Tacrolimus intrapatient variability in solid organ transplantation: A multiorgan perspective

Abstract

Background Tacrolimus therapy in solid organ transplant (SOT) recipients is challenging due to its narrow therapeutic window and pharmacokinetic variability both between patients and within a single patient. Intrapatient variability (IPV) of tacrolimus trough concentrations has become a novel marker of interest for predicting transplant outcomes. The purpose of this review is to evaluate the association of tacrolimus IPV with graft and patient outcomes and identify interventions to improve IPV in SOT recipients. Methods A systematic review of the literature was performed using PubMed and Embase from database inception to September 20, 2020. Studies were eligible only if they evaluated an association between tacrolimus IPV and transplant outcomes. Both pediatric and adult studies were included. Measures of variability were limited to standard deviation, coefficient of variation, and time in therapeutic range. Results Forty‐four studies met the inclusion criteria. Studies were published between 2008 and 2020 and were observational in nature. Majority of data were published in adult kidney transplant recipients and identified an association with rejection, de novo donor specific antibody (dnDSA) formation, graft loss, and patient survival. Evaluation of IPV‐directed interventions was limited to small preliminary studies. Conclusions High tacrolimus IPV has been associated with poor outcomes including acute rejection, dnDSA formation, graft loss, and patient mortality in SOT recipients. Future research should prospectively explore IPV‐directed interventions to improve transplant outcomes.

Clinical Implications of Tacrolimus Time in Therapeutic Range and Intrapatient Variability in Urban Renal Transplant Recipients Undergoing Early Corticosteroid Withdrawal

“…It is classified as a narrow therapeutic index medication, displaying wide interpatient variability and intrapatient variability (IPV) and requiring frequent therapeutic drug monitoring of trough levels. [2][3][4][5] Therefore, it is critical to maintain therapeutic levels to preserve allograft function.…”

“…In addition to assessing adequate trough levels, tacrolimus IPV is another important consideration for allograft longevity. 5 Increased tacrolimus IPV, as measured by coefficient of variation (CV%) or SD, is associated with deleterious outcomes in RT recipients, including increased allograft fibrosis, rejection, development of DSA, and decreased allograft survival. [5][6][7][8][9][10][11][12][13][14] Several studies assessing time in therapeutic range (TTR) with tacrolimus have demonstrated that patients with lower TTR values have been associated with de novo DSA (dnDSA) development and inferior allograft outcomes.…”

“…5 Increased tacrolimus IPV, as measured by coefficient of variation (CV%) or SD, is associated with deleterious outcomes in RT recipients, including increased allograft fibrosis, rejection, development of DSA, and decreased allograft survival. [5][6][7][8][9][10][11][12][13][14] Several studies assessing time in therapeutic range (TTR) with tacrolimus have demonstrated that patients with lower TTR values have been associated with de novo DSA (dnDSA) development and inferior allograft outcomes. [15][16][17] However, many of these aforementioned studies were in the setting of triple immunosuppression therapy with immediate-release tacrolimus, antimetabolite, and longterm corticosteroid therapy.…”

Monitoring Tacrolimus Concentrations in Whole Blood and Peripheral Blood Mononuclear Cells: Inter- and Intra-Patient Variability in a Cohort of Pediatric Patients

“…These physiopathological changes can be particularly marked in the pediatric context. In recent years, high intra-individual variability of TAC concentrations in WB was also described as significantly associated with the risk of graft rejection (Del Bello et al, 2018;Schumacher et al, 2020).…”

Solid organ transplant pharmacotherapy: Complicated and continually changing

“…Tacrolimus is the mainstay of immunosuppression therapy and in recent years, intrapatient variability (IPV) in tacrolimus trough concentrations has become recognized as a novel marker to identify transplant recipients at risk for rejection and graft loss 15–17 . Schumacher et al 18 evaluated the association of tacrolimus IPV with patients and allograft outcomes and subsequently identified interventions to improve IPV in a systematic review. Pilch et al 19 provide readers with a broad description of the past, present, and future of immunosuppression in solid organ transplantation and sets the stage for how optimal long‐term outcomes can be achieved during the next era of transplantation with a focus on patient‐specific optimization over universal protocols.…”