Association of Tacrolimus Variability and Adherence in Kidney Transplant Recipients: A Systematic Review and Meta-Analysis

Pheeraphat Sarppreuttikun; Kaniknan Jumpathip; Sirintip Watchanathepin; Sukrit Kanchanasurakit

doi:10.22146/ijp.17301

Pheeraphat Sarppreuttikun Department of Pharmaceutical Care, Faculty of Pharmacy, Thammasat University, Pathum Thani, 12120 Thailand; Clinical Pharmacy Service Center, Faculty of Pharmacy, Thammasat University, Pathum Thani, 12120 Thailand https://orcid.org/0000-0001-6455-2013
Kaniknan Jumpathip Department of pharmaceutical care, faculty of pharmacy, Thammasat university, Pathum Thani, 12120 Thailand https://orcid.org/0009-0009-7094-4166
Sirintip Watchanathepin Department of pharmaceutical care, faculty of pharmacy, Thammasat university, Pathum Thani, 12120 Thailand https://orcid.org/0009-0005-3978-5495
Sukrit Kanchanasurakit Division of Clinical Pharmacy, Department of Pharmaceutical Care, School of Pharmaceutical Sciences, University of Phayao, Phayao, 56000 Thailand; Division of Pharmaceutical Care, Department of Pharmacy, Phrae Hospital, Phrae, 54000 Thailand; Center of Health Outcomes Research and Therapeutic Safety (Cohorts), School of Pharmaceutical; Sciences, University of Phayao, Phayao, 56000 Thailand; Unit of Excellence on Clinical Outcomes Research and IntegratioN (UNICORN), School of Pharmaceutical Sciences, University of Phayao, Phayao, 56000 Thailand; Unit of Excellence on Herbal Medicine, School of Pharmaceutical Sciences, University of Phayao, Phayao, 56000 Thailand

Keywords: Tacrolimus, kidney transplantation, intra-patient variability, medication adherence

Abstract

Tacrolimus has a narrow therapeutic window and exhibits high intrapatient variability (IPV) in its pharmacokinetics. Kidney transplant recipients with high IPV in tacrolimus exposure are at increased risk of graft rejection and failure. One potential contributor to tacrolimus IPV is drug adherence. However, the relationship between tacrolimus IPV and drug adherence remains unclear. The aim of this study is to determine the association between tacrolimus IPV and adherence among stable kidney transplant recipients by performing systematic review and meta-analysis. PubMed, Embase, Cochrane, OpenGrey, Scopus, Clinicaltrial.gov, Web of Science, CINAHL, and medRxiv were searched from inception through October 23, 2024. The focus was on observational studies and randomized controlled trials comparing tacrolimus IPV in adherence and non-adherence groups. To account for differences between studies, we used a random-effects model to analyze tacrolimus IPV, with standardized mean difference (SMD) and a 95% confidence interval (95%CI). Four studies were included for meta-analysis. All of which are observational studies with a pooled sample size of 790, divided into 655 participants in adherence group and 135 participants in non-adherence group. The pooled estimate found a statistically significant difference of tacrolimus IPV between adherence and non-adherence group (SMD -0.24, 95% CI: -0.44, -0.04; p=0.017; I²=0.0%). Recent observational research indicates a relationship between variability in tacrolimus concentration and adherence among stable kidney transplant recipients. However, due to the quality concerns and their limited number of these studies, it is important to exercise caution in interpreting these results.

