The serum and cerebrospinal fluid pharmacokinetics of anakinra after intravenous administration to non-human primates

doi:10.1016/j.jneuroim.2010.03.022

Journal of Neuroimmunology

Volume 223, Issues 1–2, June 2010, Pages 138-140

https://doi.org/10.1016/j.jneuroim.2010.03.022 Get rights and content

Abstract

Anakinra improves the central nervous system manifestations of neonatal-onset multisystem inflammatory disease, which is mediated by IL-1ß oversecretion. The cerebrospinal fluid (CSF) penetration of the IL-1 receptor antagonist anakinra was studied in rhesus monkeys after intravenous doses of 3 and 10 mg/kg. Drug exposure (area under concentration–time curve) in CSF was 0.28% of that in serum. The average CSF concentration at 3 mg/kg was 1.8 ng/mL, which is 30-fold higher than endogenous CSF levels of IL-1Ra. The CSF penetration was not dose-dependent, indicating that the CSF penetration was not saturated in the 3 to 10 mg/kg dose range.

Introduction

Interleukin-1 (IL-1), implicated in the pathogenesis of neonatal-onset multisystem inflammatory disease (NOMID), mediates pro-inflammatory effects through binding to the IL-1 receptor which is present on many nucleated cells (Dinarello, 2004). The recombinant IL-1 receptor antagonist, anakinra (IL-1Ra, Kineret™), improves the clinical and laboratory manifestations of NOMID in patients treated with 1–2 mg/kg daily by subcutaneous injection (Goldbach-Mansky et al., 2006, Lovell et al., 2005). In addition to the disappearance of the cutaneous manifestations, an improvement in the central nervous system (CNS) manifestations was observed, including alleviation of headache, reduction in increased intracranial pressure, and decreased leptomeningeal and cochlear enhancement on MRI. The median (interquartile range) serum IL-1Ra concentration in patients with NOMID was 0.36 ng/mL (0.23–1.26 ng/mL) pretreatment and 43 ng/mL (8.8–200 ng/mL) after 3 months of anakinra. In CSF, IL-1Ra concentration was 0.21 ng/mL (0.077–0.35 ng/mL) and increased 5-fold on anakinra to 1.14 ng/mL (0.50–1.69 ng/mL) (Goldbach-Mansky et al., 2006).

The clinical improvement in the CNS manifestations of NOMID and the increase in CSF IL-1Ra concentrations measured at a single time point post-treatment in children treated with anakinra prompted us to more fully characterize the CSF pharmacokinetics of anakinra in a non-human primate model, which is highly predictive of CNS pharmacology in humans (Bacher et al., 1994, McCully et al., 1990, Jacobs et al., 2005, Meany et al., 2007, Muscal et al., 2010). Animals have chronically indwelling Ommaya reservoirs that permit serial atraumatic sampling of ventricular CSF to assess the time course of CSF drug concentrations after a systemic dose of drug. Drug exposure in CSF is compared to serum using the area under the concentration–time curve (AUC) rather than single time point measurements. CSF drug penetration in this model is a surrogate for blood-brain barrier penetration (Fox et al., 2002).

Section snippets

Drug

Anakinra (100 mg/0.67 mL; Biovitrum, AB, Stockholm, Sweden) was purchased from commercial sources. Anakinra (17.3 kDa) differs from native human IL-1Ra (23–25 kDa) by the addition of a methionine at the amino terminus and the absence of glycosylation. Two dose levels (3 and 10 mg/kg) were studied. Each dose was diluted in normal saline to a final concentration of 25–50 mg/mL in 1–3 mL and administered as an intravenous (IV) bolus.

Animals

Three adult male rhesus monkeys (Macaca mulatta), weighing 10.2–14.4 kg,

Results

Pretreatment serum and CSF native IL-1Ra concentrations were detectable (> 0.032 ng/mL) but not quantifiable (< 0.062 ng/mL). Serum and CSF pharmacokinetic parameters for anakinra are provided in Table 1, and the mean serum and CSF concentration–time profiles for the 3 and 10 mg/kg doses are shown in Fig. 1. After the bolus dose, serum anakinra concentrations declined by 5 logs over 24 to 48 h with a mean (± SD) terminal half-life in serum of 2.9 ± 1.3 h. The AUC_0–∞ was 16,200 ± 1800 ng h/mL at 3 mg/kg and

Discussion

The overall drug exposure in CSF as measured by the AUC_0–∞ was < 1% of the AUC_0–∞ in serum. Bolus IV dosing of anakinra permitted accurate measurement of the systemic and CSF exposure and calculation of the CSF penetration as the ratio of the AUC_CSF:AUC_serum. The half-life was similar to the 1.8 h half-life reported for healthy humans after IV administration of anakinra (Granowitz et al., 1992). Unlike comparing single time point serum and CSF measurements, the AUC_CSF:AUC_serum method of assessing

