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

Abstract

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.

Keywords: Aurora A kinase; alisertib; exposure-safety; pediatric; population pharmacokinetics.

Conflict of interest statement

X.Z., Y.Y., and D.V.F. disclose employment by Millennium Pharmaceuticals, Inc, Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. D.R.M. is a paid consultant for Millennium Pharmaceuticals, Inc, Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. K. V. discloses previous employment by Millennium Pharmaceuticals, Inc. E.F. and E.G. have no disclosures to report.

© 2021 Millennium Pharmaceuticals Inc. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.

Figures

Figure 1

BSA covariate effect in the final model. BSA, body surface area; BSV, between subject variability; eta, empirical Bayes prediction of the interindividual random effect.

Figure 2

Alisertib CL/F (A) and BSA‐normalized CL/F (B) by age group for pediatric patients. Estimates were obtained under the final model. Data for age groups 2 to 5, 6 to 11, and 12 to 16 are pooled for the group “2 through 16” box. Note that CL/F is presented as reference CL/F (ie, CL/F associated with capsule formulation). BSA, body surface area; CL/F, apparent clearance.

Figure 3

Formulation covariate effect in the final model. BASENOBIO refers to the base model without a bioavailability term for the enteric‐coated tablet rather than the base model, which includes this term. The FINAL model includes the effects of formulation on F and of BSA on CL/F and V1/F. BSA, body surface area; BSV, between subject variability; CL/F, apparent clearance; eta, empirical Bayes estimate of the interindividual random effect; F, bioavailability; V1/F, apparent central volume.

Figure 4

Visual predictive check for base and final models for (A) powder‐in‐capsule and (B) enteric‐coated tablet formulations for day 1 of once daily regimen. The observed analysis data (symbols) were compared to 200 data sets simulated using the base and final models. Black circles are observed data, red lines are observed data 5th, 50th, and 95th percentiles. Pink shaded regions are 95% prediction intervals for the 5th, 50th, and 95th percentiles of simulated data.

Figure 5

Alisertib AUCss by age group—pediatric simulated 80 mg/m2. Post hoc clearance used to calculate AUCss, and enteric‐coated tablet doses were adjusted for relative bioavailability. Results pooled across analyses. Results are presented for final pediatric model using 80 mg/m2 (recommended pediatric dose) using the enteric‐coated tablet formulation (F = 0.671). Results for adults are derived from the final adult model using 50 mg twice daily (100 mg total daily dose, recommended clinical dose for adults). Only adult data from Western region are presented. AUCss, area under the concentration time curve at a steady state.

Figure 6

Logistic regression fitted model and 95% confidence intervals for (A) grade ≥2 stomatitis and (B) febrile neutropenia. Circles represent observed incidence in each tertile of alisertib average concentration. Logistic regression model was used to estimate adverse event incidence of clinical interest with alisertib average concentration as a predictor (base model). The covariate effects that may potentially modulate the exposure–safety relationship were examined in a full model via a stepwise procedure, where a covariate was entered into the model if it was significant at the 10% level. A covariate remained in the model at the backward elimination step when the covariate was significant at the 5% level. The covariates considered in the full model include age (2 to ≤12 years, >12 to ≤16 years, >16 years), sex (male, female), Eastern Cooperative Oncology Group performance score (0, >0), number of prior therapy regimens (≤1, ≥2), cancer type (hematologic, nonhematologic) and number of treatment cycles while on study (1, ≥2). For the adverse event end point “grade ≥2 stomatitis” (A) the full model is reduced to the base model after the stepwise selection procedure. For the adverse event end point “febrile neutropenia” (B), the full model with stepwise selection identified that the covariate of “cancer type” is significant. As the sample size of patients with hematologic malignancies was small (n = 19; 13% of the evaluable data set), the relationship between exposure and probability of febrile neutropenia for the base model is shown here.