Assessment of tacrolimus intrapatient variability in stable adherent transplant recipients: Establishing baseline values

Abstract

The purpose of this study was to determine the intrapatient (within the same patient) variability of tacrolimus in adherent patients. Daily tacrolimus trough levels were obtained at home using dried blood spot technology in kidney and liver transplant recipients. Patients were randomized to receive 3 formulations of tacrolimus, each for two 1-week periods. Adherence was monitored by patient diary, pill counts, and use of the Medication Event Monitoring System (MEMS). Variability was quantified as the coefficient of variation (CV). Comparison of CV between groups was by independent t test or one-way ANOVA as appropriate. The population was found to be adherent with a rate of 99.9% with a mean interval between the evening and morning dose of tacrolimus of 11.86 hours. The median CV for the entire population was 15.2% (range 4.8%-110%). There were no differences in CV by allograft type or tacrolimus formulation. The multivariate analysis did not identify any demographic characteristics associated with a CV > 30%. In a highly adherent population, tacrolimus did not display high intrapatient variability. Given the association between IPV and poor allograft outcomes, future studies are needed to quantitate the influence of adherence and establish target IPV goals. K E Y W O R D S clinical research/practice, compliance/adherence, immunosuppressant -calcineurin inhibitor, immunosuppression/immune modulation, kidney transplantation/nephrology, liver transplantation/hepatology, tacrolimus | 1411 LEINO Et aL.

Clinical application of a dried blood spot assay for sirolimus and everolimus in transplant patients

“…Traditionally, venous blood samples are used for monitoring of immunosuppressive drug concentrations and patients have to travel to the hospital on a regular basis to have their blood drawn. To decrease the burden for patients, dried blood spot (DBS) home sampling has been developed among various micro sampling methods for several drugs, including immunosuppressants, to enable home sampling [5][6][7][8][9][10][11][12][13][14][15][16]. For this, a drop of blood from a fingerprick is applied to a sampling card and dried.…”

“…Therefore, a clinical validation study showing interchangeability between DBS and venous sampling is required before clinical application [18]. This is shown for tacrolimus, cyclosporin A and creatinine [5,[7][8][9][10][11][12][13][14][15]19]. For sirolimus, Dickerson et al report agreement between fingerprick DBS and venous samples in 25 pediatric transplant patients, where mean DBS concentrations were on average 0.8 μg/L lower than venous samples [15].…”

Impact of low tacrolimus exposure and high tacrolimus intra-patient variability on the development of de novo anti-HLA donor-specific antibodies in kidney transplant recipients

“…Tacrolimus also has a high intra-patient variability (IPV), which means that despite the tacrolimus dose remaining unchanged, concentrations can vary greatly within an individual over time, which may result in episodes of sub-therapeutic or supra-therapeutic exposure. While environmental factors [23] and genetic variability [24,25] can influence tacrolimus IPV, non-adherence has been presented as the most common cause for a high IPV [26,27]. In 2010, Borra et al showed that a high tacrolimus IPV was associated with poor outcome after kidney transplantation [28].…”

Identification of Factors Affecting Tacrolimus Trough Levels in Latin American Pediatric Liver Transplant Patients

“…Although the optimization of immunosuppressive therapies and the improvements in surgical procedures have contributed to longer overall survival and graft survival rates in pediatric liver transplantation patients, clinical issues, such as acute rejection and adverse drug reactions to tacrolimus, confer morbidity and mortality . Previous reports have described a significant association between variability in tacrolimus C0 and the development of acute rejection and adverse drug reactions . Furthermore, other factors, including time after transplant, body weight, hematocrit, age, liver function parameters, and type of graft, contribute to the pharmacokinetic variability in pediatric liver transplant patients …”

“…(1,4) Previous reports have described a significant association between variability in tacrolimus C0 and the development of acute rejection and adverse drug reactions. (1,(5)(6)(7) Furthermore, other factors, including time after transplant, body weight, hematocrit, age, liver function parameters, and type of graft, contribute to the pharmacokinetic variability in pediatric liver transplant patients. (1,(8)(9)(10)(11)(12)(13)(14)(15)(16) Different polymorphisms of cytochrome P450 enzymes, especially for cytochrome P450 3A5 (CYP3A5), affect tacrolimus clearance.…”