Jing Yang, Haoran Wang, Dongmei Liu, Weijie Cao, Han Xing, Peile Wang
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引用次数: 0
Abstract
Background: Venetoclax is a selective small-molecule BCL-2 inhibitor that has been approved for treating hematologic malignancies. Co-administration with CYP3A inhibitors, such as voriconazole, poses a high risk of drug-drug interactions (DDIs) that can increase venetoclax exposure. This study aimed to develop a population pharmacokinetics (PopPK) model to characterize the PK properties of venetoclax when co-administered with voriconazole.
Methods: Patients (≥18 years of age) treated with venetoclax for hematologic malignancies and concomitant with voriconazole were enrolled. A PopPK model of venetoclax was developed, and Monte Carlo simulations were performed to optimize dosing regimens.
Results: A total of 261 samples from 30 patients were collected as the development dataset, and 55 samples from 43 patients as the external validation dataset. Venetoclax concentrations were adequately described by a two-compartment linear model with first-order absorption and elimination and absorption lag-time. Albumin was identified as a significant covariate influencing the clearance, with a typical value of 1.31 ± 0.08 L/h. Simulation indicated that the exposure to venetoclax (75 mg/day and 100 mg/day) concomitant with voriconazole was higher than that to venetoclax (400 mg/day) alone and tended to accumulate over two weeks.
Conclusion: Co-administration of voriconazole contributed to elevated venetoclax exposure. These potential DDIs suggest the need for therapeutic drug monitoring of venetoclax.
期刊介绍：
Drug Design, Development and Therapy is an international, peer-reviewed, open access journal that spans the spectrum of drug design, discovery and development through to clinical applications.
The journal is characterized by the rapid reporting of high-quality original research, reviews, expert opinions, commentary and clinical studies in all therapeutic areas.
Specific topics covered by the journal include:
Drug target identification and validation
Phenotypic screening and target deconvolution
Biochemical analyses of drug targets and their pathways
New methods or relevant applications in molecular/drug design and computer-aided drug discovery*
Design, synthesis, and biological evaluation of novel biologically active compounds (including diagnostics or chemical probes)
Structural or molecular biological studies elucidating molecular recognition processes
Fragment-based drug discovery
Pharmaceutical/red biotechnology
Isolation, structural characterization, (bio)synthesis, bioengineering and pharmacological evaluation of natural products**
Distribution, pharmacokinetics and metabolic transformations of drugs or biologically active compounds in drug development
Drug delivery and formulation (design and characterization of dosage forms, release mechanisms and in vivo testing)
Preclinical development studies
Translational animal models
Mechanisms of action and signalling pathways
Toxicology
Gene therapy, cell therapy and immunotherapy
Personalized medicine and pharmacogenomics
Clinical drug evaluation
Patient safety and sustained use of medicines.
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