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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
Author(s) -
Hanley Michael J.,
Mould Diane R.,
Taylor Timothy J.,
Gupta Neeraj,
Suryanarayan Kaveri,
Neuwirth Rachel,
Esseltine DixieLee,
Horton Terzah M.,
Aplenc Richard,
Alonzo Todd A.,
Lu Xiaomin,
Milton Ashley,
Venkatakrishnan Karthik
Publication year - 2017
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.906
Subject(s) - dosing , body surface area , pharmacokinetics , medicine , population pharmacokinetics , population , nonmem , range (aeronautics) , pharmacology , environmental health , materials science , composite material
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/m 2 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/m 2 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.