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

Abstract

Tacrolimus is a mainstay medication for graft-versus-host disease (GVHD) prophylaxis in combination with other immunosuppressive agents. Achieving therapeutic tacrolimus levels is vital in preventing acute GVHD (aGVHD), while supratherapeutic levels may increase risk of toxicity and relapse. We performed a single center retrospective chart review including all adult patients post-allogeneic hematopoietic stem-cell transplantation who received initial tacrolimus continuous intravenous infusion for GVHD prophylaxis between June 1, 2017 and December 31, 2019. The primary outcome was the percent of patients with an initial therapeutic tacrolimus level, defined as 5–12 ng/mL, after empiric weight-based dosing at 0.02 mg/kg/day. Secondary outcomes included evidence of tacrolimus toxicity within seven days of initiation, incidence of aGVHD by day 100, and relapse after six months. An initial therapeutic level was achieved in 47% of patients with a median initial level of 12.4 ng/mL. Fifty-two percent of patients had supratherapeutic levels. No significant nephrotoxicity, hepatotoxicity, or neurotoxicity occurred within a week of starting tacrolimus or at neutrophil engraftment. Grade II-IV aGVHD by day 100 was observed in 22% of patients, and relapse after six months was found in 16% of patients. These results have led to consideration of an empiric 20% dose reduction to 0.016 mg/kg/day or an expanded initial tacrolimus target of 5–15 ng/mL as there was low aGVHD incidence and no increased risk of toxicity.

Effects of Posaconazole on Tacrolimus Population Pharmacokinetics and Initial Dose in Children With Crohn’s Disease Undergoing Hematopoietic Stem Cell Transplantation

“…Thus, it is vital to prevent the risk of developing GVHD. Tacrolimus is currently the first-line drug used for the prevention of GVHD following HSCT and has played an important role in addressing this urgent clinical need ( Gao and Ma, 2019 ; Ishiwata et al, 2020 ; Soskind et al, 2020 ; Zhou et al, 2020 ). With the exception of potential rejection reactions, IFD has become a significant cause of morbidity and mortality in HSCT patients, and at present, posaconazole is often used as prophylactic therapy for prevention of IFD ( Zhang et al, 2017 ).…”

“…It has been reported that HSCT significantly improves the quality of life of CD patients, and 50% of CD patients who underwent HSCT achieved complete healing of the mucosa and clinical remission ( Lindsay et al, 2017 ; Lopez-Garcia et al, 2017 ; Ruiz et al, 2020 ). However, for HSCT patients, long-term tacrolimus treatment is necessary to prevent rejection ( Gao and Ma, 2019 ; Ishiwata et al, 2020 ; Soskind et al, 2020 ; Zhou et al, 2020 ). Similarly, posaconazole is also needed for the prevention of invasive fungal disease (IFD) in HSCT patients ( Busca et al, 2016 ; Zhang et al, 2017 ).…”

Effects of voriconazole on population pharmacokinetics and optimization of the initial dose of tacrolimus in children with chronic granulomatous disease undergoing hematopoietic stem cell transplantation

“…Tacrolimus is a first-line agent for GVHD prevention and has been routinely employed to stop rejection of HSCT [15][16][17][18]. However, tacrolimus has a narrow therapeutic range; the use of high concentrations seems to be related to toxicity, while lower concentrations are related to an acute rejection's increased risk (23).…”

“…HSCT may adjust superoxide generation, making neutrophil function within normal range and improvement in inflammatory progression (14). However, HSCT patients must take tacrolimus, a potent immunosuppressant, for a prolonged period to prevent transplant rejection (15)(16)(17)(18). In addition, voriconazole, a second-generation triazole with potent broad-spectrum antifungal activity, is used for prophylaxis against invasive fungal disease (IFD), which is a major cause of morbidity and mortality in pediatric patients after HSCT (19,20).…”

Population pharmacokinetics and initial dose optimization of tacrolimus in children with severe combined immunodeficiency undergoing hematopoietic stem cell transplantation

“…For HSCT patients, tacrolimus, an immunosuppressant, needs to be taken for a long time to prevent rejection (Gao and Ma, 2019;Ishiwata et al, 2020;Soskind et al, 2020). However, tacrolimus had high pharmacokinetic variability, making it difficult to formulate an individual administration schedule, especially in children with SCID undergoing HSCT.…”