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Mechanism of Action
VORAXAZE (glucarpidase) is a recombinant bacterial enzyme that hydrolyzes the carboxylterminal glutamate residue from folic acid and classical antifolates such as methotrexate. VORAXAZE converts methotrexate to its inactive metabolites 4-deoxy-4-amino-N10- methylpteroic acid (DAMPA) and glutamate. VORAXAZE provides an alternate non-renal pathway for methotrexate elimination in patients with renal dysfunction during high-dose methotrexate treatment.
Plasma methotrexate concentrations within 48 hours following administration of VORAXAZE can only be reliably measured by a chromatographic method because DAMPA interferes with the immunoassays [see WARNINGS AND PRECAUTIONS]. Following administration of VORAXAZE 50 Units/kg to patients in Study 1, methotrexate concentration measured by a chromatographic method was reduced by ≥ 97% within 15 minutes in all 22 treatment-evaluable patients, and was maintained at a > 95% reduction up to 8 days in 20 of the 22 patients [see Clinical Studies].
The pharmacokinetics of glucarpidase in the absence of methotrexate were studied in eight healthy subjects following an intravenous injection of VORAXAZE 50 Units/kg over 5 minutes. Serum glucarpidase activity levels were measured by an enzymatic assay and serum total glucarpidase concentrations were measured by ELISA.
Serum glucarpidase activity levels declined with a mean elimination half-life (t½) of 5.6 hours. The mean Cmax was 3.3 μg/mL and the mean area under the curve (AUC0-inf) was 23.3 μg·h/mL. The mean systemic clearance (CL) was 7.5 mL/min. The mean volume of distribution (Vd) was 3.6 L, suggesting that glucarpidase distribution is restricted to plasma volume. The pharmacokinetic parameters derived from the serum total glucarpidase concentrations were similar to those generated by serum glucarpidase activity levels except for a longer t½ of 9 hours.
The pharmacokinetics of glucarpidase in the absence of methotrexate were studied in four subjects with severe renal impairment (creatinine clearance < 30 mL/min). Following an intravenous dose of 50 Units/kg of VORAXAZE, the mean pharmacokinetic parameters were similar to those observed in healthy subjects except for a longer t½ of 8.2 hours as compared to 5.6 hours in healthy subjects by the enzymatic assay.
In a study of cancer patients receiving a high-dose methotrexate ( ≥ 1 g/m²) and leucovorin rescue regimen, intravenous administration of 50 Units/kg VORAXAZE 2 hours before leucovorin reduced (6S)-leucovorin AUC0-3h by 33% and Cmax by 52%, and also reduced its active metabolite, (6S)-5-methyltetrahydrofolate, AUC0-3h by 92% and Cmax by 93% [see DRUG INTERACTIONS].
The efficacy of VORAXAZE was evaluated in a subset consisting of 22 treatment-evaluable patients enrolled in Study 1. Study 1 was a single-arm, open-label study in patients who had markedly delayed methotrexate clearance (defined as more than 2 standard deviations greater than the mean excretion curve for methotrexate) secondary to renal dysfunction. All patients received VORAXAZE 50 Units/kg as an intravenous injection over 5 minutes; those patients with pre-VORAXAZE methotrexate concentrations > 100 μmol/L were to receive a second dose of VORAXAZE 48 hours after the first dose. The protocol specified that patients continue receiving intravenous hydration, urinary alkalinization and leucovorin, and that leucovorin administration be adjusted to ensure that it was not administered within two hours before or after VORAXAZE.
Efficacy was evaluated in a subset of patients enrolled in Study 1 who met the inclusion criteria for the study, had a pre-VORAXAZE methotrexate concentration > 1 μmol/L, and had both preand post-treatment plasma samples available for determination of methotrexate concentration by a chromatographic method analysis. The main outcome measure was the proportion of patients who achieved a rapid and sustained clinically important reduction (RSCIR) in plasma methotrexate concentration, defined as an attainment of plasma methotrexate concentration ≤ 1 μmol/L at 15 minutes that was sustained for up to 8 days following the initial injection.
Of the 22 patients in the efficacy dataset, the median age was 15.5 years (5 to 84 years); 59% were male, and the most common underlying cancers were osteogenic sarcoma (50%) and leukemia or lymphoma (45%).
Ten of the 22 patients achieved RSCIR [45% (95% CI 27, 65%)]. Of the 12 patients who failed to achieve RSCIR, 5 patients (23%) attained a transient plasma methotrexate concentration of ≤ 1 μmol/L. In these 5 patients, the median increase of plasma methotrexate concentration from their nadir was 1.4 μmol/L (0.3 to 2.5 μmol/L).
Table 2 summarizes the results of RSCIR and exploratory analyses following the first dose administration of VORAXAZE. An exploratory analysis in subgroups determined by pre-VORAXAZE methotrexate concentration suggests that the likelihood of attaining a RSCIR following the first VORAXAZE injection correlates with the pre-VORAXAZE methotrexate concentration (Table 2). In an additional exploratory analysis, all 9 patients with pre-glucarpidase methotrexate concentrations > 50 μmol/L achieved greater than a 95% reduction in methotrexate concentrations for up to 8 days following the initial injection of VORAXAZE although none of them achieved a RSCIR.
Table 2: Results of RSCIR
and Exploratory Analyses Following the First Dose of VORAXAZE
|Pre-VORAXAZE Methotrexate Concentration (μmol/L)||Number of Patients||Patients Achieving RSCIR n (%)||Patients with >95% Rapid Reduction in Methotrexate Concentration and Maintained up to 8 Days n (%)|
|> 1||22||10 (45%)||20 (91%)|
|> 1 to ≤ 50||13||10 (77%)||11 (85%)|
|> 50 to ≤ 100||2||0||2 (100%)|
|> 100||7||0||7 (100%)|
|RSCIR: rapid and sustained clinically important reduction in methotrexate concentration.|
Lack of Efficacy with a Second Dose of VORAXAZE
Six of the seven patients with pre-first dose VORAXAZE methotrexate concentrations > 100 μmol/L received a second 50 Units/kg dose of VORAXAZE administered 48 hours after the first dose. Among them, none of the four patients with pre-second dose VORAXAZE methotrexate concentrations > 1 μmol/L achieved a RSCIR. The remaining two patients achieved a RSCIR but their pre-second dose VORAXAZE methotrexate concentrations were already ≤ 1 μmol/L.
Deaths Attributable to Methotrexate Toxicity
There are no controlled trials comparing VORAXAZE plus supportive care to supportive care measures alone in patients with toxic plasma methotrexate concentrations due to impaired renal function, therefore there are no data regarding the effect of VORAXAZE on survival or toxic deaths due to methotrexate. VORAXAZE did not prevent fatal methotrexate toxicity in 3% of patients in the safety population.
Last reviewed on RxList: 4/15/2013
This monograph has been modified to include the generic and brand name in many instances.
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