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Predictors of tacrolimus dose optimization when drug-drug interaction associated with voriconazole in heart transplant recipients
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  • Xiao Huang,
  • Ying Zhou,
  • Jing Zhang,
  • Hongping Xiang,
  • Hao Mei,
  • Li Liu,
  • Lu Tong,
  • Fang Zeng,
  • Yifei Huang,
  • Hong Zhou,
  • Yu Zhang
Xiao Huang
Huazhong University of Science and Technology Tongji Medical College

Corresponding Author:[email protected]

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Ying Zhou
Huazhong University of Science and Technology Tongji Medical College
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Jing Zhang
Huazhong University of Science and Technology Tongji Medical College
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Hongping Xiang
Huazhong University of Science and Technology Tongji Medical College
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Hao Mei
Huazhong University of Science and Technology Tongji Medical College
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Li Liu
Huazhong University of Science and Technology Tongji Medical College
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Lu Tong
Huazhong University of Science and Technology Tongji Medical College
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Fang Zeng
Huazhong University of Science and Technology Tongji Medical College
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Yifei Huang
Huazhong University of Science and Technology Tongji Medical College
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Hong Zhou
Huazhong University of Science and Technology Tongji Medical College
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Yu Zhang
Huazhong University of Science and Technology Tongji Medical College
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Abstract

Aims: Voriconazole is the mainstay for the treatment for invasive fungal infections in heart transplant patients and significantly increase tacrolimus exposure because of drug-drug interaction (DDI). However, the magnitude of this DDI is highly variable and hard to predicted. The purpose of this study was to present the characteristics of DDI between tacrolimus and voriconazole, and further identify the predictors of tacrolimus dose modification. Methods: We retrospectively enrolled 69 heart transplant recipients without using voriconazole as the control and 68 patients received voriconazole treatment in voriconazole group. CYP3A4*1G, CYP3A5*3 and CYP2C19*2 or *3 were genotyped by Sanger sequencing. The requirement of tacrolimus dose for therapeutic concentrations and tacrolimus dose-corrected trough concentration (C0/D) before and after VRC administration were evaluated. Results: The DDI between tacrolimus and voriconazole was in a large inter-individual variability with more than ten-fold changes in tacrolimus dose (range 1.28–13.00) and C0/D (range 1.43–13.75). Besides, the fold changes of tacrolimus dose were associated with CYP2C19 genotype, which was significantly lower in CYP2C19 extensive metabolizers than that in CYP2C19 intermediate metabolizers or poor metabolizers (4.06±1.85 vs 5.49±2.47, p=0.0031). While no significant difference was found in both CYP3A4 and CYP3A5 genotypes. Moreover, CYP2C19 genotype and hematocrit were independent predicting factors for tacrolimus dose modification after voriconazole co-therapy. Conclusions: This study provided a potential basis for comprehensive factors to adjust tacrolimus dosage when co-administrated with voriconazole in individual patients. CYP2C19 genotype and hematocrit should be considered in tailoring tacrolimus dose.
29 Nov 2021Submitted to British Journal of Clinical Pharmacology
30 Nov 2021Submission Checks Completed
30 Nov 2021Assigned to Editor
13 Feb 2022Reviewer(s) Assigned
23 Feb 2022Review(s) Completed, Editorial Evaluation Pending
28 Feb 2022Editorial Decision: Revise Major
28 Mar 20221st Revision Received
29 Mar 2022Assigned to Editor
29 Mar 2022Submission Checks Completed
29 Mar 2022Review(s) Completed, Editorial Evaluation Pending
29 Mar 2022Reviewer(s) Assigned
19 Apr 2022Editorial Decision: Revise Minor
21 Apr 20222nd Revision Received
25 Apr 2022Assigned to Editor
25 Apr 2022Submission Checks Completed
25 Apr 2022Review(s) Completed, Editorial Evaluation Pending
26 Apr 2022Editorial Decision: Accept