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Population Pharmacokinetics and Exposure-Response Analysis of nab-Paclitaxel in Pediatric Patients With Recurrent or
Yan Li1, Nastya Kassir2, Nianhang Chen1
1Translational Development and Clinical Pharmacology, Celgene Corporation, Summit, New Jersey, USA.
Insights
This study is the first to analyze nanoparticle albumin-bound (nab)-paclitaxel pharmacokinetics in children. Results indicate that patient age and maturation influence drug disposition, with higher doses potentially increasing adverse events.
Area of Science:
- Pediatric Oncology
- Pharmacokinetics
- Drug Development
Background:
- Pediatric cancers often involve the central nervous system or hematopoietic system.
- Refractory and relapsed diseases are primary causes of cancer mortality in children, necessitating novel therapeutic strategies.
- Nanoparticle albumin-bound (nab)-paclitaxel offers improved efficacy and reduced toxicity compared to traditional paclitaxel.
Purpose of the Study:
- To investigate the pharmacokinetics (PK) of nab-paclitaxel in pediatric patients.
- To develop a population PK model describing nab-paclitaxel disposition in children.
- To explore the relationship between nab-paclitaxel exposure and safety events in pediatric oncology.
Main Methods:
- Analysis of data from the ABI-007-PST-001 clinical trial, the first pediatric trial of nab-paclitaxel.
- Development of a 3-compartment population PK model with saturable elimination, incorporating allometric scaling for ontogeny and maturation.
- Exposure-safety analysis correlating drug exposure (AUC) with adverse events and neutropenia.
Main Results:
- Nab-paclitaxel PK disposition in children is influenced by ontogeny and maturation, with increasing clearance and volume of distribution across pediatric age groups and into adulthood.
- The developed population PK model accurately describes paclitaxel whole blood concentrations in pediatrics, consistent with adult PK findings.
- Higher doses of nab-paclitaxel were associated with an increased probability of grade >2 adverse events and neutropenia in cycle 1, but no statistically significant exposure-safety association was found.
Conclusions:
- Ontogeny and maturation significantly impact nab-paclitaxel pharmacokinetics in pediatric patients.
- A population PK model can effectively characterize nab-paclitaxel disposition in children, aiding in dose optimization.
- While higher doses correlate with certain adverse events, further research is needed to establish definitive exposure-safety relationships in pediatric oncology.
Abstract:
Pediatric malignancies are most commonly of primary central nervous system or hematopoietic origin. The main reason for cancer death in pediatrics is refractory and relapsed disease, and improved therapeutic options are needed in the pediatric population. Nanoparticle albumin-bound (nab)-paclitaxel (Abraxane) is a human albumin-stabilized formulation of paclitaxel and was designed to improve the chemotherapeutic effects of paclitaxel and to reduce toxicities. Although nab-paclitaxel pharmacokinetics (PK) has been extensively studied in adults, no information is available on its PK in children. ABI-007-PST-001 was the first nab-paclitaxel clinical trial conducted in pediatrics, and the current analysis is the first study of nab-paclitaxel PK in pediatrics. Our analyses suggested that ontogeny and maturation play a role in nab-paclitaxel PK disposition, as demonstrated by the finding that both blood clearance and volume of distribution increased from younger to older pediatric age groups and from pediatrics to adults. A 3-compartment population PK (PPK) model with saturable elimination was developed to describe the paclitaxel whole blood concentrations in pediatrics. The PPK model was customized by estimating the allometric function on PK parameters to take into account the ontogeny/maturation of patients. PPK estimates are consistent with the fast and deep distribution of paclitaxel that was previously observed in adults. Finally, the exposure-safety analysis showed an increased probability of drug-related adverse events (>grade 2) in cycle 1 and the first cycle of neutropenia (>grade 2) associated with higher doses. However, there is no statistically significant association between exposures (measured by area under the concentration-time curve) and the probabilities of either safety event.
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