Immunosuppressive agents, such as tacrolimus, are frequently used as graft-versus-host disease (GVHD) prophylaxis in patients undergoing allogeneic stem cell transplantation (HSCT). However, according to Daniel Marco and colleagues, tacrolimus efficacy suffers from a narrow therapeutic window and high inter- and intrapatient pharmacokinetic variability (IPV) between patients.
The research group evaluated the impact of tacrolimus IPV in HSCT recipients and found that high tacrolimus IPV was an independent risk factor for acute GVHD (aGVHD)—a finding that could enable more effective identification of at-risk patients compared with current strategies. Their results were published in Pharmaceuticals.
Investigators retrospectively examined IPV in 128 patients who underwent allogeneic HSCT with high-dose posttransplant cyclophosphamide. Tacrolimus IPV was qualified by comparing predose concentrations and 1-month concentrations. The primary end point was the 100-day cumulative incidence of aGVHD, and additional end points included acute kidney injury, neurotoxicity, and tacrolimus-related thrombotic microangiopathy.
At day 100, the incidences of grade II-IV and grade III-IV aGVHD were 22.7% and 7%, respectively. The authors noted higher tacrolimus IPV was associated with higher risk of GVHD, particularly in patients with IPV over the 50th percentile.
These patients showed significantly higher incidences of grade II-IV aGVHD (34.9% vs 10.8%; hazard ratio [HR], 3.858; P<.01) and grade III-IV aGVHD (12.7% vs 1.5%; HR, 9.69; P=.033) compared with patients at or below the 50th percentile.
Likewise, patients in the top quartile of IPV had higher rates of grade II-IV aGVHD (41.9% vs 16.5%; HR, 3.30; P<.001) and grade III-IV aGVHD (16.1% vs 4.1%; HR, 4.99; P=.012) compared with those among the 75th percentile. In multivariate models, the authors verified that tacrolimus IPV above the 50th percentile was an independent risk factor for grade II-IV aGVHD (HR, 2.99; P=.018) and grade III-IV aGVHD (HR, 9.12; P=.047).
“Patients with high [tacrolimus] IPV during the first month after transplantation should therefore be closely monitored for aGVHD during the following weeks after discharge from the hospital,” the authors concluded.
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