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Biogeneric Native and Polyethylene Glycol-conjugated Escherichia coli Asparaginases for Treating Children with Acute
Neerajana Datta1, Bishwaranjan Jana1, Srijani Goswami1
1Tata Translational Cancer Research Centre, Tata Medical Center, Kolkata, India.
Insights
Optimizing Escherichia coli asparaginase (EcASNase) dosing improves treatment for childhood leukemia in low-income countries. Pharmacokinetic monitoring enhances generic asparaginase efficacy and safety.
Area of Science:
- Pharmacology
- Oncology
- Drug Development
Background:
- Suboptimal quality of Escherichia coli asparaginase (EcASNase) in low-middle income countries impacts outcomes for children with acute lymphoblastic leukemia.
- There is a need for improved therapeutic strategies for pediatric acute lymphoblastic leukemia.
Purpose of the Study:
- To analyze the pharmacokinetics, activity, and immunogenicity of native and PEGylated asparaginase biogenerics.
- To optimize dosing strategies for generic asparaginase products.
Main Methods:
- Comparative analysis of native EcASNase and PEG-EcASNase pharmacokinetics and activity.
- Intramuscular administration of biogeneric EcASNase and PEG-EcASNase at different dosing frequencies.
- Monitoring of trough activity, hypersensitivity, pancreatitis, and antidrug antibodies.
Main Results:
- Higher dosing frequency of native EcASNase improved trough activity, eliminating suboptimal levels.
- PEG-EcASNase demonstrated sustained activity, though suboptimal levels were observed in some patients.
- Adverse events like hypersensitivity and pancreatitis varied between native and PEGylated formulations, with antidrug antibodies linked to silent inactivation and hypersensitivity.
Conclusions:
- Pharmacological monitoring is crucial for optimizing EcASNase dosing and detecting silent inactivation.
- Induction dosing intensity is a key factor for sustained activity of generic asparaginase products.
- These findings support improved therapeutic strategies for acute lymphoblastic leukemia in resource-limited settings.
Background:
Escherichia coli asparaginases (EcASNase) available for the treatment of children with acute lymphoblastic leukemia are largely of suboptimal quality in low-middle income countries and contribute to inferior outcomes.
Methods:
The pharmacokinetics, activity, and immunogenicity of a native (EcASNase) and a PEGylated ASNase (PEG-EcASNase) were analyzed. Biogeneric EcASNase (10,000 IU/m2) was administered intramuscularly every 72 hours (cohort 1, 76 patients) or every 48 hours (cohort 2, 69 patients). Cohort 3 (176 patients) received a PEG-EcASNase biogeneric (1000 IU/m2) intramuscularly every 14 days.
Results:
In cohort 1, 69% of trough induction samples were suboptimal (<100 IU/L). Cohort 2 achieved a median trough activity >600 IU/L during induction, with no suboptimal activity. The median trough activity during induction in cohort 3 was 467 IU/L, with suboptimal activity observed in 7%-16%. Patients receiving 1 induction PEG-EcASNase dose had 8-fold higher odds of suboptimal activity postinduction. Hypersensitivity was higher with EcASNase (12% versus 5%) and pancreatitis, more often with PEG-EcASNAse (5% versus 1%). Antidrug antibodies were strongly associated with silent inactivation and hypersensitivity (P < 0.0001).
Conclusions:
Pharmacological monitoring enabled optimization of EcASNase dosing, detection of silent PEG-EcASNase inactivation, and identification of induction dosing intensity as a determinant of sustained activity for generic ASNase products marketed in low-middle income countries.
