Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Immunosuppressants, Interleukin inhibitors, ATC code: L04AC03 
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 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 Kineret 100 mg solution for injection 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.

In patients with FMF, mutation of the MEFV gene encoding for pyrin is leading to malfunctioning and overproduction of interleukin-1β (IL-1β) in the FMF inflammasome.
Untreated FMF is characterized by increased CRP and SAA. Administration of Kineret 100 mg solution for injection results in a decrease in acute phase reactants (e.g. CRP and SAA).


Clinical efficacy and safety in RA
The safety and efficacy of anakinra in combination with methotrexate have been demonstrated in 1,790 RA patients ≥ 18 years of age with varying degrees of disease severity.

A clinical response to anakinra generally appeared within 2 weeks of initiation of treatment and was sustained with continued administration of anakinra. Maximal clinical response was generally seen within 12 weeks after starting treatment.

Combined anakinra and methotrexate treatment demonstrates a statistically and clinically significant reduction in the severity of the signs and symptoms of RA in patients who have had an inadequate response to methotrexate alone (38% vs. 22% responders as measured by ACR20 criteria). Significant improvements are seen in the pain, tender joint count, physical function (HAQ score), acute phase reactants and in the patient’s and physician’s global assessment.

X-ray examinations have been undertaken in one clinical study with anakinra. These have shown no deleterious effect on joint cartilage.

Clinical efficacy and safety in CAPS
The safety and efficacy of Kineret 100 mg solution for injection have been demonstrated in CAPS patients with varying degrees of disease severity. In a clinical study including 43 adult and paediatric patients (36 patients aged 8 months to < 18 years) with severe CAPS (NOMID/CINCA and MWS), a clinical response to anakinra was seen within 10 days after initiation of treatment in all patients and was sustained for up to 5 years with the continued administration of Kineret 100 mg solution for injection.

Kineret 100 mg solution for injection treatment significantly decreases the manifestations of CAPS, including a reduction in frequently occurring symptoms as fever, rash, joint pain, headache, fatigue, and eye redness. A rapid and sustained decrease in the levels of the inflammatory biomarkers; serum amyloid A (SAA), C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), and a normalization of inflammatory hematological changes are seen.
In the severe form of CAPS, long-term treatment improves the systemic inflammatory organ manifestations of the eye, inner ear, and CNS. Hearing and visual acuity did not deteriorate further during anakinra treatment.

Analysis of treatment-emergent AEs classified by presence of CIAS1 mutation showed that there were no major differences between the CIAS1 and non-CIAS1 groups in overall AE reporting rates, 7.4 and 9.2, respectively. Similar rates were obtained for the groups on the SOC level, except for eye disorders with 55 AEs (rate 0.5), whereof 35 ocular hyperemia (which could also be a symptom of CAPS) in the CIAS1 group, and four AEs in the non-CIAS1 group (rate 0.1).
Clinical efficacy and safety in FMF
The safety and efficacy of Kineret 100 mg solution for injection in the treatment of patients with colchicine resistant FMF has been demonstrated in a randomized, double blind, and placebo- controlled published study with a treatment period of 4 months. Primary efficacy outcomes were number of attacks per month, and number of patients with a mean of <1 attack per month. 25 patients with colchicine resistant FMF were enrolled; 12 randomized to receive Kineret 100 mg solution for injection and 13 to receive placebo. The mean number of attacks per patient per month was significantly lower in those receiving Kineret 100 mg solution for injection (1.7) compared to placebo (3.5). The number of patients with <1 attack per month was significantly higher in the Kineret 100 mg solution for injection group; 6 patients, compared to none in the placebo group.

Additional published data in patients with FMF, intolerant to colchicine or with colchicine resistant FMF, demonstrate that the clinical effect of Kineret 100 mg solution for injection is evident in both clinical symptoms of attacks as well as in reduced levels of inflammatory markers, such as CRP and SAA. In the published studies the safety profile of anakinra in patients with FMF was generally similar to that in other indications.


Paediatric population
Overall, the efficacy and safety profile of Kineret 100 mg solution for injection is comparable in adult and paediatric patients with CAPS.

The European Medicines Agency has waived the obligation to submit the results of studies with Kineret 100 mg solution for injection in one or more subsets of the paediatric population in CAPS and RA (JIA) (see section 4.2 for information on paediatric use).

Safety in paediatric RA (JIA) patients
Kineret 100 mg solution for injection was studied in a single randomized, blinded multi-center trial in 86 patients with polyarticular course JIA (ages 2-17 years) receiving a dose of 1 mg/kg subcutaneously daily, up to a maximum dose of 100 mg. The 50 patients who achieved a clinical response after a 12-week open-label run-in were randomized to Kineret 100 mg solution for injection (25 patients) or placebo (25 patients), administered daily for an additional 16 weeks. A subset of these patients continued open-label treatment with Kineret 100 mg solution for injection for up to 1 year in a companion extension study. An adverse event profile similar to that seen in adult RA patients was observed in these studies. These study data are insufficient to demonstrate efficacy and, therefore, Kineret 100 mg solution for injection is not recommended for paediatric use in JIA.

Immunogenicity
See section 4.8.

Pharmacokinetic Properties

5.2   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.


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. See section 4.2.

Renal impairment
The mean plasma clearance of Kineret 100 mg solution for injection 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 Kineret 100 mg solution for injection 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). See section 4.2.