Background
opportunistic infection, malignancy, end-stage liver disease
ADVERSE EFFECTS, LIVER, OPPORTUNISTIC INFECTION, EMA
Liver transplantation (LTx) is the treatment of choice for patients with end-stage liver disease. The liver is the second most frequently transplanted organ with a transplantation rate of 5500 livers per year in Europe [Since the first experimental LTx in 1963, survival rates have improved significantly. This trend can be attributed to improved surgical techniques, donor organ preservation methods and, in particular, to the development and improvement of immunosuppressive medication [Despite major advances in transplantation medicine, graft rejection remains the key obstacle to long-term success. In clinical practice, a combination of two or three immunosuppressants is normally used to control the immune response in the immediate post-LTx period; this multi-drug regimen typically involves a combination of glucocorticoid (e.g. prednisone), calcineurin inhibitor (CNI) (cyclosporine or tacrolimus) and anti-proliferative agent (e.g. mycophenolate mofetil, azathioprine or everolimus). Other therapeutic agents include interleukin-2 receptor antagonists, such as basiliximab, often used as induction therapy to delay or reduce the need for CNIs. Once graft function has stabilised and the early immune response is controlled, the number and dose of immunosuppressive medications may be gradually reduced to minimise the wide range of overlapping adverse effects that include increased susceptibility to opportunistic infection and increased risk of malignancy.Therefore, effective immunosuppressive strategies must strike a balance between suppressing the immune response against the transplanted organ whilst simultaneously minimising toxic side effects of the pharmacological interventions. Furthermore, side effects of the immunosuppressive therapy may affect patient compliance with the drug regimen, which is vital for maintaining immunosuppression and therefore assuring graft survival.Tacrolimus, a macrolide CNI, was introduced to transplant practice in the early 1990s and since then has become the first-line immunosuppressive medication in most LTx programs [Currently marketed formulations of tacrolimus, such as Prograf® and Advagraf™, exhibit limitations primarily in terms of pharmacokinetic properties and tolerability. Tacrolimus has a narrow therapeutic index; blood trough level concentrations between 3 and 15 ng/ml are recommended during the first year after transplantation, provided that tacrolimus is given in combination with mycophenolate, steroids and induction with an anti-CD25 antibody [Both Prograf® and Advagraf™ exhibit significant inter- and intra-individual variability in absorption owing to interactions with food and concomitant medications; also functional polymorphisms in the cytochrome P-450 system cause inconsistencies. In addition, both Prograf® and Advagraf™ exhibit a rather low bioavailability due to poor water solubility and pre-systemic gastrointestinal metabolism [Transplant recipients also typically require an array of concomitant medications for comorbidities, which means that interaction and tolerability profiles may cause issues. In addition, the intake schedule of many different medications may not easily be integrated into the patients’ daily life, which increases the risk of low patient compliance. As non-compliance with immunosuppressant dosing can result in graft rejection and failure, the once daily formulation of tacrolimus, Advagraf™, was designed to reduce the daily pill burden compared to Prograf® (taken twice daily). However, this potential benefit of Advagraf™ is counterbalanced by delayed achievement of therapeutic trough levels after transplantation and the need for an up to 50% higher dosage to maintain trough levels similar to Prograf® [A new once-daily formulation of tacrolimus, Envarsus®, was approved in 2014 by the European Medicines Agency (EMA) for the prophylaxis of rejection in kidney or liver allograft recipients and treatment of rejection resistant to other immunosuppressants [