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Pharmacogenetic and clinical predictors of voriconazole concentration in hematopoietic stem cell transplant recipients receiving CYP2C19-guided dosing

The Pharmacogenomics Journal volume 23, pages 201–209 (2023)Cite this article

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Abstract

CYP2C19-guided voriconazole dosing reduces pharmacokinetic variability, but many patients remain subtherapeutic. The aim of this study was to evaluate the effect of candidate genes and a novel CYP2C haplotype on voriconazole trough concentrations in patients receiving CYP2C19-guided dosing. This is a retrospective candidate gene study in allogeneic hematopoietic cell transplant (HCT) patients receiving CYP2C19-guided voriconazole dosing. Patients were genotyped for ABCB1, ABCG2, CYP2C9, CYP3A4, CYP3A5, and the CYP2C haplotype. Of 185 patients, 36% were subtherapeutic (of which 79% were normal or intermediate metabolizers). In all patients, CYP2C19 (p < 0.001), age (p = 0.018), and letermovir use (p = 0.001) were associated with voriconazole concentrations. In the subset receiving 200 mg daily (non-RM/UMs), CYP2C19 (p = 0.004) and ABCG2 (p = 0.015) were associated with voriconazole concentrations; CYP2C19 (p = 0.028) and letermovir use (p = 0.001) were associated with subtherapeutic status. CYP2C19 phenotype and letermovir use were significantly associated with subtherapeutic voriconazole concentrations and may be used to improve voriconazole precision dosing, while further research is needed to clarify the role of ABCG2 in voriconazole dosing.

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The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Authors and Affiliations

  1. Department of Cancer Pharmacology and Pharmacogenomics, Levine Cancer Institute, Atrium Health, Charlotte, NC, USA

    Jai N. Patel, Sarah A. Morris, Elizabeth Jandrisevits & Karine Eboli Lopes

  2. Department of Biostatistics, Levine Cancer Institute, Atrium Health, Charlotte, NC, USA

    Myra Robinson

  3. Molecular Biology and Genomics Core Laboratory, Levine Cancer Institute, Atrium Health, Charlotte, NC, USA

    Alicia Hamilton & Nury Steuerwald

  4. Hematology/Oncology Translational Research Laboratory, Levine Cancer Institute, Atrium Health, Charlotte, NC, USA

    Lawrence J. Druhan

  5. Department of Hematologic Malignancies and Blood Disorders, Levine Cancer Institute, Atrium Health, Charlotte, NC, USA

    Belinda Avalos, Edward Copelan, Nilanjan Ghosh & Michael R. Grunwald

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Contributions

JNP, MR, SAM, and EJ wrote the manuscript; JNP, MR, and SAM designed the research; all authors performed the research; JNP, MR, SAM, and EJ analyzed the data; all authors reviewed and approved the manuscript.

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Correspondence to Jai N. Patel.

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JNP serves as a paid consultant for VieCure and Clarified Precision Medicine.

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Patel, J.N., Robinson, M., Morris, S.A. et al. Pharmacogenetic and clinical predictors of voriconazole concentration in hematopoietic stem cell transplant recipients receiving CYP2C19-guided dosing. Pharmacogenomics J 23, 201–209 (2023). https://doi.org/10.1038/s41397-023-00320-z

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