Aldesleukin.
Physicochemical Characteristics
Incompatibility.
Aldesleukin 33 800 units/mL in glucose 5% lost significant biological activity when mixed with other drugs including ganciclovir sodium, lorazepam, pentamidine isetionate, prochlorperazine edisilate, and promethazine hydrochloride. However, the incompatibility was not detectable by spectrophotometric methods and only lorazepam was visually incompatible, suggesting that these methods may be invalid for assessing the compatibility of proteins.
Stability.
Aldesleukin lost 75 to 100% of activity when reconstituted with glucose 5% or sodium chloride 0.9% in a plastic syringe and given over 24 hours with a syringe driver. Loss of activity was not seen if aldesleukin was reconstituted with water alone or with the addition of albumin. It was suggested that loss of activity could be suspected because of lack of toxicity, and that the lack of toxicity in some published studies could be due to this. However, the authors of these studies indicated that they had reconstituted aldesleukin with albumin. Reconstitution with low concentrations of albumin has been advocated to avoid bioavailability problems, but is not recommended for currently licensed preparations
For short intravenous infusion, the US licensed product information indicates that dilution outside of a specified range (below 30 micrograms/mL and above 70 micrograms/mL) results in increased variability in drug delivery.
Dilution of aldesleukin preparations with sodium chloride 0.9% is not recommended because increased aggregation occurs.
Units
100 units of human interleukin-2 are contained in one ampoule of the first International Standard Preparation (1987). The activity of interleukin-2 has also been expressed in Nutley and Cetus units: 100 international units is reportedly equivalent to about 83.3 Nutley units and to about 16.7 Cetus units. According to the manufacturers, 18 million international units of aldesleukin are equivalent to 1.1 mg of protein.
Adverse Effects and Treatment
Toxicity is related to dose and route and is often severe; fatalities have been recorded. Decreased vascular resistance and increased capillary permeability (the 'capillary leak syndrome') is common in patients given aldesleukin, and results in hypotension, reduced organ perfusion, and oedema. The incidence and severity of this syndrome is lower after subcutaneous than intravenous dosage. Fluid replacement may be necessary to treat the resultant hypovolaemia and dopamine or other pressor agents may be needed to help maintain organ perfusion. Capillary leak syndrome may also be associated with cardiac effects including tachycardia, angina, myocardial infarction; respiratory effects such as dyspnoea, pulmonary oedema, and respiratory failure; renal abnormalities including uraemia and oliguria or anuria; mental status changes including irritability, depression, confusion, and drowsiness. Therapy should be stopped if patients develop severe lethargy or somnolence, as continuing may result in coma. Raised liver enzymes, gastrointestinal disturbances, fever and flu-like symptoms (malaise, rigors, chills, arthralgia, and myalgia), rashes, pruritus, anaemia, leucopenia, and thrombocytopenia, are also relatively common. Paracetamol (but not NSAIDs, see Effects on the Kidneys,) may be used prophylactically for fever. Pethidine may be used to control rigors. Antiemetics and antidiarrhoeals may also be required. Antihistamines may benefit some patients with pruritic rash. Injection site reactions are common after subcutaneous doses; necrosis has occurred. Aldesleukin therapy is associated with impaired neutrophil function, and an increased risk of bacterial infections ,including sepsis and bacterial endocarditis; this has been reported mainly after intravenous use, and antibacterial prophylaxis may be necessary.
Bacterial infections.
The incidence of sepsis and bacteraemia is increased in patients receiving interleukin-2 via intravenous catheters, and possibly subcutaneously, although others have not found this to be the case. The increased incidence of nonopportunistic bacterial infection may be a particular problem in patients with AIDS who are treated with interleukin-2. The mechanism is uncertain, but may be related to impairment of neutrophil function by the cytokine.
Effects on endocrine function.
It has been suggested that patients with adrenal metastases may be particularly susceptible to adrenal haemorrhage and consequent failure during interleukin therapy. Results also suggested that lack of endogenous steroid production may increase the risk of early severe interleukin-2 toxicity.
Effects on thyroid function have also been reported, with the development of hypothyroidism and goitre.
Effects on the kidneys.
