Intravenous anakinra can achieve experimentally effective concentrations in the central nervous system within a therapeutic time window: results of a dose-ranging study

James Galea, Kayode Ogungbenro, Sharon Hulme, Andrew Greenhalgh, Leon Aarons, Sylvia Scarth, Peter Hutchinson, Samantha Grainger, Andrew King, Stephen J Hopkins, Nancy Rothwell, Pippa Tyrrell, James Galea, Kayode Ogungbenro, Sharon Hulme, Andrew Greenhalgh, Leon Aarons, Sylvia Scarth, Peter Hutchinson, Samantha Grainger, Andrew King, Stephen J Hopkins, Nancy Rothwell, Pippa Tyrrell

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.

Figures

Figure 1
Figure 1
Screening and recruitment schema (black=SRFT, gray=Cambridge). IMP, investigational medicinal product.
Figure 2
Figure 2
Neutrophil count pre and days 1, 2, 3, and 7 after administration of anakinra (*P<0.05).
Figure 3
Figure 3
Predicted plasma (red lines) and cerebrospinal fluid (CSF) (blue lines) mean and interval concentration profiles, and actual plasma (red points) and CSF (blue points) for each regime. IL, interleukin.
Figure 4
Figure 4
Mean plasma (A) and cerebrospinal fluid (CSF) (B) interleukin (IL)-1RA concentrations for patients in regimes 1–5.

