Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1     Pharmacodynamic properties

Pharmacotherapeutic group: Detoxifying agent for antineoplastic treatment, ATC code: V03AF09.

Mechanism of action and pharmacodynamic effects
Glucarpidase is a recombinant bacterial enzyme that hydrolyses the carboxyl-terminal glutamate residue from folic acid and structurally related molecules such asMTX. 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.
Clinical efficacy

The efficacy of glucarpidase has been evaluated in four open-label multi-center, compassionate use, single arm, open label studies in patients with delayed MTX elimination due to renal dysfunction. The primary endpoint in the clinical studies was referred to as a clinically important reduction (CIR) in MTX concentration and was based on central MTX HPLC data. A patient was considered to have achieved a CIR if all central MTX HPLC plasma concentrations after the first dose of glucarpidase were ≤1 µmol/L.

In Study 001, 44 male and female patients were in the Safety population (median age 53.0; range 10 – 78 years) and received a median dose of 50 U/kg (range 9.80 to 58.14 U/kg). Of the 28 patients with central HPLC data, 85.7% (95% CI: 68.5% to 94.3%) achieved a CIR.

In Study 002, 214 male and female patients were in the Safety population (median age 17.0; range 0 - 82 years) and received a median dose of 49.23 U/kg (range 10.87 to 63.73 U/kg). Of the 84 patients with central HPLC data, 54.8% (95% CI: 44.2% to 65.0%) achieved a CIR.

In Study 003, 69 male and female patients were in the Safety population (median age 15.0; range 0 - 71 years) and received a median dose of 50 U/kg (range 16.64 to 100 U/kg). Of the 30 patients with central HPLC data, 66.7% (95% CI: 48.8% to 80.8%) achieved a CIR.

In Study 006, 149 male and female patients were in the Safety population (median age 18.0; range 10 – 78 years) and received a median dose of 48.73 U/kg (range 17.86 to 98.04 U/kg). Of the 27 patients with central HPLC data, 51.9% (95% CI: 34.0% to 69.3%) achieved a CIR.

A total of 169 patients were included in the pooled central MTX HPLC population and received a median initial dose of 50 Units/kg (range 11 to 60 Units/kg). A CIR was achieved by 61.5% (95% CI: 54.0% to 68.5%) of patients in the central MTX HPLC population that was sustained for up to 8 days.
Amedian reduction of > 98% in MTX concentration occurred within 15 minutes following glucarpidase administration.

Rebound (defined as MTX concentration increase of at least 1 μmol/L and at least two times the post- glucarpidase nadir) occurred in 19.4% of patients in the central MTX HPLC population. Overall half of the patients with rebound had a maximum absolute increase in MTX concentration of between 1 and 2 µmol/L, and only 1 patient had an increase of >10 µmol/L (this patient had a pre-glucarpidase MTX concentration of 165.86 µmol/L and received a glucarpidase dose of 10.53 U/kg). Of the 4 patients who had rebound after their first glucarpidase dose and received a second glucarpidase dose, there was a median reduction of MTX concentration of 84% and 2 achieved a CIR.

Of the 410 patients in the pooled renal evaluable population (patients who had at least one post- glucarpidase renal function assessment) who developed serum creatinine (sCr) common toxicity criteria grade ≥2 at pre-glucarpidase baseline, 262 (63.9%) recovered to grade 0 or 1. In the renal evaluable population there was a 3.5-fold increase in mean sCr concentration from pre-MTX to pre- glucarpidase baseline (0.79mg/dL to 2.79 mg/dL). After administration of glucarpidase, sCr continued to rise (mean increase of 0.24 mg/dL over three days), then began to decrease. The mean sCr value at day 22 was 1.27 mg/dL. For the 258 patients for whom days to recovery could be calculated, the median time to recovery was 12.5 days (range 1–213 days).

Paediatric population

The pooled clinical safety database for glucarpidase includes data for 232 patients up to 17 years of age. Within the central MTX HPLC population 0% (0/1) patient aged ≥28 days to <2 years (Infant Subgroup), 31.3% (5/16) patients aged ≥2 to <12 years (Child Subgroup) and 49.1% 27/55 patients aged ≥12 to <18 years of age achieved a CIR. A median reduction of ≥ 95% in MTX concentration occurred within 15 minutes following glucarpidase administration in all paediatric subgroups.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

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 μg·h/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.

Distribution

The mean volume of distribution (Vd) was 3.55 L.
Biotransformation

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.

Elimination

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.

Specific populations

Patients with renal impairment
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.

Paediatric population
No formal evaluation of the effect of age on the pharmacokinetics of glucarpidase has been performed.