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

Content Provider	Springer Nature Link
Author	Ogungbenro, Kayode Hulme, Sharon Rothwell, Nancy Hopkins, Stephen Tyrrell, Pippa Galea, James
Copyright Year	2015
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.
Starting Page	1
Ending Page	12
Page Count	12
File Format	PDF
ISSN	1567567X
Journal	Journal of Pharmacokinetics and Pharmacodynamics
Volume Number	43
Issue Number	1
e-ISSN	15738744
Language	English
Publisher	Springer US
Publisher Date	2015-10-18
Publisher Place	New York
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Population pharmacokinetics Anakinra Interleukin-1 receptor antagonist Optimal design Simulation Pharmacology/Toxicology Pharmacy Veterinary Medicine Biomedical Engineering Biochemistry
Content Type	Text
Resource Type	Article
Subject	Pharmacology

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