Intravenous aldesleukin therapy was associated with varying degrees of acute renal dysfunction in almost all of 99 adult patients. The clinical syndrome of hypotension, oliguria, fluid retention, and associated azotaemia with intense tubular avidity for filtered sodium all support prerenal acute renal failure as the cause of renal dysfunction. However, renal function values returned to baseline levels within 7 days in 62% of patients and in 95% by 30 days. Patients with elevated pretreatment serum-creatinine values, particularly those aged over 60 years, and those who had previously undergone a nephrectomy, were at risk of more severe and prolonged changes in renal function, and might be particularly vulnerable to the use of indometacin for associated fever and chills, which could potentiate renal impairment through its effects on intrarenal prostaglandin production. Similar effects were noted in a study of 15 children given continuous infusion of aldesleukin. A further study of the renal haemodynamic effects of aldesleukin infusion found it to have a specific renal vasoconstrictor effect; changes in renal prostaglandin synthesis contributed to the decreased renal blood flow.
Precautions
Aldesleukin should be given with great care, if at all, to patients with pre-existing cardiac or pulmonary disease, and those with severe renal or hepatic impairment. It should be avoided in patients with CNS metastases or seizure disorders.
Risk factors for toxicity and poor response include restricted physical activity (Eastern Cooperative Oncology Group performance status of 1 or greater), 2 or more metastatic sites, and a period of less than 24 months between diagnosis of primary tumour and consideration for aldesleukin therapy. UK licensed product information states that aldesleukin should not be used to treat metastatic renal cell carcinoma in patients with all three of these risk factors.
Aldesleukin may worsen auto-immune diseases, and should be used with caution in patients with these conditions. Bacterial infections should be adequately treated before beginning therapy. Aldesleukin may increase effusions from serosal surfaces, and these should generally be treated before aldesleukin therapy.
Vital signs, blood counts, renal and hepatic function, serum electrolytes, and pulmonary and cardiac function should be monitored before starting treatment and then regularly during therapy.
Activity.
For mention of the loss of activity when aldesleukin was given by continuous infusion without albumin, see Stability.
Inflammatory bowel disease.
Two patients with a history of Crohn's disease had a recurrence of the condition when given aldesleukin. It was suggested that interleukin-2 should be contra-indicated in such patients.
Psoriasis.
Exacerbations of psoriasis developed in 3 patients during therapy with aldesleukin alone or with lymphokine-activated killer cells. The psoriatic symptoms remitted with topical therapy.
Interactions
Corticosteroids (which reduce some of the adverse effects of interleukin-2) may also reduce its antineoplastic properties: use together should generally be avoided. The use of iodinated contrast media after aldesleukin therapy may result in symptoms resembling the immediate adverse effects of aldesleukin. Although most events were reported to occur within 2 to 4 weeks of the last dose of aldesleukin, some occurred several months afterward.
Antivirals.
For the effect of interleukin-2 on plasma concentrations of indinavir,See above.
NSAIDs.
NSAIDs are effective in preventing or reducing fever and myalgia caused by interleukin-2. However, there is concern that they could exacerbate renal toxicity (see also Effects on the Kidneys). Use of indometacin in patients receiving interleukin-2 led to more severe weight gain, oliguria, and azotaemia in 1 study. However, ibuprofen was used successfully to reduce interleukin-2 toxicity in another study.
Pharmacokinetics
After intravenous bolus, the serum distribution and elimination half-lives of aldesleukin are 13 and 85 minutes, respectively. After subcutaneous doses, the absorption half-life is 45 minutes and the elimination half-life is 5.3 hours, while bioavailability ranges between 35 and 47%.
Aldesleukin is metabolised to amino acids by the kidneys.
Uses and Administration
Interleukin-2 is a lymphokine which stimulates the proliferation of T-lymphocytes and thus amplifies immune response to an antigen; it also has actions on B-lymphocytes, and induces the production of interferon-? and the activation of natural killer cells. Interleukin-2 is used in the immunotherapy of metastatic renal cell carcinoma in selected patients .It is also used in melanoma, and has been tried in non-Hodgkin's lymphoma and acute myeloid leukaemia.
