Once– versus twice–daily tacrolimus: are the formulations equivalent?

Tacrolimus is one of the most often used immuno-suppressive drugs in organ transplantation. It was first approved in 1994 for use in liver transplanta-tion, replacing cyclosporine A, due to better absorption properties regardless of bile secretion. Then it use was extended to other organs and nowadays more that 90% of kidney graft recipient in the United States receive tacrolimus as a basic immunosup-pressant [1]. The use of tacrolimus is complicated by its narrow therapeutic index and wide intra– and in-terpatient pharmacokinetics variability, thus it dosage should be based on monitoring trough drug blood concentration. The main complications of drug over-dosage are nephro– and neurotoxicity and metabolic disturbances like posttransplant diabetes mellitus and hyperlipidemia. On the other hand low, non– therapeutic drug blood level can lead to graft rejection and loss. Patients' noncompliance is the main cause of fluctuating tacrolimus blood concentration and in many cases could be the reason of acute graft rejection episodes. It is an important problem both in young, active but also in older kidney graft recipients and reduction of immunosuppressive drugs daily doses is one method to overcome this problem [2]. The once–daily (OD) extended–release formulation of tacrolimus (Advagraf, Astellas) was launched in 2007 in 0.5, 1, 3, and 5 mg doses. This drug formulation allows most of liver transplant and some kidney transplant recipients (on tacrolimus monotherapy or in dual therapy with prednisone) to use only one morning dose of immunosuppressants. Such therapy simplifies treatment protocol and increases patient compliance. Converting patients from twice daily (BID) to OD tacrolimus was proposed on equivalent daily dose but there was a concern of adequate blood levels after treatment switch. We observed in our center that OD tacrolimus doses had to be 10–15% higher than BID formulation to get the same trough blood drug concentration after conversion. In a mul-ticenter, open–label, phase III study in stable adult liver transplant recipients converted from tacro-limus BID to OD (1:1 [mg:mg] total daily dose basis). Following conversion, mean tacrolimus trough levels were reduced by approximately 15% (7.5 ng/ ml vs. 6.5 ng/ml; P <0.0001) but were more consistent , showing reduction between– and within–pa-tient variability in trough levels [3]. However, in our retrospective analysis of 60 kidney graft recipients converted from tacrolimus BID to OD formulation in identical (1:1) daily doses in late posttransplant period trough blood drug concentration did not significantly differ pre and after conversion. OD tacrolimus doses were …