Chemical formula: C₂₀H₂₃N₅O₇S₂  Molecular mass: 509.6 g/mol 

Mechanism of action

Anakinra neutralises the biologic activity of interleukin-1α (IL-1α) and interleukin-1β (IL-1β) by competitively inhibiting their binding to interleukin-1 type I receptor (IL-1RI). Interleukin-1 (IL-1) is a pivotal pro-inflammatory cytokine mediating many cellular responses including those important in synovial inflammation.

Pharmacodynamic properties

Pharmacodynamic effects

IL-1 is found in the plasma and synovial fluid of patients with rheumatoid arthritis, and a correlation has been reported between IL-1 concentrations in the plasma and the activity of the disease. Anakinra inhibits responses elicited by IL-1 in vitro, including the induction of nitric oxide and prostaglandin E2 and/or collagenase production by synovial cells, fibroblasts, and chondrocytes.

Spontaneous mutations in the CIAS1/NLRP3 gene have been identified in a majority of patients with CAPS. CIAS1/NLRP3 encodes for cryopyrin, a component of the inflammasome. The activated inflammasome results in proteolytic maturation and secretion of IL-1β, which has a broad range of effects including systemic inflammation. Untreated CAPS patients are characterized by increased CRP, SAA and IL-6 relative to normal serum levels. Administration of anakinra results in a decrease in the acute phase reactants and a decrease in IL-6 expression level has been observed. Decreased acute phase protein levels are noted within the first weeks of treatment.

Still’s disease, in addition to various degrees of arthritis, is characterised by systemic inflammatory features such as spiking fever, skin rash, hepatosplenomegaly, serositis, and increased acute phase reactants driven by IL-1 activity. Systemically, IL-1 is known to cause the hypothalamic fever response and promote hyperalgesia. The role of IL-1 in the pathogenesis of Still’s disease has been demonstrated by ex vivo and gene expression studies.

Pharmacokinetic properties

The absolute bioavailability of anakinra after a 70 mg subcutaneous bolus injection in healthy subjects (n=11) is 95%. The absorption process is the rate-limiting factor for the disappearance of anakinra from the plasma after subcutaneous injection. In subjects with RA, maximum plasma concentrations of anakinra occurred at 3 to 7 hours after subcutaneous administration of anakinra at clinically relevant doses (1 to 2 mg/kg; n=18). The plasma concentration decreased with no discernible distribution phase and the terminal half-life ranged from 4 to 6 hours. In RA patients, no unexpected accumulation of anakinra was observed after daily subcutaneous doses for up to 24 weeks. Mean (SD) estimates of clearance (CL/F) and volume of distribution (Vd/F) by population analysis of data from two PK studies in 35 RA patients were 105(27) ml/min and 18.5(11) l, respectively. Human and animal data demonstrated that the kidney is the major organ responsible for elimination of anakinra. The clearance of anakinra in RA patients increased with increasing creatinine clearance.

The influence of demographic covariates on the pharmacokinetics of anakinra was studied using population pharmacokinetic analysis encompassing 341 patients receiving daily subcutaneous injection of anakinra at doses of 30, 75, and 150 mg for up to 24 weeks. The estimated anakinra clearance increased with increasing creatinine clearance and body weight. Population pharmacokinetic analysis demonstrated that the mean plasma clearance value after subcutaneous bolus administration was approximately 14% higher in men than in women and approximately 10% higher in subjects <65 years than in subjects ≥65 years. However, after adjusting for creatinine clearance and body weight, gender and age were not significant factors for mean plasma clearance. No dose adjustment is required based on age or gender.

In general the pharmacokinetics in CAPS patients is similar to that in RA patients. In CAPS patients approximate dose linearity with a slight tendency to higher than proportional increase has been noted. Pharmacokinetic data in children < 4 years are lacking, but clinical experience is available from 8 months of age, and when started at the recommended daily dose of 1-2 mg/kg, no safety concerns have been identified. Pharmacokinetic data are lacking in older CAPS patients. Distribution into the cerebrospinal fluid has been demonstrated.

The median steady-state dose-normalized anakinra concentration in SJIA patients over 28 weeks was comparable to that observed in RA patients.

Hepatic impairment

A study including 12 patients with hepatic dysfunction (Child-Pugh Class B) given a single 1mg/kg intravenous dose has been performed. Pharmacokinetic parameters were not substantially different from healthy volunteers, other than a decrease in clearance of approximately 30% in comparison with data from a study with healthy volunteers. A corresponding decrease in creatinine clearance was seen in the hepatic failure population. Accordingly, the decrease in clearance is most likely explained by a decrease in renal function in this population. These data support that no dose adjustment is required for patients with hepatic dysfunction of Child-Pugh Class B.

Renal impairment

The mean plasma clearance of anakinrat in subjects with mild (creatinine clearance 50-80 ml/min) and moderate (creatinine clearance 30-49 ml/min) renal insufficiency was reduced by 16% and 50%, respectively. In severe renal insufficiency and end stage renal disease (creatinine clearance < 30 ml/min), mean plasma clearance declined by 70% and 75%, respectively. Less than 2.5% of the administered dose of anakinrat was removed by hemodialysis or continuous ambulatory peritoneal dialysis. These data support that no dose adjustment is needed for patients with mild renal impairment (CLcr 50 to 80 ml/minute).

Preclinical safety data

Anakinra had no observed effect on the fertility, early development, embryo-foetal development, or peri- and postnatal development in the rat at doses up to 100 times the human dose (2 mg/kg/day). No effects on embryo-foetal development in the rabbit were observed at doses 100 times the human dose.

In a standard battery of tests designed to identify hazards with respect to DNA, anakinra did not induce bacterial or mammalian cell gene mutations. Neither did anakinra increase the incidence of chromosomal abnormalities or micronuclei in bone marrow cells in mice. Long-term studies have not been performed to evaluate the carcinogenic potential of anakinra. Data from mice over expressing IL-1ra and IL-1ra mutant knock-out mice, did not indicate an increased risk of tumour development.

A formal toxicologic and toxicokinetic interaction study in rats revealed no evidence that anakinra alters the toxicologic or pharmacokinetic profile of methotrexate.

Juvenile rats treated at doses up to 100 times the human dose from day 7 postparturition up to adolescence did not show any signs of adverse effects of the treatment.

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