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Population Pharmacokinetics of Voriconazole in Chinese Patients with Hematopoietic Stem Cell Transplantation

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European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

Abstract

Background and Objective

Voriconazole is widely recommended for the prevention and treatment of invasive fungal infections in hematopoietic stem cell transplantation patients. However, its use is limited by a narrow therapeutic range and large inter-individual variability. This study aimed to characterize the pharmacokinetics of voriconazole in Chinese hematopoietic stem cell transplantation patients, to explore factors affecting its pharmacokinetic parameters, and to provide recommendations for its optimal dosing regimens.

Methods

A total of 121 serum concentration samples from 23 patients were retrospectively included. Voriconazole concentrations were detected, and patient clinical data were recorded. Population pharmacokinetic analysis was performed by a non-linear, mixed-effect modeling approach. Goodness-of-fit plots, bootstrap method, prediction-corrected visual predictive check and external validation by an independent group of seven patients were performed to evaluate the final model.

Results

A one-compartment model with first-order elimination successfully described the data. The absorption rate constant was fixed at 1.1 h−1 and bioavailability was fixed at 0.895. The typical values for voriconazole clearance and distribution volume were 9.52 L/h and 155 L, respectively. CYP2C19*2 genotype and mycophenolate mofetil combination presented a significant impact on the clearance. Compared with CYP2C19*2 carriers, voriconazole clearance was proven to be higher in CYP2C19*1/*1 patients.

Conclusions

A population pharmacokinetic model of voriconazole was successfully established in Chinese hematopoietic stem cell transplantation patients. Based on the final model, CYP2C19*2 genotyping coupled with therapeutic drug monitoring seems to be useful to guide voriconazole dosing and to explain subtherapeutic concentrations in clinical practice.

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Acknowledgements

The authors are grateful to the physicians and nurses for their support of this study, and to all the patients who participated in the study.

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Authors and Affiliations

  1. Department of Pharmacy, Peking University First Hospital, No. 6, Da Hong Luo Chang Street, Beijing, 100034, China

    Chaoyang Chen, Ting Yang, Xinran Li, Lingyun Ma, Yaou Liu, Ying Zhou & Yimin Cui

  2. School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, China

    Xinran Li, Ying Zhou & Yimin Cui

  3. Department of Hematology, Peking University First Hospital, No. 8, Xishiku Street, Xicheng District, Beijing, 100034, China

    Hanyun Ren

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  1. Chaoyang Chen
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  2. Ting Yang
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Correspondence to Hanyun Ren or Yimin Cui.

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No source of funding.

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All authors declare no conflict of interest.

Ethics approval

All procedures in this study were in accordance with the 1964 Helsinki declaration (and its amendments), and the details of the Ethics Committee or institutional review board which approved the study.

Informed consent

Informed consent was obtained from all patients or care givers.

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Chen, C., Yang, T., Li, X. et al. Population Pharmacokinetics of Voriconazole in Chinese Patients with Hematopoietic Stem Cell Transplantation. Eur J Drug Metab Pharmacokinet 44, 659–668 (2019). https://doi.org/10.1007/s13318-019-00556-w

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  • DOI: https://doi.org/10.1007/s13318-019-00556-w

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