LB-031 - POPULATION PHARMACOKINETICS OF BORTEZOMIB: MODEL-BASED META-ANALYSIS

K. Ryu¹, S. Jung², H. Lee², H. Kim², J. Lim³, H. Kim³, M. Chang⁴; ¹Department of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, , , ²Department of Pharmaceutical Medicine and Regulatory Science, Yonsei University, , , ³Graduate Program of Industrial Pharmaceutical Science, Yonsei University, , , ⁴Yonsei University, , .

Background: Bortezomib is a 20S proteasome inhibitor approved by the food and drug administration (FDA) for the treatment of multiple myeloma and mantle cell lymphoma. Bortezomib is also currently used to treat acute lymphoblastic leukemia, and while pharmacokinetic (PK) studies have been conducted in adults, dosing guidelines have not yet been developed to account for PK variability, particularly in pediatrics. Therefore, we developed a pooled model-based meta-analysis (MBMA) of the population pharmacokinetics (POP-PK) of bortezomib by incorporating modeling results from previous bortezomib-related POP-PK studies.

Methods: This is a MBMA of published POP-PK data for bortezomib. We searched PubMed using the keywords "bortezomib", "population pharmacokinetics", and "clinical trial". Patient population and drug concentration simulation results were extracted from the modeling data of each POP-PK study using mrgsolve software, an R package (CRAN; https ://cran.rproject.org/web/packages/mrgsolve/index.html). A normal distribution was used for simulating patient population covariates. POP-PK model analysis was performed using the Matlab software MONOLIX version 2023R1. The combined additive and proportional residual error model were used to develop the error model for inter-individual variability and residual variability. PK parameters including systemic clearance (CL), intercompartmental clearance (Q), central volume of distribution (Vc), and peripheral volume of distribution (Vp) were evaluated using first-order estimation with an iterative approach.

Results: The study included two POP-PK studies of bortezomib in pediatric patients with acute lymphoblastic leukemia. The final concentration-time profiles were described by a two-compartment model. The final PK parameters were Vc 85.8 L, Vp 476.9 L and CL 9.57 L/h, Q 19.9 L/h. The objective function value of the final base model decreased from -706060.79 to -734075.79.

Conclusion: This study is the first MBMA and POP-PK study of bortezomib in pediatric patients with acute lymphoblastic leukemia. This study provides further support for bortezomib PK studies and dose selection in pediatric patients with acute lymphoblastic leukemia.