Relationship of tacrolimus whole blood levels to efficacy and safety outcomes after unrelated donor marrow transplantation

Concomitant use of tacrolimus and voriconazole, both competitive inhibitors of the CYP450 3A4 isoenzyme, requires tacrolimus dose reduction. On the basis of clinical observations, we developed a preemptive dose-reduction strategy in allograft recipients who received voriconazole to maintain tacrolimus concentrations within a target range. A total of 27 patients started i.v. tacrolimus at an average daily dose of 0.022 mg/kg on day À1 (30% lesser than the usual starting dose). The dose was reduced by 30-40% if the 48-h steady-state concentration was 7-10 ng/ml, and by 40-50% if it was 10-15 ng/ml. No change was made if the concentration was o7 ng/ml. Subsequently, concentrations were generally monitored 2-3 times a week with dose adjustments as necessary. None of the 170 levels (3-12 per patient; median 5) obtained between days þ 1 and þ 16 were subtherapeutic (o5 ng/ml) and only 34 levels (20%) were 415 ng/ml. Each patient required dose reduction at least twice. The dose had to be increased in only two patients after the initial dose reduction. The median tacrolimus doses in mg/kg declined with time; being 0.022, 0.008 and 0.006 on days 0, 7 and 14, respectively. We conclude that a preemptive dose-reduction strategy is effective in maintaining tacrolimus concentrations within the desired therapeutic range, although serial monitoring remains prudent.

Section: Methodssupporting

confidence: 72%

Tacrolimus use in adult allogeneic stem cell transplant recipients receiving voriconazole: preemptive dose modification and therapeutic drug monitoring

Trifilio

Scheetz

et al. 2009

“…The upper range of 20 ng/ml was derived from analyses of correlated toxicities. 1,5 In contrast, the relationship between blood concentration of tacrolimus and control of acute GVHD using lower target levels has not been well defined. Przepiorka et al 2 reported that tacrolimus levels of o5 ng/ ml were associated with an increased risk of acute GVHD after unrelated donor marrow transplantation.…”

Section: Discussionmentioning

confidence: 99%

Relationship between tacrolimus blood concentrations and clinical outcome during the first 4 weeks after SCT in children

Watanabe¹,

Matsumoto²,

Muramatsu

et al. 2009

The relationship between tacrolimus concentration and acute GVHD is not well known, with few published data available for lower target levels. We hypothesized that lower levels of tacrolimus would correlate with higher incidence of acute GVHD and poorer prognosis. Receiver operator characteristic curves (ROC) were used to quantify tacrolimus blood levels as predictors of grade II-IV acute GVHD. A total of 97 pediatric patients with hematological malignancies met the study criteria. On the ROC, a cutoff of 7 ng/ml provided the best balance between sensitivity and specificity (62.8 vs 68.2%, respectively). Cumulative incidence of acute GVHD was 65.9% (range 58.5-73.3%) in patients with mean tacrolimus concentration of p7 ng/ml and 34.8% (range 27.8-41.8%) in patients with mean tacrolimus concentration of 47 ng/ml (P ¼ 0.002). Incidence of non-relapse mortality (NRM) was higher in patients with tacrolimus of p7 ng/ml (42.9%; range 35.6-50.2%) than in patients with tacrolimus of 47 ng/ml (28.3%; range 17.4-39.2%; P ¼ 0.008). This translated into better EFS in patients with tacrolimus of 47 ng/ml (48.9%; range 39.8-58.0%) than in patients with tacrolimus of p7 ng/ml (31.8%; range 25.0-38.6%; P ¼ 0.031). Multivariate analysis showed that tacrolimus concentration was significantly associated with clinical outcomes. Mean whole-blood level of tacrolimus as continuous infusion should be maintained at X7 ng/ml for pediatric patients.

“…Przepiorka et al 17 reported a lack of correlation between the levels of tacrolimus and risk of acute GVHD within a concentration range of 5-40 ng/ml, but a significant increase in the risk of nephrotoxicity above levels Ͼ20 ng/ml. It is noticeable that the blood level of tacrolimus in this patient, measured the day before the start of pancreatitis, was within the target range of 10-20 ng/ml.…”

Section: Discussionmentioning

confidence: 99%

Acute pancreatitis during immunosuppression with tacrolimus following an allogeneic umbilical cord blood transplantation

Nieto¹,

Russ²,

Everson

et al. 2000

Summary:Tacrolimus is increasingly used for graft-versus-host disease (GVHD) prophylaxis and therapy in the allogeneic stem cell transplant (allo-SCT) setting. Pancreatitis, previously described as a side-effect of cyclosporine, has not been reported in allo-SCT recipients receiving tacrolimus. We present here a case of acute pancreatitis in a 28-year-old patient with chronic myelogenous leukemia (CML) who received an unrelated umbilical cord blood transplant (UCBT) and tacrolimus for GVHD prophylaxis. On day +31 post-transplant, she developed severe acute pancreatitis with multiorgan failure, from which she recovered completely. Tacrolimus was the probable cause of pancreatitis in this patient. Bone Marrow Transplantation (2000) 26, 109-111. Keywords: tacrolimus; FK506; pancreatitis; cord blood transplant Tacrolimus is a new immunosuppressive agent with an emerging role in allo-SCT. While its chemical structure is different from that of cyclosporine, both drugs share a similar mechanism of action, inhibiting signaling initiated by the T cell receptor that stimulates production of interleukin-2. 1 A recent randomized phase III trial comparing both agents for GVHD prophylaxis in the unrelated marrow transplant setting, showed that patients receiving tacrolimus had a significantly lower incidence of acute GVHD, and similar rates of chronic GVHD, relapse, and overall survival. 2 The toxic profile of tacrolimus, compared to that of cyclosporine, includes similar nephrotoxicity, hepatotoxicity, neurologic complications, hypomagnesemia, and immunosuppression-related infections. There appears to be less hypertension, hypertrichosis, and gingival hyperplasia, and more hyperkalemia and hyperglycemia with tacrolimus. 3,4 To our knowledge, pancreatitis has not been described in association to tacrolimus in the allo-SCT setting. Case reportThe patient was a 28-year-old female with chronic myelogenous leukemia (CML), diagnosed in 1996. She was treated with ␣-interferon plus hydroxyurea, and never achieved a complete cytogenetic remission. She had no HLAmatched sibling donors, nor an unrelated donor in any of the bone marrow registries. An unrelated 5/6 cord unit, HLA-mismatched for the DR locus, was identified at the University of Colorado Umbilical Cord Blood Bank. She consented to participate in a clinical trial of ex vivo expanded UCBT for adult patients.Conditioning therapy consisted of fractionated TBI at 12 Gy, melphalan at 140 mg/m 2 i.v., and antithymocyte globulin at 30 mg/kg × 3 days. On day 0, cord blood cells, a fraction of which (40%) were expanded ex vivo, were infused. Supportive care included standard antimicrobials, and GVHD prophylaxis with cyclosporine at a dose of 4 mg/kg/day, adjusted to a whole blood level of 350-450 ng/ml, and methylprednisolone at 0.2 mg/kg twice a day from day 0 to +4, 0.5 mg/kg twice a day from day +5 to +20, and in a tapering schedule thereafter. On day +16 posttransplant, tacrolimus was substituted for cyclosporine because of the patient's complaints of severe headache and visual...