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Impact of Pharmacogenomics on Tacrolimus Blood Concentrations and Clinical Outcomes After Heart Transplantation

Robinson, Katherine (2023) Impact of Pharmacogenomics on Tacrolimus Blood Concentrations and Clinical Outcomes After Heart Transplantation. Master's Thesis, University of Pittsburgh. (Unpublished)

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The pharmacokinetics of tacrolimus exhibits wide inter- and intra-patient variability. CYP3A5 is the major enzyme involved in tacrolimus metabolism, but the activity of CYP3A5 is dependent on the activity of cytochrome P450 oxidoreductase (POR). Furthermore, tacrolimus is also a substrate of CYP3A4 and p-glycoprotein. While pharmacogenomic variants are not consistently associated with clinical outcomes such as rejection, measures of tacrolimus variability have been associated with lower event-free survival and higher risk of rejection in other transplant organs. We hypothesized that pharmacogenomic variants associated with increased activity and/or expression of genes involved in the disposition of tacrolimus significantly contribute to inter- and intra-patient variability in attainment and maintenance of therapeutic tacrolimus blood concentrations, and that the variability influences rejection risk after heart transplant. This was an IRB-approved, retrospective study of 119 heart transplant patients. Biobanked samples were genotyped for CYP3A5, CYP3A4, POR, and ABCB1. Dose-normalized concentrations were assessed approximately 60 days after transplant. Time in therapeutic range (TTR) was calculated using the Rosendaal method over different time points. Acute cellular rejection was defined as biopsy-proven rejection of Grade 2R or higher based on the ISHLT revised criteria. In our cohort, 27% of patients were CYP3A5 expressors, 10% were carriers of CYP3A4*22, 55% were carriers of POR*28, and 19% were homozygous for ABCB1 1236C/2677G/3435C haplotype. In multivariate analysis, CYP3A5 expressor status and each copy of POR*28 were associated with a longer time to reach the therapeutic range of tacrolimus and lower dose-normalized blood concentrations. CYP3A5 expressor and patients homozygous for the ABCB1 1236C/2677G/3435C haplotype had a lower mean TTR during the initial hospital stay. No genetic variant was associated with TTR over the first 90 days, but CYP3A5 expressors had a lower TTR over the first 180 days. A mixed linear model revealed an improvement in mean TTR over time for CYP3A5 expressors, likely due to therapeutic drug monitoring. In a Cox proportional hazards model with TTR included as a time-varying covariate, lower TTR was associated with an increased likelihood of rejection over the first year. Our results support the use of pharmacogenomics to optimize immunosuppression and outcomes in heart transplantation.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Robinson, Katherinekatherine.robinson@pitt.edukmr1800000-0003-0737-4892
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairEmpey, Philip Epempey@pitt.edupempey0000-0001-7474-2339
Committee MemberVenkataramanan, Ramanrv@pitt.edurv0000-0003-1893-3290
Committee MemberHorn, Edward Thorne@upmc.eduethorn0000-0001-8521-7038
Date: 5 December 2023
Date Type: Publication
Defense Date: 15 August 2023
Approval Date: 5 December 2023
Submission Date: 1 December 2023
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 109
Institution: University of Pittsburgh
Schools and Programs: School of Pharmacy > Pharmaceutical Sciences
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: tacrolimus; pharmacogenomics; pharmacokinetics; transplant
Date Deposited: 05 Dec 2023 14:53
Last Modified: 05 Dec 2023 14:53


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