Interleukin-2 is usually given by intravenous infusion or subcutaneous injection of one of its recombinant forms, such as aldesleukin.
A variety of dosage regimens have been tried. In the UK, the recommended dose of aldesleukin for metastatic renal cell carcinoma is 18 million units given subcutaneously once daily for 5 days, followed by 2 days rest for the first week. For the next 3 weeks, 18 million units are then given on days 1 and 2 of each week, and 9 million units on days 3 to 5 of each week, followed by 2 days rest. This 4-week cycle may be repeated after an interval of 1 week. Doses may be delayed or reduced if the regimen is not tolerated.
Aldesleukin was formerly given by intravenous infusion, but this is no longer advocated in the UK because of an association with capillary leak syndrome (see Adverse Effects and Treatment). However, in the USA, aldesleukin is given by intravenous infusion for metastatic renal cell carcinoma or melanoma. The recommended dose is an infusion of 600 000 units/kg over 15 minutes, every 8 hours for up to 14 doses. This 5-day cycle is repeated after 9 days. Further courses may be given at intervals of at least 7 weeks in patients who respond. Doses should be withheld for toxicity.
Aldesleukin given by inhalation is being investigated in the treatment of renal cell carcinoma.
Interleukin-2 has also been given in adoptive immunotherapy with lymphokine-activated killer (LAK) cells or tumour-infiltrating lymphocytes (TIL), which are harvested from the patient, activated ex vivo, and then re-infused.
Interleukin-2 is also being tried in patients with HIV infection and AIDS in an attempt to restore immune response and has been given in some other infections or immune diseases.
Other interleukins are under investigation (see also Interleukin-1). Conjugates of interleukin-2 with macrogol (PEG-IL2; pegaldesleukin) have also been investigated and liposome-encapsulated interleukin-2 has also been investigated for the treatment of renal, brain and CNS tumours.
HIV infection and AIDS.
The immunodeficiency of HIV infection and AIDS has been associated with a defect in interleukin-2 production. Interleukin-2 stimulates the proliferation of lymphocytes and activates natural killer cells and a number of studies have therefore examined the potential benefits of adding interleukin-2 to the treatment of patients with HIV infection. Following earlier pilot studies, trials of antiretroviral therapy plus interleukin-2 have shown it to produce a much greater increase in CD4 cell counts than antiretroviral therapy alone, even where therapy included HAART. Given the efficacy of current therapies, demonstrating additional benefits on survival or disease progression is difficult, although some studies have been undertaken. In the interim, a pooled analysis of earlier results showed a non-significant trend towards improved clinical outcome.
Although teceleukin has been tried most studies of interleukin-2 therapy in HIV have used aldesleukin. Doses and routes have varied: in general doses seem to have ranged from 6 to 18 million units daily by intravenous infusion, or 3 to 30 million units daily subcutaneously, given in most cases for a 5-day cycle every 8 weeks. Subcutaneous dosage appears to be as effective as intravenous, is more convenient, and may be less toxic. There is evidence that 5-day dose cycles of 3, 4.5 or 7.5 million units twice daily by subcutaneous injection are effective, whereas cycles with a lower dose of 1.5 million units twice daily are not. A meta-analysis of 3 trials found that subcutaneous doses of 7.5 million units twice daily for 5 days every 8 weeks resulted in greater increases in CD4 cell counts after 3 cycles of therapy than doses of 4.5 million units or 1.5 million units. However, others have reported benefit from a dose as low as 3 million units daily when used with HAART in patients with advanced disease. Continuous low-dose daily therapy appears to accelerate the normalisation of T-cell and natural killer cell concentrations over the course of several months.
Adverse effects are common, particularly at higher doses and with intravenous infusion rather than subcutaneous use. However, concerns about a potential stimulant effect on viral replication with a consequent increase in viral load do not seem to have been borne out. Some studies have reported reduced viral loads in interleukin-treated patients, including decreases in hepatitis C viral load in those HIV patients co-infected with hepatitis C.
The macrogol conjugate of interleukin-2, PEG-IL2, has also been investigated in this context, but results have been disappointing, since it appears markedly less effective than aldesleukin in stimulating CD4 counts.