Individualization of Immunosuppressive Therapy after Solid Organ Transplantation

__Abstract__ When an individual’s kidneys fail, there are three treatment options: hemodialysis, peritoneal dialysis or kidney transplantation. A successful kidney transplantation results in the best patient survival and a better quality of life compared to the two other treatment modalities. Kidney transplantation is therefore the preferred therapy for renal failure. The first deceased donor kidney transplantation in the United States was performed in 1950 by Lawler and colleagues on Ruth Tucker, a 44-year-old woman with polycystic kidney disease. Although the kidney transplant was rejected ten months later because no immunosuppressive therapy was available at the time, the intervening time allowed Tucker’s remaining native kidney (it was an orthotopic transplantation) to recover and she lived for another five years. At the same time in France, Küss, Hamburger, and others also performed a number of kidney transplantations

Concomitant intraperitoneal and systemic chemotherapy for extensive peritoneal metastases of colorectal origin: protocol of the multicentre, open-label, phase I, dose-escalation INTERACT trial

INTRODUCTION: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) has become standard of care for patients with peritoneal metastases of colorectal origin with a low/moderate abdominal disease load. In case of a peritoneal cancer index (PCI) score >20, CRS-HIPEC is not considered to be beneficial. Patients with a PCI >20 are currently offered palliative systemic chemotherapy. Previous studies have shown that systemic chemotherapy is less effective against peritoneal metastases than it is against haematogenous spread of colorectal cancer. It is suggested that patients with peritoneal metastases may benefit from the addition of intraperitoneal chemotherapy to systemic chemotherapy. Aim of this study is to establish the maximum tolerated dose of intraperitoneal irinotecan, added to standard of care systemic therapy for colorectal cancer. Secondary endpoints are to determine the safety and feasibility of this treatment and to establish the pharmacokinetic profile of intraperitoneally administered irinotecan. METHODS AND ANALYSIS: This phase I, '3+3' dose-escalation, study is performed in two Dutch tertiary referral centres. The study population consists of adult pa

Increased risk of errors in children parenterals - Balance scale:Accurate drug preparation and administration for the child

Een weegbalans kan medicatiefouten bij voor toediening gereedmaken (VTGM) van parenterale geneesmiddelen voor kinderen voorkomen. Deze extra stap in het VTGM-proces kost relatief weinig tijd en zorgt voor een betere kwaliteitsborging

Increased risk of errors in children parenterals - Balance scale:Accurate drug preparation and administration for the child

Een weegbalans kan medicatiefouten bij voor toediening gereedmaken (VTGM) van parenterale geneesmiddelen voor kinderen voorkomen. Deze extra stap in het VTGM-proces kost relatief weinig tijd en zorgt voor een betere kwaliteitsborging

The Pharmacogenetics of Calcineurin Inhibitor-Related Nephrotoxicity

Chronic calcineurin inhibitor (CNI)-induced nephrotoxicity is associated with prolonged use of cyclosporine and tacrolimus and has been observed after all types of transplantation, as well as during treatment of autoimmune disease. Extensive alterations in the renal architecture including glomerular sclerosis, tubular atrophy and interstitial fibrosis may lead to end-stage renal failure. Increasing evidence shows that pharmacogenetic factors explain part of the between-patient differences in susceptibility to developing CNI-induced nephrotoxicity. In this paper this evidence is reviewed, with special emphasis on the role of genetic factors influencing metabolism and transportation of CNIs in both acceptor and donor

The Role of Pharmacogenetics in the Disposition of and Response to Tacrolimus in Solid Organ Transplantation

The calcineurin inhibitor tacrolimus is the backbone of immunosuppressive drug therapy after solid organ transplantation. Tacrolimus is effective in preventing acute rejection but has considerable toxicity and displays marked inter-individual variability in its pharmacokinetics and pharmacodynamics. The genetic basis of these phenomena is reviewed here. With regard to its pharmacokinetic variability, a single nucleotide polymorphism (SNP) in cytochrome P450 (CYP) 3A5 (6986A > G) has been consistently associated with tacrolimus dose requirement. Patients expressing CYP3A5 (those carrying the A nucleotide, defined as the *1 allele) have a dose requirement that is around 50 % higher than non-expressers (those homozygous for the G nucleotide, defined as the *3 allele). A randomised controlled study in kidney transplant recipients has demonstrated that a CYP3A5 genotype-based approach to tacrolimus dosing leads to more patients reaching the target concentration early after transplantation. However, no improvement of clinical outcomes (rejection incidence, toxicity) was observed, which may have been the result of the design of this particular study. In addition to CYP3A5 genotype, other genetic variants may also contribute to the variability in tacrolimus pharmacokinetics. Among these, the CYP3A4*22 and POR*28 SNPs are the most promising. Individuals carrying the CYP3A4*22 T-variant allele have a lower tacrolimus dose requirement than individuals with the CYP3A4*22 CC genotype and this effect appears to be independent of CYP3A5 genotype status. Individuals carrying the POR*28 T-variant allele have a higher tacrolimus dose requirement than POR*28 CC homozygotes but this association was only found in CYP3A5-expressing individuals. Other, less well-defined SNPs have been inconsistently associated with tacrolimus dose requirement. It is envisaged that in the future, algorithms incorporating clinical, demographic and genetic variables will be developed that will aid clinicians with the determination of the tacrolimus starting dose for an individual transplant recipient. Such an approach may limit early tacrolimus under-exposure and toxicity. With regard to tacrolimus pharmacodynamics, no strong genotype-phenotype relationships have been identified. Certain SNPs associate with rejection risk but these observations await replication. Likewise, the genetic basis of tacrolimus-induced toxicity remains unclarified. SNPs in the genes encoding for the drug transporter ABCB1 and the CYP3A enzymes may relate to chronic nephrotoxicity but findings have been inconsistent. No genetic markers reliably predict new-onset diabetes mellitus after transplantation, hypertension or neurotoxicity. The CYP3A5*1 SNP is currently the most promising biomarker for tailoring tacrolimus treatment. However, before CYP3A5 genotyping is incorporated into the routine clinical care of transplant recipients, prospective clinical trials are needed to determine whether such a strategy improves patient outcomes. The role of pharmacogenetics in tacrolimus pharmacodynamics should be explored further by the study of intra-lymphocyte and tissue tacrolimus concentrations