Correlation of Tacrolimus Levels and Metabolizer Status Based on CYP3A5 Polymorphism in Indian Lung Transplant Recipients

Abstract

Purpose Tacrolimus (Tac) variable pharmacokinetics influences its efficacy and toxicity. CYP3A5 gene polymorphism leads to marked differences in metabolism of Tac. Aim is to assess the impact of CYP3A5 polymorphism on Tac. dose. Methods Retrospective analysis of 3 months post-op, weekly Tac. levels, on lung transplant recipients between 01/2018 to 09/2018. Tac levels monitored every 3 days, aiming therapeutic range of 8 to 12 ng/mL. Monitoring continued twice weekly for 4 weeks, then weekly till 12 weeks. Genomic DNA was extracted from 0.1 ml of blood by silica column based protocol. A few ng of the DNA sample was subjected to AS-rtPCR-MPA in duplicates, thus yielding a total of 2 replicates. CYP3A5 polymorphisms was detected from each of the 2 replicates, thus dividing the patients into poor, intermediate or extensive metabolizer phenotypes Results 18 patients were divided into 3 groups - poor, intermediate, and rapid metabolizers, n = 5, 10, 3 respectively. As shown in Graph 1, most variation in weekly mean Tac dose was noted in rapid metabolizers. C/D ratio (Concentration Dose ratio) was calculated using the formula: C/D ratio = blood Tacrolimus trough level / daily Tac. dose, and plotted over time, displaying significant variation in the rapid metabolizers. Conclusion Results suggest CYP3A5 genetic polymorphism significantly influences Tac. pharmacokinetics. This can help plan Tac. dose, obtain therapeutic levels, & minimize toxicity. Larger studies are required to establish the clinical correlation across age, sex and ethnic variations. Tacrolimus (Tac) variable pharmacokinetics influences its efficacy and toxicity. CYP3A5 gene polymorphism leads to marked differences in metabolism of Tac. Aim is to assess the impact of CYP3A5 polymorphism on Tac. dose. Retrospective analysis of 3 months post-op, weekly Tac. levels, on lung transplant recipients between 01/2018 to 09/2018. Tac levels monitored every 3 days, aiming therapeutic range of 8 to 12 ng/mL. Monitoring continued twice weekly for 4 weeks, then weekly till 12 weeks. Genomic DNA was extracted from 0.1 ml of blood by silica column based protocol. A few ng of the DNA sample was subjected to AS-rtPCR-MPA in duplicates, thus yielding a total of 2 replicates. CYP3A5 polymorphisms was detected from each of the 2 replicates, thus dividing the patients into poor, intermediate or extensive metabolizer phenotypes 18 patients were divided into 3 groups - poor, intermediate, and rapid metabolizers, n = 5, 10, 3 respectively. As shown in Graph 1, most variation in weekly mean Tac dose was noted in rapid metabolizers. C/D ratio (Concentration Dose ratio) was calculated using the formula: C/D ratio = blood Tacrolimus trough level / daily Tac. dose, and plotted over time, displaying significant variation in the rapid metabolizers. Results suggest CYP3A5 genetic polymorphism significantly influences Tac. pharmacokinetics. This can help plan Tac. dose, obtain therapeutic levels, & minimize toxicity. Larger studies are required to establish the clinical correlation across age, sex and ethnic variations.