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

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Abstract

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 <15 and 35 % respectively. A dose-ranging study was successfully designed using modelling and simulation.

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Acknowledgments

The authors would like to thank Amgen Inc (CA, USA) for providing IL-1Ra, anakinra as Kineret®, the Medical Research Council (MRC; UK) for funding the study, and Salford Royal Foundation Trust for funding and sponsoring the study, the patients that participated in this study and the neurosurgical team at Salford Royal Foundation Trust and Addenbrooke’s Hospital for their support.

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Authors and Affiliations

  1. Centre for Applied Pharmacokinetics Research, Manchester Pharmacy School, Manchester Academic Health Sciences Centre, The University of Manchester, Manchester, M13 9PT, UK

    Kayode Ogungbenro

  2. Vascular and Stroke Group, Clinical Sciences Building, Salford Royal NHS Foundation Trust, Stott Lane, Salford, M6 8HD, UK

    Sharon Hulme, Stephen Hopkins, Pippa Tyrrell & James Galea

  3. Faculty of Life Sciences, Manchester Academic Health Sciences Centre, The University of Manchester, AV Hill Building, Oxford Road, Manchester, M13 9PT, UK

    Nancy Rothwell & James Galea

  4. Ninewells Hospital and Medical School, Dundee, DD1 9SY, UK

    James Galea

Authors
  1. Kayode Ogungbenro
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  2. Sharon Hulme
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  3. Nancy Rothwell
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  4. Stephen Hopkins
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  5. Pippa Tyrrell
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  6. James Galea
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Corresponding author

Correspondence to Kayode Ogungbenro.

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Conflict of Interest

NJR is a non-executive director of AstraZeneca plc, but this has no relation with the present study.

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Ogungbenro, K., Hulme, S., Rothwell, N. et al. Study design and population pharmacokinetic analysis of a phase II dose-ranging study of interleukin-1 receptor antagonist. J Pharmacokinet Pharmacodyn 43, 1–12 (2016). https://doi.org/10.1007/s10928-015-9450-0

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  • DOI: https://doi.org/10.1007/s10928-015-9450-0

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