References (19)

C.A. Dinarello
Therapeutic strategies to reduce IL-1 activity in treating local and systemic inflammation
Curr. Opin. Pharmacol.
(2004)
E.V. Granowitz et al.
Pharmacokinetics safety and immunomodulatory effects of human recombinant interleukin-1 receptor antagonist in healthy humans
Cytokine
(1992)
E.G. Gutierrez et al.
Blood-borne interleukin-1 receptor antagonist crosses the blood-brain barrier
J. Neuroimmunol.
(1994)
J.D. Bacher et al.
Cerebral subarachnoid sampling of cerebrospinal fluid in the rhesus monkey
Lab. Anim. Sci.
(1994)
W.A. Banks et al.
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)
W.A. Banks et al.
Passage of cytokines across the blood-brain barrier
Neuroimmunomodulation
(1995)
S.R. Clark et al.
Interleukin-1 receptor antagonist penetrates human brain at experimentally therapeutic concentration
J. Cereb. Blood Flow Metab.
(2008)
E. Fox et al.
Zidovudine concentration in brain extracellular fluid measured by microdialysis: steady-state and transient results in rhesus monkey
J. Pharmacol. Exp. Ther.
(2002)
M. Gibaldi et al.
Pharmacokinetics
(1982)

There are more references available in the full text version of this article.

Cited by (43)

