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Population Pharmacokinetics and Exposure‐Response Analysis of nab‐Paclitaxel in Pediatric Patients With Recurrent or Refractory Solid Tumors

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.