CLINICAL PHARMACOLOGY
In humans, uric acid is the final step in the catabolic pathway of purines. Rasburicase catalyzes enzymatic oxidation of uric acid into an inactive and soluble metabolite (allantoin). Rasburicase is only active at the end of the purine catabolic pathway.
Pharmacokinetics of rasburicase were evaluated in two studies that enrolled patients with lymphoid leukemia (B and T cell), non-Hodgkin's lymphoma (including Burkitt's lymphoma) or acute myelogenous leukemia. ELITEK exposure, as measured by AUC0-24 hr and Cmax, tended to increase linearly with doses over a limited dose range (0.15 to 0.20mg/kg). The overall elimination half-life was 18 hours. No accumulation of rasburicase was observed between days 1 and 5 of dosing. ELITEK mean volume of distribution was 110 to 127 mL/kg in pediatric patients. There are insufficient data to characterize pharmacokinetics in adult patients.
CLINICAL STUDIES
ELITEK was administered in three studies to 265 patients with acute leukemia or non-Hodgkin's lymphoma. The clinical studies were largely limited to pediatric patients (246 of 265). ELITEK was administered as a 30-minute infusion once (n=251) or twice (n=14) daily at a dose of 0.15 or 0.20 mg/kg/dose (total daily dose 0.20-0.40 mg/kg/day). ELITEK was administered prior to and concurrent with anti-tumor therapy, which consisted of either systemic chemotherapy (n=196) or steroids (n=69).
STUDY 1
Study 1 was a randomized, open-label, controlled study conducted at six institutions, in which 52 pediatric patients were randomized to receive either ELITEK (n=27) or allopurinol (n=25). 1 The dose of allopurinol varied according to local institutional practice. ELITEK was administered as an intravenous infusion over 30 minutes once (n=26) or twice (n=1) daily at a dose of 0.20 mg/kg/dose (total daily dose 0.20-0.40 mg/kg/day). Initiation of dosing was permitted at any time between 4 to 48 hours before the start of anti-tumor therapy and could be continued for 5 to 7 days after initiation of anti-tumor therapy. Patients were stratified at randomization on the basis of underlying malignant disease (leukemia or lymphoma) and baseline serum or plasma uric acid levels (<8.0 mg/dL and >/=8.0 mg/dL). The primary study objective was to demonstrate a greater reduction in uric acid concentration over 96 hours (AUC0-96 hr) in the ELITEK group as compared to the allopurinol group. Uric acid AUC0-96 hr was defined as the area under the curve for plasma uric acid levels (mg·hr/dL), measured from the last value prior to the first dose of ELITEK until 96 hours after that first dose. Plasma uric acid levels were used for all uric acid AUC0-96 hr calculations (see PRECAUTIONS, Laboratory Test Interactions).
The demographics of the two study arms (ELITEK vs. allopurinol) were as follows: age <13 years (82% vs. 76%), males (59% vs. 72%), Caucasian (59% vs. 72%), ECOG performance status 0 (89% vs. 84%), and leukemia (74% vs. 76%). The median interval, in hours, between initiation of ELITEK and of anti-tumor treatment was 20 hours, with a range of 70 hours before to 10 hours after the initiation of anti-tumor treatment (n=24, data not reported for 3 patients).
The uric acid AUC0-96 hr was significantly lower in the ELITEK group (128 ± s.e. 14 mg·hr/dL) as compared to the allopurinol group (328 ± s.e. 26 mg·hr/dL). All but one patient in the ELITEK arm had reduction and maintenance of uric acid levels to within or below the normal range during the treatment. The incidence of renal dysfunction was similar in the two study arms; one patient in the allopurinol arm developed acute renal failure.
