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A Population Pharmacokinetics Study of Venetoclax Concomitant with Voriconazole in Patients with Hematologic
Jing Yang1,2,3, Haoran Wang1, Dongmei Liu1
1Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, People's Republic of China.
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.
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