Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2020 Publisher: Clinigen Healthcare Ltd., Pitcairn House, Crown Square, First Avenue, Burton-on-Trent, Staffordshire, DE14 2WW, United Kingdom
Pharmacotherapeutic group: immunostimulants, cytokines and immunomodulators, interleukins, aldesleukin
ATC code: L03AC01
Proleukin acts as a regulator of the immune response. The biological activities of aldesleukin and native human IL-2, a naturally occurring lymphokine, are comparable. The in-vivo administration of Proleukin in animals and humans produces multiple immunological effects in a dose dependent manner. The administration of aldesleukin in murine tumour models has been shown to reduce both tumour growth and spread. The exact mechanism by which aldesleukin-mediated immunostimulation leads to antitumour activity is not yet known.
There were a very small number of patients aged 65 and over in clinical trials of Proleukin. The response rates were similar in patients 65 years and over as compared to those less than 65 years of age. The median number of courses and the median number of doses per course were similar between older and younger patients (see section 4.2 and 5.2).
The pharmacokinetic parameters of IL-2, following an intravenous or subcutaneous administration of aldesleukin in metastatic renal cell carcinoma and metastatic malignant melanoma patients is as follows:
The pharmacokinetic profile of aldesleukin is characterized by high plasma concentrations after a short intravenous infusion followed by rapid distribution into the extravascular space.
Following subcutaneous administration, peak plasma levels are attained 2 to 6 hours after injection.
Absolute bioavailability of subcutaneous aldesleukin ranges between 31-47%.
Following a continuous intravenous infusion-fixed and continuous intravenous infusion-decrescendo administration of aldesleukin, the mean tmax of IL-2 was 11 hours and 4.4 hours, respectively. Compared to the serum levels following the subcutaneous administration, the observed serum levels following the continuous intravenous infusion-fixed and continuous intravenous infusion-decrescendo administration of aldesleukin are 3.20 and 1.95-fold higher.
Observed aldesleukin serum levels following intravenous administration are proportional to the dose of Proleukin.
The serum half-life curves of aldesleukin in humans following short intravenous (bolus) administration can be described as bi-exponential. The half-life in the α phase is 13 minutes and the half-life in the β phase is 85 minutes. The α phase accounts for clearance of 87% of a bolus injection. The mean clearance rate of Proleukin aldesleukin in cancer patients is 155 to 420 mL/min. Pharmacokinetic parameters based on a recent study, where Proleukin was administered intravenously to patients with metastatic renal cell carcinoma and metastatic melanoma, (n=4 MRCC, 16 metastatic melanoma) was comparable to results from the previous studies, with a mean clearance of 243.2 to 346.3 mL/min and a terminal half-life (t1/2) of 100.4 to 123.9 min.
The subcutaneous kinetics can be described by a one-compartment model. The IL-2 absorption half-life is 45 minutes, while the elimination half-life is 3-5 hours. The longer half-life estimate, compared with the intravenous result is likely due to continued absorption of IL-2 from the subcutaneous injection site during the plasma elimination phase.
The kidney is the major clearance route of recombinant IL-2 (rIL-2) in animals, and most of the injected dose is metabolized in the kidney with no biologically active aldesleukin appearing in the urine. A secondary elimination pathway is IL-2 receptor- mediated uptake. This active process is induced after chronic dosing. After an aldesleukin-free period between dosing cycles (9-16 days), the clearance of IL-2 is restored to its original value.
Fifty-seven of 77 (74%) metastatic renal cell carcinoma (MRCC) patients treated with an every 8-hour Proleukin regimen and 33 of 50 (66%) metastatic melanoma patients treated with a variety of i.v. regimens developed low titers of non-neutralizing anti-aldesleukin antibodies. Neutralizing antibodies were not detected in this group of patients, but have been detected in 1/106 (<1%) patients treated with i.v. Proleukin using a wide variety of schedules and doses. The clinical significance of anti-aldesleukin antibodies is unknown.
A recent study examined the influence of anti-IL2 antibodies after one cycle on therapy on the pharmacokinetics of Proleukin administered as a 15 minute i.v. infusion in patients with MRCC or metastatic melanoma. 84.2% of patients developed anti-IL2 antibodies in this study. The formation of anti-IL-2 antibodies after one cycle of therapy did not result in a decrease in aldesleukin exposure in MRCC or MM. Overall, steady-state concentration (Css) and elimination half-life (t1/2) were comparable between Cycle 1 and Cycle 2 in patients with presence of anti-aldesleukin antibodies.
No formal studies have been conducted for patients with pre-existing renal impairment.
Pharmacokinetics of aldesleukin following intravenous bolus administration of IL-2 was evaluated in a small patient population of 15 cancer patients who were developing renal toxicity. Creatine clearance (CLcr) decreased following repeated doses of IL-2. Decrease in CLcr was not associated with a decrease in IL-2 clearance.
No formal clinical trials were conducted to compare the pharmacokinetics, efficacy or safety of Proleukin in geriatric patients to those in younger patients; since decline in renal and hepatic function may occur with increasing age, caution is recommended in the treatment of such patients (see section 4.2 and 5.1).
Animal data on repeated dose toxicity and local tolerance do not add any information to what is already mentioned in other sections of the SPC. Aldesleukin has not been evaluated for effects on fertility, early embryonic development, and prenatal and postnatal development. Embryo-foetal development studies in rats have demonstrated embryolethality in the presence of maternal toxicity. Teratogenicity in rats was not observed.
Aldesleukin has not been evaluated for mutagenicity or carcinogenicity. The potential for mutagenicity or carcinogenicity is considered low given the similarities in structure and function between aldesleukin and endogenous IL-2.
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