title: Intravenous anakinra can achieve experimentally effective concentrations in the central nervous system within a therapeutic time window: results of a dose-ranging study.
abstract: The naturally occurring antagonist of interleukin-1, IL-1RA, is highly neuroprotective experimentally, shows few adverse effects, and inhibits the systemic acute phase response to stroke. A single regime pilot study showed slow penetration into cerebrospinal fluid (CSF) at experimentally therapeutic concentrations. Twenty-five patients with subarachnoid hemorrhage (SAH) and external ventricular drains were sequentially allocated to five administration regimes, using intravenous bolus doses of 100 to 500 mg and 4 hours intravenous infusions of IL-1RA ranging from 1 to 10 mg per kg per hour. Choice of regimes and timing of plasma and CSF sampling was informed by pharmacometric analysis of pilot study data. Data were analyzed using nonlinear mixed effects modeling. Plasma and CSF concentrations of IL-1RA in all regimes were within the predicted intervals. A 500-mg bolus followed by an intravenous infusion of IL-1RA at 10 mg per kg per hour achieved experimentally therapeutic CSF concentrations of IL-1RA within 45 minutes. Experimentally, neuroprotective CSF concentrations in patients with SAH can be safely achieved within a therapeutic time window. Pharmacokinetic analysis suggests that IL-1RA transport across the blood-CSF barrier in SAH is passive. Identification of the practicality of this delivery regime allows further studies of efficacy of IL-1RA in acute cerebrovascular disease.
authors.affiliation: Manchester Academic Health Sciences Centre, Salford Royal NHS Foundation Trust, Salford, UK. james.galea@manchester.ac.uk
authors.forename: James
authors.initials: J
authors.lastname: Galea
authors.forename: Kayode
authors.initials: K
authors.lastname: Ogungbenro
authors.forename: Sharon
authors.initials: S
authors.lastname: Hulme
authors.forename: Andrew
authors.initials: A
authors.lastname: Greenhalgh
authors.forename: Leon
authors.initials: L
authors.lastname: Aarons
authors.forename: Sylvia
authors.initials: S
authors.lastname: Scarth
authors.forename: Peter
authors.initials: P
authors.lastname: Hutchinson
authors.forename: Samantha
authors.initials: S
authors.lastname: Grainger
authors.forename: Andrew
authors.initials: A
authors.lastname: King
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Hopkins
authors.forename: Nancy
authors.initials: N
authors.lastname: Rothwell
authors.forename: Pippa
authors.initials: P
authors.lastname: Tyrrell
mesh_terms: D000328:Adult; D000368:Aged; D002490:Central Nervous System / Q000378:metabolism*; D002552:Cerebral Ventricles / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D053590:Interleukin 1 Receptor Antagonist Protein / Q000008:administration & dosage / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D007375:Interleukin-1 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D017711:Nonlinear Dynamics; D010865:Pilot Projects; D013345:Subarachnoid Hemorrhage / Q000378:metabolism*
chemical_list: D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D018696:Neuroprotective Agents