Rilonacept is a dimeric fusion protein consisting of the ligand-binding domains of the extracellular portions of the human type I interleukin-1 receptor (IL-1RI) and IL-1 receptor accessory protein (IL-1RAcP) linked in-line to the Fc portion of human IgG1. Rilonacept binds to and blocks the activity of the cytokine IL-1 and binds both IL-1β and IL-1α, which are the primary pro-inflammatory cytokines implicated in many inflammatory diseases. Rilonacept also binds the endogenous IL-1 receptor antagonist (IL-1ra) but with a lower affinity than IL-1β or IL-1α.
In clinical studies, CAPS patients who have uncontrolled over-production of IL-1β show a rapid response to therapy with rilonacept, i.e. laboratory parameters such as C-reactive protein (CRP) and serum amyloid A (SAA) levels, leukocytosis, and high platelet count rapidly returned to normal.
Bioavailability of rilonacept after a subcutaneous injection is estimated to be approximately 50%.
The average trough levels of rilonacept were approximately 24 µg/ml at steady state following weekly subcutaneous doses of 160 mg for up to 48 weeks in patients with CAPS. The steady state appeared to be reached by 6 weeks.
Rilonacept steady-state pharmacokinetic properties1:
| Parameter | Value2 |
|---|---|
| Cmax (mg/l) | 31.5 |
| AUC (day mg/l) | 198 |
| CL /F (l/day) | 0.808 |
| T1/2 terminal (day) | 7.72 |
1 Based on population PK modelling
2 Derived values are presented.
No pharmacokinetic data are available in patients with hepatic impairment. As with other large proteins elimination of rilonacept is expected to be via proteolytic catabolism and target mediated clearance. Consequently, impaired liver function is not expected to affect the pharmacokinetics of rilonacept in a clinically significant way.
Results of a single-dose study in patients with end-stage renal disease (ESRD) indicate that the rate of elimination of rilonacept was not decreased. Renal elimination of rilonacept is therefore considered to be a minor pathway for clearance. No dose adjustment is needed in patients with renal impairment.
No study was conducted to evaluate the effect of age, gender, or body weight on rilonacept exposure. Based on limited data obtained from the clinical study, steady-state trough concentrations were similar between male and female patients. Age (26-78 years old) and body weight (50-120 kg) did not appear to have a significant effect on trough rilonacept concentrations. The effect of race could not be assessed because only Caucasian patients participated in the clinical studies in CAPS, reflecting the epidemiology of the disease.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology and repeated-dose toxicity.
Animal studies were conducted to assess reproductive toxicity. In mice, a murine analogue of rilonacept had no effect on fertility. A study of embryo-foetal development was conducted with rilonacept in monkeys at doses up to approximately 4 times the human dose. Decreases in β-estradiol levels were seen in the treated groups, the significance of this finding is unknown. In a prenatal and postnatal reproductive toxicology study in which mice were dosed subcutaneously, with a murine analogue of rilonacept at doses of 20, 100 or 200 mg/kg three times per week (the highest dose is approximately 6-fold higher than the 160 mg maintenance dose based on body surface area), there were no treatment-related effects.
Genotoxicity or long term animal studies have not been performed to evaluate the mutagenic or carcinogenic potential of rilonacept.
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