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Pharmacodynamics of cerebrospinal fluid asparagine after asparaginase

John C Panetta1, Yiwei Liu1, Teodoro Bottiglieri2

  • 1Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Mail Stop 260, Memphis, TN, 38105, US.

Cancer Chemotherapy and Pharmacology
|June 25, 2021
PubMed

Insights

Multiple pegaspargase doses significantly extend asparagine depletion in the cerebrospinal fluid (CSF) for acute lymphoblastic leukemia (ALL) patients. This prolonged depletion may help prevent central nervous system relapses.

Area of Science:

  • Pediatric Oncology
  • Pharmacokinetics and Pharmacodynamics
  • Leukemia Research

Background:

  • Asparaginase therapy is crucial for treating acute lymphoblastic leukemia (ALL) by depleting asparagine.
  • Understanding the pharmacokinetics and pharmacodynamics of asparaginase is essential for optimizing treatment efficacy and minimizing toxicity.
  • Cerebrospinal fluid (CSF) asparagine levels are critical for preventing central nervous system (CNS) relapse in ALL.

Purpose of the Study:

  • To evaluate the impact of asparaginase dosage, administration schedule, and formulation on CSF asparagine depletion in pediatric ALL patients.
  • To determine the optimal asparaginase regimen for achieving sustained asparagine depletion in the CSF.
  • To investigate the relationship between CSF asparagine depletion and the risk of CNS relapse in ALL.

Main Methods:

  • Analysis of 2114 CSF asparagine and 5007 serum asparaginase samples from 482 children with ALL on the Total XVI study.
  • Administration of one or two IV pegaspargase doses during induction, followed by randomized continuation doses (2500 or 3500 IU/m²).
  • Utilized a pharmacokinetic-pharmacodynamic model to estimate the duration of CSF asparagine depletion below 1 µM.

Main Results:

  • Two induction doses of pegaspargase doubled CSF asparagine depletion duration compared to one dose (30.7 vs 15.3 days).
  • Higher continuation doses showed minimal impact on depletion duration, consistent with nonlinear serum asparaginase pharmacokinetics.
  • Pegaspargase achieved significantly longer CSF asparagine depletion (1.3-5.3-fold) than erwinase; lower depletion was associated with higher CNS relapse rates.

Conclusions:

  • The number of pegaspargase doses is more influential on CSF asparagine depletion than dosage.
  • Pegaspargase demonstrates superior and longer-lasting CSF asparagine depletion compared to erwinase.
  • Sustained CSF asparagine depletion may play a role in preventing CNS relapses in pediatric ALL.
Abstract

Keywords:
Acute lymphoblastic leukemiaAsparagineCerebrospinal fluidErwinia asparaginasePediatricPegylated asparaginasePharmacodynamicsPharmacokinetics

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