References

    1. Adams HP, Jr, del Zoppo G, Alberts MJ, Bhatt DL, Brass L, Furlan A, Grubb RL, Higashida RT, Jauch EC, Kidwell C, Lyden PD, Morgenstern LB, Qureshi AI, Rosenwasser RH, Scott PA, Wijdicks EF. Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: The American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Circulation. 2007;115:e478–e534.
    1. Arabi Y, Memish ZA, Balkhy HH, Francis C, Ferayan A, Al Shimemeri A, Almuneef MA. Ventriculostomy-associated infections: incidence and risk factors. Am J Infect Control. 2005;33:137–143.
    1. Banks WA, Ortiz L, Plotkin SR, Kastin AJ. Human interleukin (IL) 1 alpha, murine IL-1 alpha and murine IL-1 beta are transported from blood to brain in the mouse by a shared saturable mechanism. J Pharmacol Exp Ther. 1991;259:988–996.
    1. Banwell V, Sena ES, Macleod MR. Systematic review and stratified meta-analysis of the efficacy of interleukin-1 receptor antagonist in animal models of stroke. J Stroke Cerebrovasc Dis. 2009;18:269–276.
    1. Berrouane Y, Daudenthun I, Riegel B, Emery MN, Martin G, Krivosic R, Grandbastien B. Early onset pneumonia in neurosurgical intensive care unit patients. J Hosp Infect. 1998;40:275–280.
    1. Blamire AM, Anthony DC, Rajagopalan B, Sibson NR, Perry VH, Styles P. Interleukin-1beta -induced changes in blood-brain barrier permeability, apparent diffusion coefficient, and cerebral blood volume in the rat brain: a magnetic resonance study. J Neurosci. 2000;20:8153–8159.
    1. Boutin H, LeFeuvre RA, Horai R, Asano M, Iwakura Y, Rothwell NJ. Role of IL-1alpha and IL-1beta in ischemic brain damage. J Neurosci. 2001;21:5528–5534.
    1. Buttini M, Sauter A, Boddeke HW. Induction of interleukin-1 beta mRNA after focal cerebral ischaemia in the rat. Brain Res Mol Brain Res. 1994;23:126–134.
    1. Cicala C, Cirino G. Linkage between inflammation and coagulation: an update on the molecular basis of the crosstalk. Life Sci. 1998;62:1817–1824.
    1. Clark SR, McMahon CJ, Gueorguieva I, Rowland M, Scarth S, Georgiou R, Tyrrell PJ, Hopkins SJ, Rothwell NJ. Interleukin-1 receptor antagonist penetrates human brain at experimentally therapeutic concentrations. J Cereb Blood Flow Metab. 2008;28:387–394.
    1. Deng YZ, Reeves MJ, Jacobs BS, Birbeck GL, Kothari RU, Hickenbottom SL, Mullard AJ, Wehner S, Maddox K, Majid A. IV tissue plasminogen activator use in acute stroke: experience from a statewide registry. Neurology. 2006;66:306–312.
    1. Doczi T. The pathogenetic and prognostic significance of blood-brain barrier damage at the acute stage of aneurysmal subarachnoid haemorrhage. Clinical and experimental studies. Acta Neurochir (Wien) 1985;77:110–132.
    1. Dorhout Mees SM, Rinkel GJ, Feigin VL, Algra A, van den Bergh WM, Vermeulen M, van Gijn J.2007Calcium antagonists for aneurysmal subarachnoid haemorrhage Cochrane Database Syst Rev 1–50.CD000277
    1. Emsley HC, Smith CJ, Georgiou RF, Vail A, Hopkins SJ, Rothwell NJ, Tyrrell PJ. A randomised phase II study of interleukin-1 receptor antagonist in acute stroke patients. J Neurol Neurosurg Psychiatry. 2005;76:1366–1372.
    1. Gueorguieva I, Clark SR, McMahon CJ, Scarth S, Rothwell NJ, Tyrrell PJ, Hopkins SJ, Rowland M. Pharmacokinetic modelling of interleukin-1 receptor antagonist in plasma and cerebrospinal fluid of patients following subarachnoid haemorrhage. Br J Clin Pharmacol. 2008;65:317–325.
    1. Gutierrez EG, Banks WA, Kastin AJ. Blood-borne interleukin-1 receptor antagonist crosses the blood-brain barrier. J Neuroimmunol. 1994;55:153–160.
    1. Hara H, Friedlander RM, Gagliardini V, Ayata C, Fink K, Huang Z, Shimizu-Sasamata M, Yuan J, Moskowitz MA. Inhibition of interleukin 1beta converting enzyme family proteases reduces ischemic and excitotoxic neuronal damage. Proc Natl Acad Sci USA. 1997;94:2007–2012.
    1. Hawkins PN, Lachmann HJ, Aganna E, McDermott MF. Spectrum of clinical features in Muckle-Wells syndrome and response to anakinra. Arthritis Rheum. 2004;50:607–612.
    1. Huang J, Upadhyay UM, Tamargo RJ. Inflammation in stroke and focal cerebral ischemia. Surg Neurol. 2006a;66:232–245.
