Impact of pharmacogenetics on the population pharmacokinetics and toxicity of L-asparaginase in children with acute lymphoblastic leukemia

Introduction/Background/Significance: L-asparaginase (L-Asp) remains an essential component in the treatment of pediatric acute lymphoblastic leukemia (ALL). However, its use is often limited by adverse events (AEs), primarily hypersensitivity and pancreatitis.

Materials and Methods/Case Presentation/Objective: The aim of this study was to identify the impact of specific single nucleotide variants (SNVs) on the population pharmacokinetics and toxicity of L-asparaginase in children with acute lymphoblastic leukemia in a Mexican pediatric cohort. A total of 74 pediatric patients with ALL treated with Escherichia coli-derived L-Asp were included, all receiving care at two hospital centers in Mexico. A population pharmacokinetic/pharmacodynamic (PK/PD) model was developed to estimate interindividual variability in PK/PD parameters. Simultaneously, three SNVs GRIA1 rs4958351, rs6889909, and NFATC2 rs6021191 were genotyped, and associations between their genotypic status and variations in PK/PD parameters, the occurrence of AEs, and the formation of anti-L-Asp antibodies were evaluated.

Results/Description/Main Outcome Measures: The presence of anti-L-Asp antibodies was significantly associated with increased clearance (CL) (r = 0.813, p = 0.01) and IC50 (r = 0.734, p = 0.01), as well as a decreased central compartment volume of distribution (V1) (r = −0.723, p = 0.003), suggesting drug neutralization and accelerated elimination. In contrast, patients who developed pancreatitis did not present antibodies but showed rapid asparagine depletion (< 24 h), which may represent an early risk marker for this adverse event. Female sex was associated with higher V1 and IC50 values, indicating reduced pharmacological efficacy. At the genetic level, patients homozygous for the AA allele of GRIA1 rs4958351 showed a higher risk of adverse events (OR = 4.05, p = 0.04) and antibody formation (OR = 3.43, p = 0.04), identifying this SNV as a potential predictive biomarker of immunogenicity.

Conclusions: This integrative PK/PD and pharmacogenetic analysis identifies the GRIA1 rs4958351 SNV and rapid asparagine depletion as key factors in predicting L-Asp-related toxicity. These findings support the implementation of individualized genetic and pharmacokinetic profiling to optimize L-Asp therapy and minimize the risk of adverse events in the pediatric treatment of ALL.