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

Native forms of asparaginase stem from different biological sources. Previously reported data from children treated with Erwinase^TM 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 × 20 000 IU/m² i.v.) instead of 4 × 10 000 IU/m² of E. coli asparaginase (twice weekly for 2 weeks). Asparaginase trough activities were measured as the primary parameter, targeting 100–200 IU/l 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 < 0.2–1.5 μm. We concluded that an increased dose of 9 × 20 000 IU/m² of Erwinia asparaginase within 3 weeks resulted in a pharmacokinetic dose intensity comparable to former observations made with 4 × 10 000 IU/m² of the E. coli product Crasnitin^TM which is no longer marketed. High interindividual variability and the phenomenon of ‘silent’ inactivation necessitate monitoring wherever possible.