Mechanism of NLRP3 Inflammasome in Epilepsy and Related Therapeutic Agents
2024, Neuroscience
Epilepsy is one of the most widespread and complex diseases in the central nervous system (CNS), affecting approximately 65 million people globally, an important factor resulting in neurological disability-adjusted life year (DALY) and progressive cognitive dysfunction. Medication is the most essential treatment. The currently used drugs have shown drug resistance in some patients and only control symptoms; the development of novel and more efficacious pharmacotherapy is imminent. Increasing evidence suggests neuroinflammation is involved in the occurrence and development of epilepsy, and high expression of NLRP3 inflammasome has been observed in the temporal lobe epilepsy (TLE) brain tissue of patients and animal models. The inflammasome is a crucial cause of neuroinflammation by activating IL-1β and IL-18. Many preclinical studies have confirmed that regulating NLRP3 inflammasome pathway can prevent the development of epilepsy, reduce the severity of epilepsy, and play a neuroprotective role. Therefore, regulating NLRP3 inflammasome could be a potential target for epilepsy treatment. In summary, this review describes the priming and activation of inflammasome and its biological function in the progression of epilepsy. In addition, we reviewes the current pharmacological researches for epilepsy based on the regulation of NLRP3 inflammasome, aiming to provide a basis and reference for developing novel antiepileptic drugs.
Immune therapies of B-cell acute lymphoblastic leukaemia in children and adults
2024, Critical Reviews in Oncology/Hematology
B-cell acute lymphoblastic leukaemia (B-cell ALL) is a common haematologic cancer in children and adults. About 10 percent of children and 50 percent of adults fail to achieve a histological complete remission or subsequently relapse despite current anti-leukaemia drug therapies and/or haematopoietic cell transplants. Several new immune therapies including monoclonal antibodies and chimeric antigen receptor (CAR)-T-cells are proved safe and effective in this setting. We review data on US Food and Drug Administration (FDA)-approved immune therapies for B-cell ALL in children and adults including blinatumomab, inotuzumab ozogamicin, tisagenlecleucel, and brexucabtagene autoleucel. We also summarize pharmaco-dynamics, pharmaco-kinetics, and pharmaco-economics of these interventions.
Protein-protein interactions and related inhibitors involved in the NLRP3 inflammasome pathway
2023, Cytokine and Growth Factor Reviews
NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) receptor serves as the central node of immune sensing in the innate immune system, and plays an important role in the initiation and progression of chronic diseases. Cryo-electron microscopy (cryo-EM) has provided insights into the conformation of various oligomers within the NLRP3 activation pathway, significantly advancing our understanding of the mechanisms underlying NLRP3 inflammasome activation. Despite the extensive network of protein-protein interactions (PPIs) involved in the assembly and activation of NLRP3 inflammasome, the utilization of protein-protein interactions has been relatively overlooked in the development of NLRP3 inhibitors. This review focuses on summarizing PPIs within the NLRP3 inflammasome activation pathway and small molecule inhibitors capable of interfering with PPIs to counteract the NLRP3 overactivation. Small molecule NLRP3 inhibitors have been gained significant attention owing to their remarkable efficacy, excellent safety profiles, and unique mechanisms of action.
Switching from salvage chemotherapy to immunotherapy in adult B-cell acute lymphoblastic leukemia
2023, Blood Reviews
About one-half of adults with acute B-cell lymphoblastic leukemia (B-ALL) who do not achieve molecular complete remission or who subsequently relapse are not cured by current chemo- or targeted therapies. Previously, the sole therapeutic option for such persons was a hematopoietic stem cell transplant. Recently, several immune therapies including monoclonal antibodies, bispecific T-cell engagers (BiTEs), antibody-drug conjugates (ADCs), and chimeric antigen receptor T-cells (CARs) have been shown safe and effective in this setting. In this manuscript, we summarize data on US FDA-approved immune therapies of advanced adult B-ALL including rituximab, blinatumomab, inotuzumab ozogamicin, tisagenlecleucel and brexucabtagene autoleucel. We consider the results of clinical trials focusing on efficacy, safety, and quality of life (QoL). Real-world evidence is presented as well. We also briefly discuss pharmacodynamics, pharmacokinetics, and pharmacoeconomics followed by risk-benefit analyses. Lastly, we present future directions of immune therapies for advanced B-ALL in adults.
Cerebrospinal fluid IL-1β is elevated in tuberculous meningitis patients but not associated with mortality
2021, Tuberculosis
Citation Excerpt :
Even though the study by Marais et al. was conducted in HIV-infected tuberculous meningitis IRIS patients, we hypothesize that targeting the pro-inflammatory IL-1β pathway could also potentially be beneficial in HIV-uninfected tuberculous meningitis patients, for example with interleukin receptor 1 inhibitors anakinra, which targets IL-1α and IL-1β. Anakinra penetrates well into the central nervous system and has been successful in treating central nervous system inflammation [5,6]. In herpes simplex virus encephalitis, IL-1β levels showed a relationship to clinical severity and outcome [7].
Inflammation contributes to the pathophysiology and high mortality of tuberculous meningitis. The IL-1β pathway has been implicated in immunopathology and could be a target for host-directed therapy. IL-1β was elevated in the cerebrospinal fluid (CSF) of 225 HIV-uninfected tuberculous meningitis patients in Indonesia compared to controls, but did not predict subsequent mortality, nor did IL-6 or IL-1Ra. Furthermore, genetic loci known to regulate IL1B gene expression did not predict mortality in 443 tuberculous meningitis patients, although two of these loci did predict CSF IL-1β concentrations. Collectively, these data argue against a role for IL-1β targeted host-directed therapy in tuberculous meningitis.
Pancreatic Cancer UK Grand Challenge: Developments and challenges for effective CAR T cell therapy for pancreatic ductal adenocarcinoma
2020, Pancreatology
Citation Excerpt :
Blockade of IL-1 using an IL-1 receptor antagonist, anakinra, showed reduction in CRS symptoms [268,269]. This could be a promising treatment avenue for neurotoxicity as anakinra is able to cross the blood-brain-barrier [270]. It is important also to consider that CRS may be required for sufficient activation and efficacy of the CAR T cells.
Death from pancreatic ductal adenocarcinoma (PDAC) is rising across the world and PDAC is predicted to be the second most common cause of cancer death in the USA by 2030. Development of effective biotherapies for PDAC are hampered by late presentation, a low number of differentially expressed molecular targets and a tumor-promoting microenvironment that forms both a physical, collagen-rich barrier and is also immunosuppressive. In 2017 Pancreatic Cancer UK awarded its first Grand Challenge Programme award to tackle this problem. The team plan to combine the use of novel CAR T cells with strategies to overcome the barriers presented by the tumor microenvironment. In advance of publication of those data this review seeks to highlight the key problems in effective CAR T cell therapy of PDAC and to describe pre-clinical and clinical progress in CAR T bio-therapeutics.

View all citing articles on Scopus

View full text

Short communicationThe serum and cerebrospinal fluid pharmacokinetics of anakinra after intravenous administration to non-human primates

Abstract

Introduction

Section snippets

Drug

Animals

Results

Discussion

Curr. Opin. Pharmacol.

Cytokine

J. Neuroimmunol.

Cerebral subarachnoid sampling of cerebrospinal fluid in the rhesus monkey

Lab. Anim. Sci.

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.

Passage of cytokines across the blood-brain barrier

Neuroimmunomodulation

Interleukin-1 receptor antagonist penetrates human brain at experimentally therapeutic concentration

J. Cereb. Blood Flow Metab.

Zidovudine concentration in brain extracellular fluid measured by microdialysis: steady-state and transient results in rhesus monkey

J. Pharmacol. Exp. Ther.

Pharmacokinetics

Short communication
The serum and cerebrospinal fluid pharmacokinetics of anakinra after intravenous administration to non-human primates