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Background <p>There is a paucity of data regarding the comparison of asparaginase activity, pharmacokinetics, pharmacodynamic outcomes, and safety of biosimilar native E.coli asparaginase (N-Asp) and biosimilar pegylated asparaginase (P-Asp) used in India.</p> Methods <p>A randomized, open-labeled, population pharmacokinetic (PopPK) and pharmacodynamic trial comparing the N-Asp (10,000&#xa0;IU/m<sup>2</sup>) and P-Asp (1000&#xa0;IU/m<sup>2</sup>) administered intramuscularly in children with newly diagnosed acute lymphoblastic leukemia. The primary endpoint was asparaginase activity on day 33 of the induction phase of chemotherapy. Population pharmacokinetic modeling was done after the first dose in both groups, and the models were simulated to assess for the subtherapeutic trough concentrations.</p> Results <p>Fourteen patients were randomized to each arm. The asparaginase activity of 434[interquartile range(IQR) 259, 629] IU/L was observed in the P-Asp compared (<i>p</i>—0.04) to the N-Asp group 64[IQR 27, 184] IU/L on day 33 of the induction phase of chemotherapy. The anti-asparaginase antibody formation, minimal residual disease, and safety were comparable between both groups. The interindividual variability of the population parameters in the PopPK model was higher with N-Asp than P-Asp. The subtherapeutic trough levels of asparaginase were observed more in the N-Asp group (9/14 in N-Asp vs. 0/14 in P-Asp, <i>p</i> &lt; 0.01).</p> Conclusion <p>The asparaginase activity was higher with P-Asp at d33. P-Asp demonstrated less interindividual variability and a predictable kinetic profile, supporting its preferability over N-Asp for first-line management of ALL in the Indian pediatric population. While routine TDM for trough level monitoring may be less critical with P-Asp, TDM retains value to identify silent inactivation, differentiate hypersensitivity from infusion reactions, and confirm adequate activity in high-risk scenarios. In contrast, the higher variability of N-Asp strongly warrants the use of TDM.</p> Clinical trial registration identification <p>CTRI/2019/06/019520 registered on 04/June/2019.</p>

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Comparative assessment of asparaginase activity, population pharmacokinetics, and safety of biosimilar native Escherichia coli and pegylated asparaginase in children with newly diagnosed acute lymphoblastic leukemia: a pharmacometrics-based randomized clinical trial

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  • 出版模式：

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  • 发表日期：

    2026年6月17日

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  • Sujitha Sethuramalingam,
  • Sonali Mohapatra,
  • Praveen Kumar Agarwal,
  • Praveen Kumar-M,
  • Debasish Hota,
  • Janhavi Gopal,
  • Aishwarya Kulkarni,
  • Anand Srinivasan

摘要

Background

There is a paucity of data regarding the comparison of asparaginase activity, pharmacokinetics, pharmacodynamic outcomes, and safety of biosimilar native E.coli asparaginase (N-Asp) and biosimilar pegylated asparaginase (P-Asp) used in India.

Methods

A randomized, open-labeled, population pharmacokinetic (PopPK) and pharmacodynamic trial comparing the N-Asp (10,000 IU/m2) and P-Asp (1000 IU/m2) administered intramuscularly in children with newly diagnosed acute lymphoblastic leukemia. The primary endpoint was asparaginase activity on day 33 of the induction phase of chemotherapy. Population pharmacokinetic modeling was done after the first dose in both groups, and the models were simulated to assess for the subtherapeutic trough concentrations.

Results

Fourteen patients were randomized to each arm. The asparaginase activity of 434[interquartile range(IQR) 259, 629] IU/L was observed in the P-Asp compared (p—0.04) to the N-Asp group 64[IQR 27, 184] IU/L on day 33 of the induction phase of chemotherapy. The anti-asparaginase antibody formation, minimal residual disease, and safety were comparable between both groups. The interindividual variability of the population parameters in the PopPK model was higher with N-Asp than P-Asp. The subtherapeutic trough levels of asparaginase were observed more in the N-Asp group (9/14 in N-Asp vs. 0/14 in P-Asp, p < 0.01).

Conclusion

The asparaginase activity was higher with P-Asp at d33. P-Asp demonstrated less interindividual variability and a predictable kinetic profile, supporting its preferability over N-Asp for first-line management of ALL in the Indian pediatric population. While routine TDM for trough level monitoring may be less critical with P-Asp, TDM retains value to identify silent inactivation, differentiate hypersensitivity from infusion reactions, and confirm adequate activity in high-risk scenarios. In contrast, the higher variability of N-Asp strongly warrants the use of TDM.

Clinical trial registration identification

CTRI/2019/06/019520 registered on 04/June/2019.