Pharmacokinetic dose adjustment of Erwinia asparaginase in protocol II of the paediatric ALL/NHL‐BFM treatment protocols

Abstract

Native forms of asparaginase stem from different biological sources. Previously reported data from children treated with Erwinase showed significantly lower trough levels and pharmacokinetic dose intensity than after E. coli-derived preparations. Hence, schedule optimization was initiated to achieve relevant serum activities. 21 children on reinduction therapy received Erwinase on Mondays, Wednesdays and Fridays for 3 weeks (9 x 20000 IU/m2 i.v.) instead of 4x 10 000IU/m2 of E. coli asparaginase (twice weekly for 2 weeks). Asparaginase trough activities were measured as the primary parameter, targeting 100-200 IU/I after 2 d and >50 IU/l after 3 d. Concurrently, asparagine trough concentrations were monitored. The mean trough activity was 156+/-99 IU/l, with 2/108 samples showing no detectable activity. Regarding trough levels per individual (three or more measurements/patient), means ranged from 52+/-29 to 276+/-114 IU/l (20 patients, 106 samples), with nine, six, and five children inside, below, and above the target range, respectively. The mean 3 d trough activity was 50+/-39 IU/l (20 patients, 51 samples). In 11 of these samples no activity was measurable. Mean trough activities calculated per individual ranged from < 20-84+/-30 IU/l (14 patients, 42 samples) with seven children below the target limit of 50 IU/l and asparagine concentrations <0.2 - 1.5microM. We concluded that an increased dose of 9x20000 IU/m2 of Erwinia asparaginase within 3 weeks resulted in a pharmacokinetic dose intensity comparable to former observations made with 4 x 10 000IU/m2 of the E. coli product Crasnitin which is no longer marketed. High interindividual variability and the phenomenon of 'silent' inactivation necessitate monitoring wherever possible.

Erwinia asparaginase after allergy to E. coli asparaginase in children with acute lymphoblastic leukemia

“…For example, higher NSAA and continuous asparagine depletion were observed in 21 children who received Erwinia asparaginase at a higher dose (20,000 IU/m 2 ) and more frequently (three times weekly, with 2 and 3-day intervals between doses) as part of a Berlin-Frankfurt-Muenster (BFM) trial. [33] Also, an extremely high mean NSAA of 1.75 IU/mL was found in 27 patients receiving 10 daily doses of Erwinia asparaginase at a dose of 30,000 IU/m 2 . [34] The impact of these dosing strategies on longterm outcome remains unclear.…”

Erwinia asparaginase achieves therapeutic activity after pegaspargase allergy: a report from the Children’s Oncology Group

“…37 Specifically, the M/W/F schedule was recommended when substituting Erwinia asparaginase for weekly E coli asparaginase. 47 The dose of Erwinia asparaginase is also a critical consideration, since only 33% of the patients receiving a 10 000-IU/m 2 intramuscular dose once every 3 days had mean trough levels >0.10 IU/mL. 48 The results of COG AALL07P2 showed that of the 55 eligible/ evaluable patients, NSAA >0.1 IU/mL was achieved in 38 (92.7%) of 41 patients, with samples meeting acceptability criteria 48 hours after dosing; hence, it was concluded that .70% of patients achieved the required trough serum asparaginase activity.…”

Pharmacokinetic and Pharmacodynamic Properties of Calaspargase Pegol Escherichia coli L-Asparaginase in the Treatment of Patients With Acute Lymphoblastic Leukemia: Results From Children's Oncology Group Study AALL07P4

“…[13][14][15][16] Some reports have noted that complete asparagine depletion can still be observed even with levels Ͻ 100 mIU/mL. 17,18 Other investigators have suggested that a higher level of asparaginase activity (Ն 400 mIU/mL) is needed to achieve optimal asparagine depletion. 19 Our Abbreviations: AE, adverse event; INR, international normalized ratio; SC-PEG, calaspargase pegol; SS-PEG, pegaspargase.…”