s. Improvement in immune function and diminished frequency of opportunistic infections compared with the natural history of combined immunodeficiency due to ADA deficiency only occurs after metabolic abnormalities are corrected. There is a lag between the correction of the metabolic abnormalities and improved immune function. This period of time is variable, and has been reported to be from a few weeks to as long as 6 months. In contrast to the natural history of combined immunodeficiency disease due to ADA deficiency, a trend toward diminished frequency of opportunistic infections and fewer complications of infections has occurred in patients receiving ADAGEN® (pegademase bovine) Injection.
Pharmacokinetics
The pharmacokinetics and biochemical effects of ADAGEN® (pegademase bovine) Injection have been studied in six children ranging in age from 6 weeks to 12 years with SCID associated with ADA deficiency.
After the intramuscular injection of ADAGEN® (pegademase bovine) Injection, peak plasma levels of ADA activity were reached 2 to 3 days following administration. The plasma elimination half-life of ADA following the administration of ADAGEN® (pegademase bovine) Injection was variable, even for the same child. The range was 3 to > 6 days. Following weekly injections of ADAGEN® (pegademase bovine) Injection at 15 U/kg, the average trough level of ADA activity in plasma was between 20 and 25 μmol/hr/mL.
Biochemical Effects
The changes in red blood cell deoxyadenosine nucleotide (dATP) and S-adenosylhomocysteine hydrolase (SAHase) have been eva luated. In patients with ADA deficiency, inadequate elimination of 2′-deoxyadenosine caused a marked elevation in dATP and a decrease in SAHase level in red blood cells. Prior to treatment with ADAGEN® (pegademase bovine) Injection, the levels of dATP in the red blood cells ranged from 0.056 to 0.899 μmol/mL of erythrocytes. After 2 months of maintenance treatment with ADAGEN® (pegademase bovine) Injection, the levels decreased to 0.007 to 0.015 μmol/mL. The normal value of dATP is below 0.001 μmol/mL. In the same period of time, the levels of SAHase increased from the pretreatment range of 0.09 to 0.22 nmol/hr/mg protein to a range of 2.37 to 5.16 nmol/hr/mg protein. The normal value for SAHase is 4.18 ± 1.9 nmol/hr/mg protein.
The optimal dosage and schedule of administration of ADAGEN® (pegademase bovine) Injection should be established for each patient, based on monitoring of plasma ADA activity levels (trough levels before maintenance injection), biochemical markers of ADA deficiency (primarily red cell dATP content), and parameters of immune function. Since improvement in immune function follows correction of metabolic abnormalities, maintenance dosage in individual patients should be aimed at achieving the following biochemical goals: 1) maintain plasma ADA activity (trough levels) in the range of 15-35 μmol/hr/mL (assayed at 37°C); and 2) decline in erythrocyte dATP to ≤ 0.005-0.015 µmol/mL packed erythrocytes, or ≤ 1% of the total erythrocyte adenine nucleotide (ATP + dATP) content, with a normal ATP level, as measured in a pre-injection sample.
In vitro immunologic data (lymphocyte response to mitogens and lymphocyte surface antigens) were obtained, but their clinical significance is unknown. Prior to treatment with ADAGEN® (pegademase bovine) Injection, immune status was si
