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. Previo usly reported data from children treated with Erwinase(TM) showed significa ntly lower trough levels and pharmacokinetic dose intensity than after E. c oli-derived preparations. Hence, schedule optimization was initiated to ach ieve relevant serum activities. 21 children on reinduction therapy received Erwinase on Mondays, Wednesdays and Fridays for 3 weeks (9 x 20 000 IU/m(2 ) i.v.) instead of 4x10 000 IU/m(2) of E. coli asparaginase (twice weekly f or 2 weeks). Asparaginase trough activities were measured as the primary pa rameter, targeting 100-200 IU/l after 2 d and >50 IU/l after 3 d. Concurren tly, asparagine trough concentrations were monitored. The mean trough activ ity 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 sample s), with nine, six, and five children inside, below, and above the target r ange, respectively. The mean 3 d trough activity was 50 +/- 39 IU/l (20 pat ients, 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 mu M. We concluded that an inc reased dose of 9 x 20 000 IU/m(2) of Erwinia asparaginase within 3 weeks re sulted in a pharmacokinetic dose intensity comparable to former observation s made with 4 x 10 000 IU/m(2) of the E. coli product Crasnitin(TM) which i s no longer marketed. High interindividual variability and the phenomenon o f 'silent' inactivation necessitate monitoring wherever possible.