Population Pharmacokinetics and Exposure-Safety Relationships of Alisertib in Children and Adolescents With Advanced Malignancies.

Population pharmacokinetic (PK) and exposure-safety analyses of alisertib were performed in children enrolled in two clinical trials: NCT024448841 and NCT01154816.2 NCT02444884 was a dose-finding study in children with relapsed/refractory solid malignancies (phase 1) or neuroblastomas (phase 2). Patients received oral alisertib 45-‍100 mg/m2 as powder-in-capsule once daily (QD) or twice daily (BID) for 7 days in 21-day cycles. Serial blood samples were collected up to 24 hours post-dose on cycle 1, day 1. NCT01154816 was a phase 2 single-arm study evaluating efficacy in children with relapsed/refractory solid malignancies or acute leukemias. Patients received alisertib 80 mg/m2 as enteric-coated tablets QD for 7 days in 21-day cycles. Sparse PK samples were collected up to 8 hours post-dose on cycle 1, day 1. Sources of alisertib PK variability were characterized and quantified using nonlinear mixed-effects modeling to support dosing recommendations in children and adolescents. A 2-compartment model with oral absorption described by 3 transit compartments was developed using data from 146 patients. Apparent oral clearance and central distribution volume were correlated with body surface area (BSA) across the age range of 2-21 years, supporting the use of BSA-based alisertib dosing in the pediatric population. The recommended dose of 80 mg/m2 QD enteric-coated tablets provided similar alisertib exposures across pediatric age groups and comparable exposure to that in adults receiving 50 mg BID (recommended adult dose). Statistically significant relationships (p < .01) were observed between alisertib exposures and incidence of grade ≥2 stomatitis and febrile neutropenia, consistent with antiproliferative mechanism-related toxicities. This article is protected by copyright. All rights reserved.