Factors associated with optimized tacrolimus dosing in hematopoietic stem cell transplantation

Abstract

Objective The primary objective was to analyze the initial tacrolimus concentrations achieved in allogeneic hematopoietic stem cell transplantation patients using the institutional dosing strategy of 1 mg IV daily initiated on day +5. The secondary objectives were to ascertain the tacrolimus dose, days of therapy, and dose changes necessary to achieve a therapeutic concentration, and to identify patient-specific factors that influence therapeutic dose. The relationships between the number of pre-therapeutic days and incidence of graft-versus-host disease and graft failure were delineated. Methods A retrospective chart review included adult allogeneic hematopoietic stem cell patients who received tacrolimus for graft-versus-host disease prophylaxis in 2012. Descriptive statistics, linear and logistic regression, and graphical analyses were utilized. Results Ninety-nine patients met the inclusion criteria. The first concentration was subtherapeutic (<10 ng/ml) in 97 patients (98%). The median number of days of tacrolimus needed to achieve a therapeutic trough was 10 with a median of two dose changes. The median therapeutic dose was 1.6 mg IV daily. Approximately 75% of patients became therapeutic on ≤2 mg IV tacrolimus daily. No relationship was found between therapeutic dose and any patient-specific factor tested, including weight. No relationship was found between the number of days of therapy required to achieve a therapeutic trough and incidence of graft-versus-host disease or graft failure. Conclusion An initial flat tacrolimus dose of 1 mg IV daily is a suboptimal approach to achieve therapeutic levels at this institution. A dose of 1.6 mg or 2 mg IV daily is a reasonable alternative to the current institutional practice.

Tacrolimus initial steady state level in post-transplant cyclophosphamide-based GvHD prophylaxis regimens

“…Butts et al examined their institutional practice using initial 1 mg FD TAC to achieve the target serum level of 10–15 ng/mL( 18 ), which they concluded required at least two dose adjustments and a median of 10 days to achieve. We found that lower TISS (<10 ng/mL) was as effective with less toxicity than higher (≥10 ng/mL), and that TISS <10ng/mL did not affect engraftment.…”

“…Weight-based dosing (WBD) has been utilized with TAC when combined with sirolimus or methotrexate( 12 , 17 ), while an initial flat dose (FD) of 1 mg TAC has been used in PTCy-based regimens( 2 , 18 ). However, TAC dosing is not standardized in PTCy-based regimens, and it is unknown whether different dosing strategies correlate with specific therapeutic TAC levels at initial steady state (TISS).…”

Population Pharmacokinetic Model Development of Tacrolimus in Pediatric and Young Adult Patients Undergoing Hematopoietic Cell Transplantation

“…Both supratherapeutic and subtherapeutic tacrolimus concentrations can result in poor outcomes. Elevated steady-state trough concentrations of tacrolimus are associated with increased risk of adverse effects, including nephrotoxicity, hepatotoxicity, electrolyte abnormalities, and neurotoxicity, while subtherapeutic levels may increase the risk of developing GVHD and graft rejection ( Kernan et al, 1986 ; Kernan et al, 1987 ; Butts et al, 2016 ; Andrews et al, 2018 ). Beyond intrinsically high PK variability, tacrolimus is primarily metabolized hepatically by cytochrome p450 3A4 and 3A5 (CYP3A4/5) and is, therefore, susceptible to many drug-drug interactions.…”

Initial tacrolimus weight-based dosing strategy in allogeneic hematopoietic stem-cell transplantation

“…5 Other dosing strategies that have been employed include 1 mg CIVI daily for all patients, resulting in 98% of patients with subtherapeutic levels 48 hours after initiation based on a lower target range of 5-15 ng/mL. 6 Another factor that must be considered when initiating tacrolimus is that it undergoes extensive metabolism by the cytochrome P450 CYP3A enzyme subfamily and by p-glycoprotein. 7 Thus, tacrolimus dosing is also complicated by potentially significant drug-drug interactions with post-alloHSCT supportive medications including azole antifungals.…”

“…7 Thus, tacrolimus dosing is also complicated by potentially significant drug-drug interactions with post-alloHSCT supportive medications including azole antifungals. [6][7][8][9] Diarrhea, a common ailment during alloHSCT, has been associated with elevated tacrolimus levels in solid organ transplant recipients, but has not been well studied in alloHSCT patients. 10 Other factors that may influence tacrolimus pharmacokinetics include the type of body weight used in weight-based dosing and the timing of initial administration in relation to transplantation and/or azole antifungal initiation.…”