The evidence for the efficacy of glucarpidase is primarily derived from a pooled analysis of efficacy data from four multicenter, single-arm trials from 1993 to 2007 (n= 476).r All 4 studies enrolled patients who had delayed methotrexate clearance due to methotrexate-induced AKI after high-dose methotrexate (HDMTX). Most patients were receiving treatment for osteosarcoma, non-Hodgkin lymphoma (NHL), primary central nervous system lymphoma (PCNSL), or acute lymphoblastic leukaemia (ALL). All patients had a pre-glucarpidase methotrexate concentration of >1 μmol/L and both pre- and post-treatment plasma samples were taken to analyse methotrexate concentration by high-performance liquid chromatography (HPLC). Pre-glucarpidase plasma methotrexate concentrations varied primarily by tumour type. Most patients with a pre-glucarpidase methotrexate concentration ≥ 50 μmol/L had osteosarcoma (31/41, 76%), whereas most patients with a pre-glucarpidase methotrexate concentration < 50 μmol/L had NHL (32/99, 32%), or ALL (27/99, 27%).
All patients received glucarpidase 50 Units/kg as an intravenous injection over 5 minutes.r Patients continued to receive intravenous hydration, urinary alkalinisation and calcium folinate (Leucovorin®). In order to avoid the known interaction between calcium folinate and glucarpidase, calcium folinate administration was adjusted to ensure that it was not administered within 2 hours before or 2 hours after glucarpidase. DAMPA and OH-DAMPA are by-products of the catabolic action of glucarpidase on methotrexate and are known to cross-react with commercial methotrexate immunoassays causing overestimation of methotrexate concentration after glucarpidase. Therefore, methotrexate concentrations were analysed by HPLC.
Of the total 476 patients with confirmed glucarpidase dosing, 169 had at least one post-glucarpidase methotrexate concentration measurement by HPLC. Those patients with a pre-glucarpidase methotrexate concentration of > 100 μmol/L received a second dose of glucarpidase 48 hours after the first dose. Of the169 evaluable patients, 118 (69.8%) received a single dose of glucarpidase, 45 (26.6%) received a second dose, and 6 (3.6%) received a third. Criteria for a second and third dose of glucarpidase differed across the four studies.
The primary endpoint was defined as rapid and sustained clinically important reduction (RSCIR) in plasma methotrexate concentration, with a concentration of ≤ 1 μmol/L or lower for all post-glucarpidase sampling times (starting at 15 minutes post-dose), that was sustained for up to 8 days following the initial injection. A reduction in methotrexate concentration was immediate in most patients, with 136 (87%) of 156 patients experiencing a ≥ 95% reduction in serum methotrexate concentration from the pre-glucarpidase measurement to the first post-glucarpidase assessment, at a median of 15 minutes post-glucarpidase.
Methotrexate concentrations after treatment with glucarpidaser
© Pharmacotherapy 2014
RSCIR was achieved by 83 (59%) of 140 patients with pre-glucarpidase methotrexate levels > 1 μmol/L. The achievement of RSCIR was clearly related to pre-glucarpidase methotrexate concentrations. Patients who had a pre-glucarpidase methotrexate concentrations of ≥ 50 μmol/L were less likely to achieve RSCIR than those with concentrations of < 50 μmol/L. However, analysis of the reduction in methotrexate concentration showed that patients with higher pre-glucarpidase methotrexate concentrations had a higher percent reduction in methotrexate concentration following glucarpidase.
98% (44/45) of patients with pre-glucarpidase methotrexate concentrations of ≥ 50 μmol/L and 83% (92/111) of patients with pre-glucarpidase concentrations of < 50 μmol/L had 95% reductions at the first post-glucarpidase measurement. A further reduction in methotrexate concentration was observed in 8 patients who received a second dose of glucarpidase ≥48 hours after the first dose and who had a methotrexate concentration > 1 μmol/L before the second dose. However, the extent of this further reduction varied (range 8% - 97%), suggesting the utilisation of extra doses of glucarpidase may be limited.
There are no controlled trials comparing glucarpidase plus supportive care to supportive care measures alone in patients with toxic plasma methotrexate concentrations due to impaired renal function, therefore, there is no data regarding the effect of glucarpidase on survival or toxic deaths due to methotrexate.r
The most common adverse reactions reported were flushing (2%), nausea & vomiting (2%), paraesthesia (2%), headache (1% ), and hypotension (1% ). Hypersensitivity reactions were reported in less than 1% of patients.r
Glucarpidase efficacy was evaluated in a subset of 156 patients with at least one post-glucarpidase methotrexate concentration measured by HPLC. A methotrexate concentration reduction of ≥ 95% was achieved in 87% of patients.
Methotrexate concentration post first glucarpidase dose
© Pharmacotherapy 2014
There were 140 patients with a pre-glucarpidase methotrexate level > 1 micromol/L, of which 59% achieved RSCIR. The table below represents the key efficacy endpoints achieved in one of the four studies (n= 22).
Treatment-evaluable subset efficacy summaryr
©BTG International Inc 2012
In a pooled analysis of 45 patients who received a second dose of glucarpidase ≥48 hours after the first dose due to sustained methotrexate concentrations >1 micromol/L, a further reduction was observed in 8 patients. However, the extent of this further reduction varied (range 8–97%), suggesting the utilisation of extra doses of glucarpidase may be limited.
There are no controlled trials comparing glucarpidase 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 glucarpidase on survival or toxic deaths due to methotrexate.r,r
The most common related adverse reactions were paraesthesia (2% of patients) and flushing (1.8%). Hypersensitivity reactions were reported in less than 1% of patients.r,r