Jing Yang,1– 3,* Haoran Wang,1,* Dongmei Liu,1 Weijie Cao,4 Han Xing,1– 3 Peile Wang1– 3 

1Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, People’s Republic of China; 2Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, Henan Province, People’s Republic of China; 3Henan Province Engineering Research Center of Application & Translation of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, Henan Province, People’s Republic of China; 4Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Peile Wang; Han Xing, Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, People’s Republic of China, Email comwpl5876@163.com; xinghankf@126.com

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.

Keywords: venetoclax, voriconazole, population pharmacokinetics model, hematologic malignancies