High Intrapatient Variability in Tacrolimus Exposure Calculated Over a Long Period Is Associated With De Novo Donor-Specific Antibody Development and/or Late Rejection in Thai Kidney Transplant Patients Receiving Concomitant CYP3A4/5 Inhibitors

Abstract

Background: High intrapatient variability in tacrolimus trough levels (Tac IPV) is associated with poor allograft outcomes. Tac IPV was previously calculated using trough levels 6-12 months after kidney transplantation (KT). Data on the accuracy of Tac IPV calculation over a longer period, the association between high Tac IPV and donor-specific antibody (DSA) development after KT in Asian patients, and the role of IPV in patients receiving concomitant cytochrome P450 (CYP)3A4/5 inhibitors (CYPinh) are limited.Methods: A retrospective review of patients who underwent KT at our center in 2005-2015, and who received Tac with mycophenolate during the first 2 years after KT was performed. IPV was calculated using Tac levels adjusted by dosage. DSA was monitored annually after KT using a Luminex microbead assay.Results: In total, 236 patients were enrolled. CYPinh were prescribed to 189 patients (80.1%): 145 (61.4%), 31 (13.1%), and 13 (5.5%) received diltiazem, fluconazole, and ketoconazole, respectively. Mean IPV calculated from adjusted Tac levels for 6-12 months (IPV [6][7][8][9][10][11][12] ) and 6-24 months (IPV 6-24 ) after KT were 20.64% 6 11.68% and 23.53% 6 10.39%, respectively. Twentysix patients (11%) showed late rejection and/or DSA occurrence, and had significantly higher IPV 6-24 (29.42% 6 13.78%) than others (22.77% 6 9.64%; P = 0.02). There was no difference in IPV [6][7][8][9][10][11][12] (24.31% 6 14.98% versus 20.17% 6 10.90%; P = 0.18). IPV [6][7][8][9][10][11][12] and IPV [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] were comparable in patients who did and did not receive CYPinh. When using mean IPV 6-24 as a cutoff, patients with higher IPV 6-24 had a higher probability of developing DSA and/or late rejection (P = 0.048).Conclusions: Tac IPV 6-24 was higher and more significantly associated with DSA development and/or late rejection than Tac IPV 6-12 , independent of Tac trough level. This is the first study to demonstrate the impact of high IPV on DSA development in Asian patients, and that Tac IPV is comparable between patients with and without CYPinh.

Comparison of Tacrolimus Intra-Patient Variability during 6–12 Months after Kidney Transplantation between CYP3A5 Expressers and Nonexpressers

“…A reduction in steroid dosage, decreased CYP3A4 activity, and increased hematocrit and albumin with time are plausible explanations for the decline of tacrolimus apparent clearance after KT [ 5 , 39 ]. Timing after KT during which tacrolimus exposure is used for IPV calculation is, therefore, one possible explanation for the differences in IPV values reported among previous studies [ 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ].…”

“…Different methods have been used to quantify IPV of tacrolimus among studies that reported the associations between high tacrolimus IPV and poor long-term outcomes. The coefficient of variation and mean absolute deviation are commonly utilized to calculate tacrolimus IPV [ 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 18 , 19 , 20 , 21 ]. A minimum of three C0 concentrations have been included in the calculation of tacrolimus IPV for each patient among studies [ 8 , 12 , 14 , 15 ].…”

“…Intra-patient variability (IPV) of tacrolimus exposure, which is defined as the fluctuation in tacrolimus blood concentrations within an individual over a certain period during which the tacrolimus dose is left unchanged [ 7 ], has garnered attention, given a growing body of evidence that suggests high IPV is associated with poor long-term outcomes, including acute rejection, de novo donor-specific antibody formation, graft loss, and patient mortality [ 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ]. It has been suggested that IPV of tacrolimus concentrations during the stable phase after transplantation (i.e., beyond six months after KT) could be considered as a tool that may help to identify high-risk patients, and early identification of patients with high IPV may allow for the implementation of appropriate actions to circumvent unwanted clinical outcomes [ 22 ].…”

Kidney transplant from HCV viremic donors to HCV‐negative recipients and risk for de novo donor specific antibodies and acute rejection

“…Sofosbuvir based therapies could also have an interaction with Tacrolimus. Intra‐patient variation in tacrolimus trough levels have been associated with increased risk for rejection and development of de novo DSA 40–42 . Theoretically, it is possible that recipients of HCV NAT+ organs were more prone to intra‐patient variability in tacrolimus trough level due to such drug interaction which might have contributed to the higher incidence of de novo DSA.…”

Effect of the Interrelation between CYP3A5 Genotype, Concentration/Dose Ratio and Intrapatient Variability of Tacrolimus on Kidney Graft Function: Monte Carlo Simulation Approach

“…It was previously demonstrated that high Tac IPV [7,[14][15][16] or low C 0 /D [3,6,17] may cause eGFR decline, graft rejection, or loss in the late post-transplant period. Still, it has not been entirely elucidated whether or not these parameters should be considered simultaneously.…”