Higher plasma asparaginase activity after intramuscular than intravenous Erwinia asparaginase

Abstract

It is unclear if dosing intervals for Erwinase can be extended with intramuscular (i.m.) versus intravenous (i.v.) dosing. Children with acute lymphoblastic leukemia received Erwinase at 30 000-42 000 IU/m 2 i.v. or i.m. I.m. Erwinase (n = 22) achieved activity above 0.1 IU/mL for longer than i.v. Erwinase (n = 33) (3.4 vs 2.9 days, P = 0.0007). With 30 000 IU/m 2 Monday, Wednesday, Friday, more patients achieved adequate concentrations over the weekend with i.m. vs i.v. dosing (P = 5 × 10 −36 ). A schedule with i.v. doses on Monday and Wednesday and i.m. doses on Friday of 30 000 IU/m 2 maintained activity > 0.1 IU/mL over the weekend in 80% of patients. K E Y W O R D S acute lymphoblastic leukemia, asparaginase, Erwinase, intramuscular, intravenous, pharmacokinetics

Comment on “Comparison of hypersensitivity rates to intravenous and intramuscular PEGasparaginase in children with acute lymphoblastic leukemia: A meta‐analysis and systematic review”

“…6 Salzer et al reported also Erwinia asparaginase efficacy data; however, they used IM Erwinia asparaginase. 8 Importantly, the route of Erwinia asparaginase administration might explain higher median asparaginase activities found in the study of Salzer et al 8 as compared to the study of Tong et al 5 Recently, Panetta et al 7 found similar results as obtained by Salzer et al 8 Of note, previous studies have shown striking results, those studies found no differences in mean levels of asparaginase activity, asparagine depletion, and asparaginase antibodies after IV or IM administration of Erwinia asparaginase. [9][10][11] To conclude, not only hypersensitivity rates of IV and IM PEGasparaginase or Erwinia asparaginase should be compared to evaluate its efficacy.…”

Multiple Asparaginase Infusions Cause Increasingly Severe Acute Hyperammonemia

“…Based on a blood volume of 7% of body weight, the infusion of 1250 U/kg of Erwinase and estimated 17,500 U/L of blood would rapidly deaminate circulating asparagine and glutamine. The half-life of Erwinase is shorter when infused [ 29 ], and a two-compartment pharmacokinetic model for a 70-kg individual [ 30 ] includes half-lives of 3.5 h during the distribution phase and 19.6 h for the elimination phase. After 48 h and more than eight half-lives, less than 100 mU/mL would remain in the blood after infusion.…”

Evaluating parameters affecting drug fate at the intramuscular injection site

“…Thus, a fundamental question to be addressed when trying to model the IM injection site is: do elements of the ECM environment affect interactions between drug release and uptake into the systemic circulation? To date, the literature has focussed on drug PK profiles following IM injection, but not on events at the injection site that might affect these outcomes [45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60].…”