Population Pharmacokinetic Analysis from First-in-Human Data for HDAC Inhibitor, REC-2282 (AR-42), in Patients with Solid Tumors and Hematologic Malignancies: A Case Study for Evaluating Flat vs. Body Size Normalized Dosing

Autor: Min Chen, Mitch A. Phelps, Sophia G. Liva, Amir Mortazavi, Craig C. Hofmeister, Jiang Wang, Kristin Dittmar, Christopher C. Coss, Alison Walker
Rok vydání: 2021
Předmět:
Zdroj: European Journal of Drug Metabolism and Pharmacokinetics
ISSN: 2107-0180
0378-7966
DOI: 10.1007/s13318-021-00722-z
Popis: Background and Objectives REC-2282 is a novel histone deacetylase inhibitor that has shown antitumor activity in in vitro and in vivo models of malignancy. The aims of this study were to characterize the population pharmacokinetics of REC-2282 (AR-42) from the first-in-human (NCT01129193) and phase I acute myeloid leukemia trials (NCT01798901) and to evaluate potential sources of variability. Additionally, we sought to understand alternate body size descriptors as sources of inter-individual variability (IIV), which was significant for dose-normalized maximum observed concentration and area under the concentration-time curve (AUC). Methods Datasets from two clinical trials were combined, and population pharmacokinetic analysis was performed using NONMEM and R softwares; patient demographics were tested as covariates. Results A successful population pharmacokinetic model was constructed. The pharmacokinetics of REC-2282 were best described by a two-compartment model with one transit compartment for absorption, first-order elimination and a proportional error model. Fat-free mass (FFM) was retained as a single covariate on clearance (CL), though it explained < 3% of the observed variability on CL. Tumor type and formulation were retained as covariates on lag time, and a majority of variability, attributed to absorption, remained unexplained. Computed tomography (CT)-derived lean body weight estimates were lower than estimated lean body weight and fat-free mass measures in most patients. Analysis of dose-normalized AUC vs. body size descriptors suggests flat dosing is most appropriate for REC-2282. Conclusions FFM was identified as a significant covariate on CL; however, it explained only a very small portion of the IIV; major factors contributing significantly to REC-2282 pharmacokinetic variability remain unidentified. Supplementary Information The online version contains supplementary material available at 10.1007/s13318-021-00722-z.
Databáze: OpenAIRE
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