters were
Original languageEnglish
Pages (from-to)1-12
Number of pages11
JournalJournal of pharmacokinetics and pharmacodynamics
Publication statusPublished - 18 Oct 2015


  • Anakinra
  • Interleukin-1 receptor antagonist
  • Optimal design
  • Population pharmacokinetics
  • Simulation


Dive into the research topics of 'Study design and population pharmacokinetic analysis of a phase II dose-ranging study of interleukin-1 receptor antagonist.'. Together they form a unique fingerprint.

Cite this