Advagraf vs. Prograf as Immunosuppressive Therapy in De Novo Renal Transplant Immunosuppressive Therapy: A Single Centre Experience

Abstract

Introduction: The prevention of allograft rejection a foremost challenge for the clinicians involved in transplant. Among the regimens aimed to suppress transplant recipient immune response against the graft, tacrolimus represents a milestone of immunosuppressive therapy. The formulation of Prograf capsules requires twice-a-day administration. Advagraf is a recently developed slow-release once-a-day oral formulation of tacrolimus, with similar efficacy and safety profile of 12-hour formulation (Prograf). It been shown that poor compliance is one relevant factor associated with graft loss: once-daily dosing can contribute to improved patient adherence. Few data are currently available on Advagraf use in clinical practice, especially as early immunosuppressive therapy in transplants. We therefore evaluated the efficacy and pharmacokinetics of single-dose formulation compared to the traditional Prograf twice-daily dosing in de novo renal transplants. Methods: During 2009-2010, 30 renal transplant recipients were recruited: 15 of them (Advagraf group), receiving single-dose tacrolimus (0.2-0.3 mg/kg/day) were compared with 15 patients (Prograft group) treated with tacrolimus in twice-a-day administration (0.2 mg/kg/day administered every 12 hours in two divided doses). In both groups, tacrolimus was associated with mycophenolate mofetil/mycophenolic acid and steroids. Tacrolimus blood levels and the adjusted dose based on tacrolimus trough whole blood concentrations were recorded at 3rd, 5th, 7th, 10th, 15th postoperative day and at discharge. Results: The groups did not differ significantly in terms of patient characteristics and drug efficacy. Drug blood levels tended to be lower in the first weeks post-transplant, particularly in Advagraf-treated patients who required higher drug doses (0.3 mg/kg/day); afterwards blood concentrations reached a stable level, with a consequent necessity to reduce Advagraf dosage (0.2-0.3 mg/kg/day after the first month). The incidence of rejection was comparable in the two groups (1 steroid-sensitive acute rejection in each group). Concerning side effects, a similar percentage of patients in the groups experienced neurological disorders (headache, tremor) (33.3% of Advagraf-treated patients vs. 26.7% of Prograf-treated patients). Likewise, the occurrence of posttransplant diabetes (according to ADA criteria) did not differ significantly between Advagraf and Prograf group (20% vs. 26.7% of the patients respectively), and the incidence of systemic infections (CMV, polyomavirus) was identical (6.7% vs. 6.7%), In both groups, arterial hypertension worsened in those patients of both groups who had a clinical history of hypertension during dialysis (33.3% vs. 33.3%), while no new-onset hypertension was found in patients without history of hypertension. In line with literature in patients receiving Advagraf displayed reduced lipid levels. Conclusions: This study suggests that in de novo kidney transplant, single-dose formulation of tacrolimus has a similar short-term efficacy compared with twice-a-day administration. The data also highlight the necessity to increase Advagraf dosage in the first week post-transplant to achieve effective therapeutic levels (11-15 ng/ml). This observation is in agreement with literature and can be explained by the once daily morning administration which inevitably leads to a lower baseline C0 value when compared with the twice-daily dosing regimen. Both formulations showed analogous efficacy as well as side effects. An emerging finding is the reduction of lipid profile with a considerable importance for cardiovascular risk.