Population Pharmacokinetic Analysis of Bortezomib in Pediatric Leukemia Patients: Model-Based Support for Body Surface Area-Based Dosing Over the 2- to 16-Year Age Range

Michael J Hanley, Diane R Mould, Timothy J Taylor, Neeraj Gupta, Kaveri Suryanarayan, Rachel Neuwirth, Dixie-Lee Esseltine, Terzah M Horton, Richard Aplenc, Todd A Alonzo, Xiaomin Lu, Ashley Milton, Karthik Venkatakrishnan, Michael J Hanley, Diane R Mould, Timothy J Taylor, Neeraj Gupta, Kaveri Suryanarayan, Rachel Neuwirth, Dixie-Lee Esseltine, Terzah M Horton, Richard Aplenc, Todd A Alonzo, Xiaomin Lu, Ashley Milton, Karthik Venkatakrishnan

Abstract

This population analysis described the pharmacokinetics of bortezomib after twice-weekly, repeat-dose, intravenous administration in pediatric patients participating in 2 clinical trials: the phase 2 AALL07P1 (NCT00873093) trial in relapsed acute lymphoblastic leukemia and the phase 3 AAML1031 (NCT01371981) trial in de novo acute myelogenous leukemia. The sources of variability in the pharmacokinetic parameters were characterized and quantified to support dosing recommendations. Patients received intravenous bortezomib 1.3 mg/m2 twice-weekly, on days 1, 4, and 8 during specific blocks or cycles of both trials and on day 11 of block 1 of study AALL07P1, in combination with multiagent chemotherapy. Blood samples were obtained and the plasma was harvested on day 8 over 0-72 hours postdose to measure bortezomib concentrations by liquid chromatography-tandem mass spectrometry. Concentration-time data were analyzed by nonlinear mixed-effects modeling. Covariates were examined using forward addition (P < .01)/backward elimination (P < .001). Data were included from 104 patients (49%/51% acute lymphoblastic leukemia/acute myelogenous leukemia; 60%/40% aged 2-11 years/12-16 years). Bortezomib pharmacokinetics were described by a 3-compartment model with linear elimination. Body surface area adequately accounted for variability in clearance (exponent 0.97), supporting body surface area-based dosing. Stratified visual predictive check simulations verified that neither age group nor patient population represented sources of meaningful pharmacokinetic heterogeneity not accounted for by the final population pharmacokinetic model. Following administration of 1.3 mg/m2 intravenous bortezomib doses, body surface area-normalized clearance in pediatric patients was similar to that observed in adult patients, thereby indicating that this dose achieves similar systemic exposures in pediatric patients.

Keywords: bortezomib; leukemia; multiple myeloma; pediatric pharmacokinetics; population pharmacokinetics; proteasome inhibitor.

© 2017, The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

Figures

Figure 1
Figure 1
Bortezomib administration in Children's Oncology Group (COG) studies AALL07P1 and AAML1031. ADE, cytarabine/daunorubicin/etoposide; ARAC, cytarabine; CPM, cyclophosphamide; DOX, doxorubicin; ETOP, etoposide; MRD, minimal residual disease; MTX, methotrexate; PEG‐ASP, pegylated asparaginase; PRED, prednisone; VCR, vincristine.
Figure 2
Figure 2
Concentration‐time profile of bortezomib after repeat dosing of 1.3 mg/m2 intravenously. Blue triangles represent individual concentration data from the 104 pediatric patients included in the population pharmacokinetic analysis data set. The black dashed line represents a LOESS curve for the observed data. Red triangles denote mean concentrations from 12 adult multiple myeloma patients on day 11 of cycle 1.8
Figure 3
Figure 3
Basic goodness‐of‐fit plots for the final population PK model. CWRES, conditional weighted residual; IWRES, individual weighted residual; RTLD, relative time since last dose.
Figure 4
Figure 4
Comparison of covariate vs η plots for the base (left column) and final (right column) population PK model: ηCL vs age, BSA, and body weight. BSA, body surface area; ηCL, interindividual variability in clearance.
Figure 5
Figure 5
Visual predictive check plots of the final population pharmacokinetic model for all data (left panel) and stratified by age group (middle and right panels). Blue circles represent the observed concentrations. The red solid and dashed lines indicate the 2.5th, 50th, and 97.5th percentiles of the observations. The black solid and dashed lines represent the 50% and 95% prediction intervals for the simulated data. The shaded green area shows the 95%CI of the simulated data. The inset shows the first 5 hours postdose.
Figure 6
Figure 6
Scatterplot of individual BSA‐normalized clearance vs age. The black line represents a linear regression line (slope of 0.0073, 95%CI [–0.087, 0.101]) with the 95% confidence band enclosed by the dashed lines. BSA, body surface area.

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