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Clinical and Pharmacogenomic Evaluation of Tacrolimus Formulations

Tremblay, Simon
http://orcid.org/0000-0003-1070-9315
http://rave.ohiolink.edu/etdc/view?acc_num=ucin154392075533049

Abstract Details

2018, PhD, University of Cincinnati, Medicine: Epidemiology (Environmental Health).
Introduction Organ transplantation is the preferred treatment for many end-stage organ diseases. However, lifelong immunosuppression is required to prevent the risk of rejection. Tacrolimus is the most prescribed immunosuppressant following transplantation but has a complex pharmacokinetic (PK) profile, significant inter-individual variability, and a narrow therapeutic index, signifying that the threshold between efficacy and toxicity is relatively small. Therefore, therapeutic drug monitoring is required to ensure adequate efficacy and safety. Many factors, including organ donor and recipient genotypes and other clinical variables have been associated with changes in tacrolimus PK. Guidelines recommend genotyping kidney transplant recipients to assist in dosing strategies but mention that there is a lack of data to make the same recommendation in liver transplant recipients. This is of particular importance, since liver transplant recipients retain their own gut and genotype but inherit the liver donor’s genotype, making the role of liver donor genotype of particular interest. In addition, novel drug formulations have been released, extending the dosing interval from twice daily to once daily, further complicating clinical use and dosing strategies. For these reasons, additional guidance for clinicians is necessary for 1) converting between different tacrolimus formulations and 2) employing clinical and pharmacogenomic data in the evaluation of dosing strategies in liver transplant recipients. Methods To address these knowledge gaps, two studies were conducted. The first one prospectively evaluated the conversion from twice-daily innovator tacrolimus to two once-daily formulations. The second study evaluated the impact of key recipient and donor genotypes on tacrolimus PK in liver transplant recipients nested in a prospective clinical trial that evaluated bioequivalence between different tacrolimus formulations. Results Upon direct evaluation of all three innovator tacrolimus formulations, two of them (Prograf® and Astagraf XL®) had similar PK profiles, whereas Envarsus XR® had a prolonged time to maximal concentration and increased apparent bioavailability. None were however bioequivalent. Final dosing recommendations for converting from Prograf® to Astagraf XL® included an 10% increase in total daily dose whereas recommendations for converting from Prograf® to Envarsus XR® included a 30% decrease in total daily dose. When considering the impact of recipient and donor genotype on tacrolimus PK parameters in stable liver transplant recipients, recipient ABCB1 3435 and donor CYP3A5 genotypes were significantly associated with alterations in apparent clearance, dose, dose-normalized area under the time concentration curve and dose-normalized trough concentration. Recipient ABCB1 genotype seemed to have a larger relative effect on these parameters than did donor CYP3A5 genotype. Additional clinical parameters associated with changes in tacrolimus PK included age, body surface area, presence of diabetes, and hematocrit. Conclusion Significant differences exist between all three innovator formulations in the United States and conversion between formulations requires close attention. In addition, genotyping liver transplant recipients alone is insufficient for explaining and predicting the dosing of tacrolimus in these patients. Further research is required to evaluate the conversion of tacrolimus formulations in different genotypic populations and to further validate the findings of key factors altering tacrolimus PK parameters in liver transplant recipients.
Erin Haynes, Dr.P.H. (Committee Chair)
Rita Alloway, PharmD (Committee Member)
Marepalli Rao, Ph.D. (Committee Member)
128 p.
Surgery
tacrolimus; pharmacokinetics; genomics; genotyping; CYP3A5; transplantation

Recommended Citations

Citations

  • Tremblay, S. (2018). Clinical and Pharmacogenomic Evaluation of Tacrolimus Formulations [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin154392075533049

    APA Style (7th edition)

  • Tremblay, Simon. Clinical and Pharmacogenomic Evaluation of Tacrolimus Formulations. 2018. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin154392075533049.

    MLA Style (8th edition)

  • Tremblay, Simon. "Clinical and Pharmacogenomic Evaluation of Tacrolimus Formulations." Doctoral dissertation, University of Cincinnati, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=ucin154392075533049

    Chicago Manual of Style (17th edition)

ucin154392075533049
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This open access ETD is published by University of Cincinnati and OhioLINK.