STUDY 2
Study 2 was a multi-institutional, single-arm study conducted in 89 pediatric and 18 adult patients with hematologic malignancies. Patients received ELITEK at a dose of 0.15 mg/kg/day. The primary efficacy objective was determination of the proportion of patients with maintained plasma uric acid concentration at 48 hours where maintenance of uric acid concentration was defined as: 1) achievement of uric acid concentration </=6.5 mg/dL (patients <13 years) or </=7.5 mg/dL (patients >/=13 years) within a designated time point (48 hours) from initiation of ELITEK and maintained until 24 hours after the last administration of study drug; and 2) control of uric acid level without the need for allopurinol or other agents.
The study population demographics were: age <13 years (76%), males (61%), Caucasian (91%), ECOG performance status = 0 (92%), and leukemia (89%).
The proportion of patients with maintenance of uric acid concentration at 48 hours in Study 2 was 99% (106/107).
STUDY 3
Study 3 was a multi-institutional, single-arm study conducted in 130 pediatric patients and 1 adult patient with hematologic malignancies. 2 Patients received ELITEK at either a dose of 0.15 mg/kg/day (n=12) or 0.20 mg/kg/day (n=119). The primary efficacy objective was determination of the proportion of patients with maintained plasma uric acid concentration at 48 hours as defined for Study 2 above.
The study population demographics were: age <13 years (76%), Caucasian (83%), males (67%), ECOG = 0 (67%), and leukemia (88%).
The proportion of patients with maintenance of uric acid concentration at 48 hours in Study 3 was 92% in the 0.15 mg/kg group (n=12) and 95% in the 0.20 mg/kg group (n=119).
POOLED ANALYSES
Dosing
For the pooled data set of the 3 clinical studies (n=265), total daily dosing for ELITEK ranged from 0.15 to 0.40 mg/kg/day with the majority receiving 0.20 mg/kg/day. The maximum daily doses received were 0.15 mg/kg/day in 116 patients, 0.20 mg/kg/day in 135 patients, 0.30 mg/kg/day (divided doses) in 3 patients, and 0.40 mg/kg/day (divided doses) in 11 patients. The safety and effectiveness of twice-daily dosing with ELITEK have not been established due to insufficient data (see DOSAGE AND ADMINISTRATION).
Reduction of Uric Acid Levels
Data from the 3 studies (n=265) were pooled and analyzed according to the plasma uric acid levels over time. The pre-treatment plasma uric acid concentration was >/=8 mg/dL in 61 patients and was <8 mg/dL in 200 patients. The median uric acid concentration at baseline, at 4 hours following the first dose of ELITEK, and the per patient fall in plasma uric acid concentration from baseline to 4 hours were calculated in those patients with both pre-treatment and 4-hour post-treatment values. Among patients with pre-treatment uric acid >/=8.0 mg/dL [baseline median 10.6 mg/dL (range 8.1-36.4)], the median per-patient change in plasma uric acid concentration by 4 hours after the first dose was a decrease of 9.1 mg/dL (0.3-19.3 mg/dL). Among the patients with a pre-treatment plasma uric acid level < 8 mg/dL [baseline median 4.6 mg/dL (range 0.2-7.9 mg/dL)], the median per-patient change in plasma uric acid concentration by 4 hours after the first dose was a decrease of 4.1 mg/dL (0.1-7.6 mg/dL).
Figure 1 is a box and whisker plot of plasma uric acid levels inclusive of 261 of the 265 ELITEK treated patients from Studies 1, 2, and 3. Of the 261 evaluable patients, plasma uric acid concentration was maintained (see CLINICAL STUDIES, Study 2, for the definition of uric acid concentration maintenance) by 4 hours for 92% of patients (240/261), by 24 hours for 93% of patients (245/261), by 48 hours for 97% of patients (254/261), by 72 hours for 99% of patients (260/261), and by 96 hours for 100% of patients (261/261). Of the subset of 61 patients whose plasma uric acid level was elevated at baseline (>/=8 mg/dL), plasma uric acid concentration was maintained by 4 hours for 72% of patients (44/61), by 24 hours for 80% of patients (49/61), by 48 hours for 92% of patients (56/61), by 72 hours for 98% of patients (60/61), and by 96 hours for 100% (61/61).
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