IL- l production is induced in response to inflammatory stimuli and mediates various physiologic responses includig inflammatory and immunological responses. IL-l has a broad range of activities including cartilage degradation by its induction of the rapid loss of proteoglycans, as well as stimulation of bone resorption.² The levels of the naturally occurring IL-lRa in synovium and synovial fluid from rheumatoid arthritis(RA) patients are not sufficient to compete with the elevated amount of locally produced IL-1.^3,4,5

Pharmacokinetics

The absolute bioavailability of Kineret^® after a 70 mg SC bolus injection in healthy subjects (n = 11) is 95%. In subjects with RA, maximum plasma concentrations of Kineret^® occurred 3 to 7 hours after SC administration of kineret^® at clinically relevant doses (1 to 2 mg/kg; n = 18); the terminal half-life ranged from 4 to 6 hours. In RA patients, no unexpected accumulation of Kineret^® was observed after daily SC doses for up to 24 weeks.

The influence of demographic covariates on the pharmacokinetics of kineret^® was studied using population pharmacokinetic analysis encompassing 341 patients receiving daily SC injection of Kineret^® at doses of 30, 75, and 150 mg for up to 24 weeks. The estimated kineret^® clearance increased with increasing creatinine clearance and body weight. After adjusting for creatinine clearance and body weight, gender and age were not significant factors for mean plasma clearance.

Patients With Renal Impairment: The mean plasma clearance of Kineret^® 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/min⁶), mean plasma clearance declined by 70% and 75%, respectively. Less than 2.5% of the administered dose of Kineret^® was removed by hemodialysis or continuous ambulatory peritoneal dialysis. Based on these observations, a dose schedule change should be considered for subjects with severe renal insufficiency or end stage renal disease (see DOSAGE AND ADMINISTRATION).

Patients With Hepatic Dysfunction: No formal studies have been conducted examining the pharmacokinetics of Kineret^® administered subcutaneously in rheumatoid arthritis patients with hepatic impairment.

CLINICAL STUDIES

The safety and efficacy of Kineret^® have been evaluated in three randomized, double-blind, placebo-controlled trials of 1790 patients ≥18 years of age with active rheumatoid arthritis (RA). . An additional fourth study was conducted to assess safety. In the efficacy trials, Kineret^® was studied in combination with other disease-modifying antirheumatic drugs (DMARDs) other than Tumor Necrosis Factor (TNF) blocking agents (studies 1 and 2) or as a monotherapy (study 3).

Study 1 involved 899 patients with active RA who had been on a stable dose of methotrexate (MTX) (10 to 25 mg/week) for at least 8 weeks. All patients had atleast 6 swollen/painful and 9 tender joints and either a C-reactive protein (CRP) of ≥1.5 mg/dL or an erythrocyte sedimentation rate (ESR) of ≥28 mm/hr. Patients were randomized to Kineret^® or placebo in addition to their stable doses of MTX. The fist 501 patients were evaluated for signs and symptoms of active RA. The total 899 patients were evaluated for progression of structural damage.

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