The emerging role of Brazil in clinical trial conduct for transplantation.

Brazil is a country with over 190 000 000 inhabitants and a health system composed of a large public, government managed system. Between 1999 and 2010 the number of deceased donors increased by 161%, from 3.8 to 9.9 pmp, and the number of solid organ transplants increased by 121%, from 2891 to 6402. This growth was a consequence of the creation of a well-organized national transplant program. Government funding, decentralization and educational investment in transplant coordinators and related professional were decisive. In 2009 Brazil was the second largest country in the absolute number of kidney transplants (n = 4259). There are significant region disparities in performance which are mainly due to the development status. Improvements in transplant and research regulations resulted in an increasing participation of Brazilian transplant centers in multicenter trials, reaching over 44 studies during the last 11 years. Brazilian centers have been involved in clinical trials using everolimus, sirolimus, fingolimod, mycophenolate mofetyl, mycophenolate sodium, tacrolimus modified-release, sotrastaurin, belatacept, JAK3 inhibitor CP690,550 and valganciclovir. The still increasing number of transplants performed every year along with more efficient regulatory and sanitary analysis, organized clinical research programs and reduction in region performance disparities will eventually increase even more the participation of Brazil in trials worldwide.

Tacrolimus once daily (ADVAGRAF) versus twice daily (PROGRAF) in de novo renal transplantation: a randomized phase III study.

This multicenter, 1:1-randomized, parallel-group, noninferiority study compared the efficacy and safety of twice-daily tacrolimus (Tacrolimus BID; Prograf) and once-daily tacrolimus prolonged release (Tacrolimus QD; Advagraf), combined with steroids and low-dose mycophenolate mofetil without antibody induction, in 667 de novo kidney transplant recipients. A double-blind, double-dummy 24-week period was followed by an open extension of up to 12 months posttransplant. Biopsy-proven acute rejection rate at 24 weeks (primary endpoint, per-protocol analysis) was 15.8% for Tacrolimus BID versus 20.4% for Tacrolimus QD (p = 0.182; treatment difference 4.5%, 95% confidence interval-1.8%, 10.9%, just outside the prespecified 10% noninferiority margin). Kaplan-Meier 12-month patient and graft survival rates were 97.5% and 92.8% for Tacrolimus BID and 96.9% and 91.5% for QD. Both treatment groups showed equally well-maintained renal function at 12 months (mean creatinine clearance approximately 67 mL/min) and similar adverse event profiles. Overall results obtained with either Tacrolimus QD or BID, without antibody induction, were good, supporting use of the once-daily formulation as an effective alternative to the established twice-daily formulation.

Clinical impact of polymorphisms of transport proteins and enzymes involved in the metabolism of immunosuppressive drugs.

Individualization of immunosuppressive therapy after solid organ transplantation is a goal that has been pursued for a long time. Nevertheless, in clinical practice, we are still stratifying patients in subgroups in which risk is assessed using demographic information and population analysis. Then, a combination of immunosuppressive drugs is chosen and doses are individualized to compensate for intra- and interindividual variabilities in drug pharmacokinetics, to obtain similar plasma/blood concentrations that are believed to be therapeutic, again based on data derived from population analysis. One step further in this strategy is to recognize, before initiation of immunotherapy, those patients at higher risk to be either under- or overexposed to currently used immunosuppressive drugs. Several studies have been undertaken to correlate single nucleotide polymorphisms in genes encoding transport proteins and metabolizing enzymes involved in the disposition of immunosuppressive drugs. Overall, the results from these studies have been mixed. The causes of these sometimes conflicting results include methodologic, genetic, or nongenetic factors. The degree of linkage disequilibrium, the measure of nonrandom associations between polymorphisms at different loci, not necessarily on the same chromosome, is perhaps the main genetic factor. The influence of the environment, physiology (such as kidney and liver functions), disease state, use of multidrug regimens, and inherent drug-to-drug interactions are present nongenetic factors. Moreover, it is also important to increase our knowledge of the genetic factors involved in the variabilities observed in drug responses of pharmacodynamics. True individualized therapy, with the ability to improve health outcomes of each transplant recipient, will depend on our knowledge of the genetic factors involved in immunological response and drug pharmacokinetics and pharmacodynamics.