Asparaginase Other names: Colaspase Crisantaspase

Asparaginase hydrolyses asparagine to aspartic acid and ammonia. In contrast to normal cells, lymphoblastic tumour cells have a very limited capacity for synthesising asparagine because of a significantly reduced expression of asparagine synthetase. Therefore, they require asparagine which diffuses from the extracellular environment. As a result of asparaginase-induced asparagine depletion in serum, protein synthesis in lymphoblastic tumour cells is disturbed while sparing most normal cells. Asparaginase may also be toxic to normal cells that divide rapidly and are dependent to some degree on exogenous asparagine supply.

Due to the asparagine concentration gradient between the extra- and intravascular space, asparagine levels are subsequently also reduced in the extravascular spaces, e.g. the cerebrospinal fluid.

Pharmacodynamic effects

In a clinical trial in children with de novo ALL (study MC-ASP.4/ALL) it was shown that immediately after the end of infusion of asparaginase mean asparagine concentrations in serum dropped from the pre-dose concentrations of about 40 µM to below the lower limit of quantification of the bioanalytical method (<0.5 µM). The mean asparagine concentrations in serum remained below 0.5 µM from immediately after the end of first infusion of asparaginase until at least three days after the last infusion. Thereafter, asparagine serum levels increased again and returned to normal values within 1–3 weeks.

In addition to asparagine, asparaginase is also able to cleave the amino acid glutamine to glutamic acid and ammonia, however with much less efficiency. Clinical trials with asparaginase have shown that glutamine levels are only moderately affected with a very high interindividual variability. Immediately after the end of infusion of asparaginase, serum levels of glutamine declined by a maximum of 50% from pre-dose levels of about 400 µM but rapidly returned to normal values within a few hours.

Pharmacokinetic parameters of asparaginase were determined in 7 adult patients after intravenous infusion of 5,000 U/m².

Absorption

Asparaginase is not absorbed by the gastrointestinal tract, thus asparaginase must be given intravenously.

Distribution

Asparaginase is distributed mainly within the intravascular space. The mean (Standard Deviation, SD) of the volume of distribution at steady state (V_dss) was 2.47 l (0.45 l). Asparaginase does not seem to penetrate the blood-brain barrier in measurable amounts. Median (range) maximum serum concentrations of asparaginase activity were 2,324 U/l (1,625–4,819 U/l). Peak (C_max) of asparaginase activity in serum was reached with a delay of approximately 2 hours after the end of the infusion. After repeated administration of asparaginase at a dose of 5,000 U/m² every third day, trough asparaginase activity levels in serum ranged from 108 to 510 U/l.

Biotransformation

The metabolism of asparaginase is not known but thought to occur via degradation within the reticulohistiocytic system and by serum proteases.

Elimination

The mean ± SD terminal half-life (elimination half-life) of asparaginase activity in serum was 25.8 ± 9.9 h, with a range between 14.2 and 44.2 h.

Pharmacokinetic/pharmacodynamic relationship(s)

In clinical trials with asparaginase, trough asparaginase serum activity levels greater than 100 U/l were achieved in the majority of patients which nearly always correlated with a complete depletion of asparagine in serum and cerebrospinal fluid (CSF). Even those few patients with trough asparaginase serum activity levels of 10–100 U/l usually experienced complete asparagine depletion in serum and CSF.

Paediatric population

Pharmacokinetic parameters after administration of 5,000 U/m² of asparaginase were determined in 14 children/adolescents (age 2–14 years) with de novo ALL (study MC-ASP.4/ALL). Results are shown in table 4.

Table 4. Pharmacokinetic parameters of asparaginase in 14 children/adolescents:

Median trough serum asparaginase activities were measured in 81 children/adolescents with de novo ALL three days after infusion of asparaginase (just before the next dose had to be given) during induction treatment and ranged from 168 to 184 U/l (study MC-ASP.5/ALL).

Trough serum activity levels were measured in 12 infants (age from birth to 1 year) with de novo ALL (study MC-ASP.6/INF). Median (range) serum trough asparaginase activities on days 18, 25, and 33 were 209 (42–330) U/l, 130 (6–424) U/l, and 32 (1–129) U/l, respectively. The lower median activity level on day 33 compared to the former two measurements was in part due to the fact that this last serum sample was taken 4 days after the last infusion of asparaginase instead of three days on the other occasions.

Non-clinical repeat-dose toxicity and safety pharmacology studies in rats revealed no special hazard for humans, except a slight but significant saluretic effect at doses below the recommended dose for ALL/LBL patients. Additionally, the urinary pH value and the relative weight of kidneys were increased at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.

Evidence from published data with asparaginase renders the mutagenic, clastogenic and carcinogenic potential of asparaginase negligible.

Asparaginase caused an increase in the incidence of malformations (including those of the central nervous system, heart and skeletal system) and foetal death at doses that are similar to or in excess of those proposed clinically (on a U/m² basis) in a number of species including the mouse, rat and/or rabbit.