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

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/m² 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/m² 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/m² 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.