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 2 clinical trials: NCT02444884 and NCT01154816. NCT02444884 was a dose‐finding study in children with relapsed/refractory solid malignancies (phase 1) or neuroblastomas (phase 2). Patients received oral alisertib 45 to 100 mg/m(2) as powder‐in‐capsule once daily or twice daily for 7 days in 21‐day cycles. Serial blood samples were collected up to 24 hours after dosing 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/m(2) as enteric‐coated tablets once daily for 7 days in 21‐day cycles. Sparse PK samples were collected up to 8 hours after dosing 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 across the age range of 2 to 21 years, supporting the use of body surface area–based alisertib dosing in the pediatric population. The recommended dose of 80 mg/m(2) once daily enteric‐coated tablets provided similar alisertib exposures across pediatric age groups and comparable exposure to that in adults receiving 50 mg twice daily (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.