Glucarpidase is a recombinant bacterial enzyme that hydrolyses the carboxyl-terminal glutamate residue from folic acid and structurally related molecules such as methotrexate (MTX). Glucarpidase converts MTX to its inactive metabolites DAMPA and glutamate. Because both DAMPA and glutamate are metabolised by the liver, glucarpidase provides an alternative route for MTX elimination in patients with renal dysfunction during high-dose MTX treatment.
Due to its large molecular size, glucarpidase does not cross the cellular membrane and therefore does not counteract the intracellular antineoplastic effects of high-dose MTX.
The pharmacokinetics of glucarpidase in the absence of MTX were studied in 8 healthy subjects following glucarpidase 50 Units/kg administered as an intravenous injection over 5 minutes. Serum glucarpidase activity levels were measured by an enzymatic assay and serum total glucarpidase concentrations were measured by enzyme linked immunosorbent assay (ELISA). The mean maximum serum concentration (Cmax) was 3.3 μg/mL and the mean area under the curve (AUC0-INF) was 23.3 μgꞏh/mL. The pharmacokinetic parameters derived from the serum total glucarpidase concentrations were similar to those generated by serum glucarpidase activity levels except for elimination half-life as described below.
A clinically relevant accumulation of glucarpidase after a repeat injection within a MTX cycle has not been observed.
The mean volume of distribution (Vd) was 3.55 L.
The product is an enzyme, and therefore a protein. The metabolism of such products entails the degradation to small peptides and individual amino acids and therefore, the metabolic pathways are generally understood. Classical biotransformation studies are therefore not required and have not been conducted.
The ability of the main metabolite produced by the action of glucarpidase on MTX (DAMPA) to induce or inhibit CYP450 metabolising isoenzymes has been investigated in vitro, which revealed possible enzyme induction with CYP1A2 and CYP2C9. Modest induction would only be expected in a minority of patients who have the highest DAMPA exposure.
Serum glucarpidase activity levels declined with a mean elimination half-life (t1/2) of 5.6 hours and serum total glucarpidase concentration declined with a mean t1/2 of 9 hours. The mean systemic clearance (CL) was 7.5 mL/min.
A study of the pharmacokinetics of glucarpidase in the absence of MTX in 4 subjects with severe renal impairment (CLcr <30 mL/min) showed that the mean pharmacokinetic parameters were similar to those observed in healthy subjects. On this basis, no dose adjustment of glucarpidase is recommended for patients with renal impairment.
No formal evaluation of the effect of age on the pharmacokinetics of glucarpidase has been performed.
Generally, effects in non-clinical studies were observed at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.
The carcinogenic, genotoxic and reproductive toxicity potential of glucarpidase have not been studied. Decreased platelets were reported in a 14 day dog study and intravenous human equivalent doses of 278 and 1389 Units/kg were associated with increasing severe dose related toxicity which resulted in deaths or premature euthanasia.
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