References

Egger, M., Smith, G. D., Schneider, M., & Minder, C. (1997). Bias in meta-analysis detected by a simple, graphical test. BMJ, 315(7109), 629–634. https://doi.org/10.1136/BMJ.315.7109.629
Ekberg, H., Tedesco-Silva, H., Demirbas, A., Vítko, Š., Nashan, B., Gürkan, A., Margreiter, R., Hugo, C., Grinyó, J. M., Frei, U., Vanrenterghem, Y., Daloze, P., & Halloran, P. F. (2007). Reduced Exposure to Calcineurin Inhibitors in Renal Transplantation. New England Journal of Medicine, 357(25), 2562–2575. https://doi.org/10.1056/NEJMoa067411
Gokoel, S. R. M., Zwart, T. C., Moes, D. J. A. R., van der Boog, P. J. M., & de Fijter, J. W. (2020). No Apparent Influence of Nonadherence on Tacrolimus Intrapatient Variability in Stable Kidney Transplant Recipients. Therapeutic Drug Monitoring, 42(5), 702–709. https://doi.org/10.1097/FTD.0000000000000772
Goodall, D. L., Willicombe, M., McLean, A. G., & Taube, D. (2017). High Intrapatient Variability of Tacrolimus Levels and Outpatient Clinic Nonattendance Are Associated with Inferior Outcomes in Renal Transplant Patients. Transplantation Direct, 3(8), e192. https://doi.org/10.1097/TXD.0000000000000710
Herblum, J., Dacouris, N., Huang, M., Zaltzman, J., Prasad, G. V. R., Nash, M., & Chen, L. (2021). Retrospective Analysis of Tacrolimus Intrapatient Variability as a Measure of Medication Adherence. Canadian Journal of Kidney Health and Disease, 8, 205435812110217. https://doi.org/10.1177/20543581211021742
Higgins, J. P. T., Morgan, R. L., Rooney, A. A., Taylor, K. W., Thayer, K. A., Silva, R. A., Lemeris, C., Akl, E. A., Bateson, T. F., Berkman, N. D., Glenn, B. S., Hróbjartsson, A., LaKind, J. S., McAleenan, A., Meerpohl, J. J., Nachman, R. M., Obbagy, J. E., O’Connor, A., Radke, E. G., … Sterne, J. A. C. (2024). A tool to assess risk of bias in non-randomized follow-up studies of exposure effects (ROBINS-E). Environment International, 186, 108602. https://doi.org/10.1016/J.ENVINT.2024.108602
Higgins, J. P. T., Thompson, S. G., Deeks, J. J., & Altman, D. G. (2003). Measuring inconsistency in meta-analyses. BMJ, 327(7414), 557–560. https://doi.org/10.1136/BMJ.327.7414.557
Hsiau, M., Fernandez, H. E., Gjertson, D., Ettenger, R. B., & Tsai, E. W. (2011). Monitoring nonadherence and acute rejection with variation in blood immunosuppressant levels in pediatric renal transplantation. Transplantation, 92(8), 918–922. https://doi.org/10.1097/TP.0B013E31822DC34F
Ko, H., Kim, H. K., Chung, C., Han, A., Min, S. K., Ha, J., & Min, S. (2021). Association between medication adherence and intrapatient variability in tacrolimus concentration among stable kidney transplant recipients. Scientific Reports, 11(1), 5397. https://doi.org/10.1038/s41598-021-84868-5
Kuypers, D. R. J. (2020). Intrapatient Variability of Tacrolimus Exposure in Solid Organ Transplantation: A Novel Marker for Clinical Outcome. Clinical Pharmacology & Therapeutics, 107(2), 347–358. https://doi.org/10.1002/CPT.1618
Leino, A. D., Abuls, K. M., Rodgers, J. K. L., & Kuntz, K. K. (2022). Evaluation of the Relationship between Medication Adherence and Tacrolimus Coefficient of Variation. Progress in Transplantation, 32(2), 184–189. https://doi.org/10.1177/15269248221087440
Lieb, M., Hepp, T., Schiffer, M., Opgenoorth, M., & Erim, Y. (2020). Accuracy and concordance of measurement methods to assess non-adherence after renal transplantation - A prospective study. BMC Nephrology, 21(1), 1–13. https://doi.org/10.1186/S12882-020-01781-1/FIGURES/3
Massey, E. K. (2016). Recommendations on how to improve medication adherence studies in the field of transplantation. Transplantation, 100(1), 12–13. https://doi.org/10.1097/TP.0000000000000972
McGillicuddy, J. W., Chandler, J. L., Sox, L. R., & Taber, D. J. (2020). Exploratory Analysis of the Impact of an mHealth Medication Adherence Intervention on Tacrolimus Trough Concentration Variability: Post Hoc Results of a Randomized Controlled Trial. Annals of Pharmacotherapy, 54(12), 1185–1193. https://doi.org/10.1177/1060028020931806
Page, M. J., McKenzie, J. E., Bossuyt, P. M., Boutron, I., Hoffmann, T. C., Mulrow, C. D., Shamseer, L., Tetzlaff, J. M., Akl, E. A., Brennan, S. E., Chou, R., Glanville, J., Grimshaw, J. M., Hróbjartsson, A., Lalu, M. M., Li, T., Loder, E. W., Mayo-Wilson, E., McDonald, S., … Moher, D. (2021). The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ, 372. https://doi.org/10.1136/BMJ.N71
Pizzo, H. P., Ettenger, R. B., Gjertson, D. W., Reed, E. F., Zhang, J., Gritsch, H. A., & Tsai, E. W. (2016). Sirolimus and tacrolimus coefficient of variation is associated with rejection, donor-specific antibodies, and nonadherence. Pediatric Nephrology (Berlin, Germany), 31(12), 2345–2352. https://doi.org/10.1007/S00467-016-3422-5
Shuker, N., Van Gelder, T., & Hesselink, D. A. (2015). Intra-patient variability in tacrolimus exposure: Causes, consequences for clinical management. Transplantation Reviews, 29(2), 78–84. https://doi.org/10.1016/J.TRRE.2015.01.002
Stifft, F., Stolk, L. M. L., Undre, N., Van Hooff, J. P., & Christiaans, M. H. L. (2014). Lower variability in 24-hour exposure during once-daily compared to twice-daily tacrolimus formulation in kidney transplantation. Transplantation, 97(7), 775–780. https://doi.org/10.1097/01.TP.0000437561.31212.0E
Wan, X., Wang, W., Liu, J., & Tong, T. (2014). Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Medical Research Methodology, 14(1), 1–13. https://doi.org/10.1186/1471-2288-14-135/TABLES/3