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Implementation of a Physiologically Based Pharmacokinetic Modeling Approach to Guide Optimal Dosing Regimens for

Jeffry Adiwidjaja1, Alan V Boddy2,3, Andrew J McLachlan1

  • 1Sydney Pharmacy School, The University of Sydney, Sydney, NSW, Australia.

Frontiers in Pharmacology
|February 22, 2020
PubMed

Insights

Physiologically based pharmacokinetic (PBPK) modeling helps determine optimal imatinib dosing for pediatric chronic myeloid leukemia (CML) patients. This approach also predicts drug interactions, ensuring safer imatinib use in children.

Area of Science:

  • Pharmacology
  • Pharmacokinetics
  • Pediatric Oncology

Background:

  • Imatinib is effective for pediatric chronic myeloid leukemia (CML), but optimal dosing and drug interactions in children are not well-defined.
  • Physiologically based pharmacokinetic (PBPK) modeling offers a promising approach to address these challenges in pediatric populations.

Purpose of the Study:

  • To develop and validate a PBPK model for imatinib in pediatric patients.
  • To investigate optimal imatinib dosing regimens for children and adolescents.
  • To predict potential drug interactions involving imatinib in the pediatric population.

Main Methods:

  • Developed a PBPK model for imatinib using in silico, in vitro, and in vivo data.
  • Validated the model with independent clinical pharmacokinetic data.
  • Extrapolated the model to pediatric populations (2-18 years) considering developmental changes.
  • Simulated drug interactions with carbamazepine (a CYP3A4 and CYP2C8 inducer).

Main Results:

  • The PBPK model accurately described imatinib pharmacokinetics in both adults and pediatric populations.
  • Predicted drug interactions with carbamazepine showed good accuracy.
  • The optimal imatinib dosing range in pediatrics was predicted as 230-340 mg/m²/d.
  • Pediatric and adult patients exhibit similar vulnerability to CYP enzyme modulations.

Conclusions:

  • A validated PBPK model for imatinib is effective for predicting pharmacokinetics across age groups.
  • This PBPK model can guide optimal imatinib dosing and predict drug interactions in pediatric CML patients.
  • The findings support the use of PBPK modeling for personalized medicine in pediatric oncology.

Keywords:
drug interactionsimatinibpaediatricsphysiologically based pharmacokinetic (PBPK)simulation

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