Accuracy of CYP3A5 Pharmacogenomics Recommended Dosing of Tacrolimus With Concomitant Azole Antifungals Early Post-Lung Transplant
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Published on: November 8, 2015
Christine Pham1, Kathy Le1, Curt Bay2
1Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona, USA.
Introduction:
Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines recommend tacrolimus starting doses based on CYP3A5 phenotypes but do not consider CYP3A4 interactions. Azoles inhibit CYP3A4 metabolism, and suggested % reduction in tacrolimus dose by azole has been published. We evaluated the accuracy of CPIC tacrolimus dose recommendations based on CYP3A5 phenotype in lung transplant recipients (LTRs) treated with azole.
Methods:
The primary outcome was accuracy (±30%) of actual vs. expected tacrolimus dose (mg/kg/day) at 1 M, 2 M, and 3 M post-LT. Secondary outcomes were median tacrolimus dose (mg/kg/day) and % difference in actual vs. expected tacrolimus dose between 1 M, 2 M, and 3 M. Formulas for expected dose were used sequentially: (1) manufacturer-recommended dose, (2) CPIC starting dose adjustment, and (3) % tacrolimus dose reduction by azole. Each patient served as their own control for calculating the % difference in dose.
Results:
85 LTRs with pharmacogenetic information were included; 91% were poor CYP3A5 metabolizers. Accuracy of CPIC and azole adjusted dose decreased at 1 M, 2 M, and 3 M (40%, 29%, and 18%; p = 0.002). Accuracy between CYP3A5 expressers and non-expressers did not show a difference at 1 M (38% vs. 40%, p = 1.00), but differences were significant at 2 M (75% vs. 25%, p = 0.002) and 3 M (63% vs. 14%, p = 0.002). Tacrolimus dose (mg/kg/day) decreased (0.03, 0.02, 0.02; p < 0.001) and % difference in actual vs. expected dose increased (-22, -35, -46; p < 0.001) between 1 M, 2 M, and 3 M post-LT. Percent difference in actual vs. expected dose was not found to be significant between phenotypes (p = 0.067).
Conclusions:
Use of an adjusted tacrolimus starting dose based on CYP3A5 phenotype and predicted azole CYP3A4 inhibition was poorly predictive of the actual required tacrolimus dose among LTRs during the early post-transplant period in CYP3A5 non-expressers. CYP3A5 expressers demonstrated a higher degree of accuracy and would benefit from further investigation in a larger cohort. Lower tacrolimus doses with patient-specific modifications are required in LTRs within the first 3 M post-LT receiving azole antifungals to ensure therapeutic levels.
Insights
Tacrolimus dosing in lung transplant recipients (LTRs) using CYP3A5 phenotype and azole adjustments is inaccurate, especially for CYP3A5 non-expressers. Patient-specific dose modifications are needed for LTRs on azoles within 3 months post-transplant.
Area of Science:
- Pharmacogenetics
- Transplantation Medicine
- Drug Metabolism
Background:
- Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines recommend tacrolimus dosing based on CYP3A5 phenotypes.
- These guidelines do not account for CYP3A4 interactions, which are significant as azoles inhibit CYP3A4 metabolism.
- Previous studies suggested dose reductions for tacrolimus when co-administered with azoles.
Purpose of the Study:
- To evaluate the accuracy of CPIC tacrolimus dose recommendations considering CYP3A5 phenotype in lung transplant recipients (LTRs) treated with azoles.
- To assess the impact of CYP3A4 inhibition by azoles on tacrolimus dosing accuracy.
- To determine if current dosing strategies ensure therapeutic tacrolimus levels in LTRs.
Main Methods:
- Retrospective analysis of 85 LTRs with pharmacogenetic data.
- Primary outcome: accuracy (±30%) of actual versus expected tacrolimus dose at 1, 2, and 3 months post-lung transplant (LT).
- Expected dose calculated sequentially using manufacturer recommendations, CPIC guidelines, and azole dose reduction percentages.
Main Results:
- 91% of LTRs were poor CYP3A5 metabolizers.
- Accuracy of CPIC and azole-adjusted tacrolimus doses decreased over time (40% at 1 month, 29% at 2 months, 18% at 3 months).
- Accuracy was significantly lower in CYP3A5 non-expressers compared to expressers at 2 and 3 months post-LT.
Conclusions:
- Adjusted tacrolimus starting doses based on CYP3A5 phenotype and azole inhibition poorly predict actual doses in LTRs, particularly CYP3A5 non-expressers.
- CYP3A5 expressers showed higher accuracy, warranting further study.
- Lower, patient-specific tacrolimus doses are necessary for LTRs on azoles within the first 3 months post-LT to achieve therapeutic levels.
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