    1. Huang P, Chen CH, Yang YH, Lin RT, Lin FC, Liu CK. Eligibility for recombinant tissue plasminogen activator in acute ischemic stroke: way to endeavor. Cerebrovasc Dis. 2006b;22:423–428.
    1. Ilowite N, Porras O, Reiff A, Rudge S, Punaro M, Martin A, Allen R, Harville T, Sun YN, Bevirt T, Aras G, Appleton B. Anakinra in the treatment of polyarticular-course juvenile rheumatoid arthritis: safety and preliminary efficacy results of a randomized multicenter study. Clin Rheumatol. 2009;28:129–137.
    1. Lacy CR, Suh DC, Bueno M, Kostis JB. Delay in presentation and evaluation for acute stroke: Stroke Time Registry for Outcomes Knowledge and Epidemiology (S.T.R.O.K.E.) Stroke. 2001;32:63–69.
    1. Larsen CM, Faulenbach M, Vaag A, Volund A, Ehses JA, Seifert B, Mandrup-Poulsen T, Donath MY. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N Engl J Med. 2007;356:1517–1526.
    1. Loddick SA, Rothwell NJ. Neuroprotective effects of human recombinant interleukin-1 receptor antagonist in focal cerebral ischaemia in the rat. J Cereb Blood Flow Metab. 1996;16:932–940.
    1. McMahon CJ, Smith D, Clark SR, Hulme S, Georgiou R, Drake S, Selvarajah J, Hopkins SJ, Rothwell NJ, Tyrrell PJ, King AT.2010Delayed cerebral ischaemia after subarachnoid haemorrhage: clinical predictors and outcome J Neurosurgsubmitted)
    1. Mulcahy NJ, Ross J, Rothwell NJ, Loddick SA. Delayed administration of interleukin-1 receptor antagonist protects against transient cerebral ischaemia in the rat. Br J Pharmacol. 2003;140:471–476.
    1. Nuki G, Bresnihan B, Bear MB, McCabe D. Long-term safety and maintenance of clinical improvement following treatment with anakinra (recombinant human interleukin-1 receptor antagonist) in patients with rheumatoid arthritis: extension phase of a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2002;46:2838–2846.
    1. O'Collins VE, Macleod MR, Donnan GA, Horky LL, van der Worp BH, Howells DW. 1,026 experimental treatments in acute stroke. Ann Neurol. 2006;59:467–477.
    1. Obrenovitch TP, Zilkha E. Inhibition of cortical spreading depression by L-701,324, a novel antagonist at the glycine site of the N-methyl-D-aspartate receptor complex. Br J Pharmacol. 1996;117:931–937.
    1. Ogungbenro K, Graham G, Gueorguieva I, Aarons L. The use of a modified Fedorov exchange algorithm to optimise sampling times for population pharmacokinetic experiments. Comput Methods Programs Biomed. 2005;80:115–125.
    1. Ohtsuki T, Ruetzler CA, Tasaki K, Hallenbeck JM. Interleukin-1 mediates induction of tolerance to global ischemia in gerbil hippocampal CA1 neurons. J Cereb Blood Flow Metab. 1996;16:1137–1142.
    1. Rabinstein AA, Friedman JA, Weigand SD, McClelland RL, Fulgham JR, Manno EM, Atkinson JL, Wijdicks EF. Predictors of cerebral infarction in aneurysmal subarachnoid hemorrhage. Stroke. 2004;35:1862–1866.
    1. Relton JK, Martin D, Thompson RC, Russell DA. Peripheral administration of interleukin-1 receptor antagonist inhibits brain damage after focal cerebral ischemia in the rat. Exp Neurol. 1996;138:206–213.
    1. Saver JL. Time is brain—quantified. Stroke. 2006;37:263–266.
    1. Schneider SW, Gaubitz M, Luger TA, Bonsmann G. Prompt response of refractory Schnitzler syndrome to treatment with anakinra. J Am Acad Dermatol. 2007;56:S120–S122.
    1. Seifert V, Trost HA, Stolke D. Management morbidity and mortality in grade IV and V patients with aneurysmal subarachnoid haemorrhage. Acta Neurochir (Wien) 1990;103:5–10.
    1. STAIR Recommendations for clinical trial evaluation of acute stroke therapies. Stroke. 2001;32:1598–1606.
    1. Topakian R, Barrick TR, Howe FA, Markus HS. Blood-brain barrier permeability is increased in normal-appearing white matter in patients with lacunar stroke and leucoaraiosis. J Neurol Neurosurg Psychiatry. 2010;81:192–197.
    1. Topcuoglu MA, Singhal AB. Effects of common medications on cerebral vasospasm after subarachnoid haemorrhage. Expert Opin Drug Saf. 2006;5:57–65.
    1. Yamasaki Y, Matsuura N, Shozuhara H, Onodera H, Itoyama Y, Kogure K.1995Interleukin-1 as a pathogenetic mediator of ischemic brain damage in rats Stroke 26676–680.discussion 81

Source: PubMed

Sponsors en medewerkers

Medische omstandigheden

Geneesmiddelinterventies

3
Abonneren