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.

Recombinant Human Interleukin-1 Receptor Antagonist in Severe Traumatic Brain Injury: A Phase II Randomized Control Trial

“…All previous studies of rhIL1ra in neurologic disease have utilized intravenous administration at much higher doses, 12,14,21 however, subcutaneous administration, as in this study, may provide a more practical method of drug delivery particularly in the emergency setting. We would expect that the maximal benefit derived from an IL1R antagonist would be in the first few hours after neurologic injury as IL1b, the natural agonist at the IL1R, rises rapidly after injury.…”

“…Previous rhIL1ra pharmacokinetic studies have measured cerebrospinal fluid concentrations. 13 However, cerebrospinal fluid may act as a sump for bulk flow of inflammatory mediators from the cerebral parenchyma 23 with some biomarkers at concentrations several orders of magnitude higher than the brain interstitial fluid. This is an important distinction, as ultimately the extracellular fluid is the biologically active compartment to which the cell surface IL1R is exposed.…”

SCIL-STROKE (Subcutaneous Interleukin-1 Receptor Antagonist in Ischemic Stroke)

“…5 We have reported previously that IV IL-1Ra administered over 72 h in a placebo-controlled phase 2 study of patients with acute stroke was safe and significantly reduced plasma inflammatory markers. 6 IV IL-1Ra penetrated cerebrospinal fluid (CSF) at experimentally therapeutic concentrations in patients with acute aneurysmal subarachnoid hemorrhage (aSAH), 7,8 and reduced CSF and plasma IL-6 concentrations. 9 IL-1Ra is now available as a commercial SC formulation used to treat rheumatoid arthritis, which is cheaper and more practical to administer.…”

Interleukin-1 in Stroke

“…IL-1 may cause upregulation of endothelin, a potent vasoconstrictor, directly causing vasospasm. 49 IL-1 exacerbates bloodbrain barrier breakdown and therefore edema, which may cause increased intracranial pressure. 50 Animal models of posthemorrhagic vasospasm have demonstrated elevated levels of IL-6 (in arteries exposed to hemorrhage), 51,52 which are known to be upregulated by IL-1.…”

“…63 This follows pharmacokinetic studies of IL-1Ra in similar cohorts where rapid and sustained CSF levels of IL-1Ra were observed, as seen in preclinical models also. 49,64 The primary aim was to determine the effect of intravenous IL-1Ra on the concentration of inflammatory mediators in plasma and CSF. Patients were randomized to recombinant IL-1Ra (given as an intravenous bolus of 500 mg administered >1 minute, followed by a 24-hour infusion of 10 mg/kg per hour) or placebo.…”