Study Aimed at Determining the Relation Between the Administered Dose and Exposure to Immunosuppressive Medication in Children After Solid Organ Transplantation

The success of solid organ transplantation is for an important part determined by the potency of the immunosuppressive regime to prevent allograft rejection. Depending on the type of organ transplanted current 5-year graft survival for liver is circa 70% and for kidney almost 80% (1-3). Although acute rejection has become less a problem, analyses of data on the follow-up of solid organ recipients has demonstrated that long-term allograft survival has not improved much in the last decade. The life expectancy of a donor organ appears limited due to phenomena such as chronic, antibody mediated, rejection and the toxic effects of immunosuppressive medication.

Unfortunately, the most commonly applied immunosuppressive agents (in particular the calcineurin-inhibitors) possess a narrow therapeutic index with potential severe consequences of drug under- or overexposure. Furthermore, in clinical practice optimal dosing is difficult to achieve due to important inter- and intraindividual variation in drug pharmacokinetics. Consequently attention has shifted towards designing a "tailored immunosuppressive maintenance therapy", aimed at optimization of drug efficacy and the prevention of these unintended and possible deleterious side effects in the individual recipient. For a "perfect fit" this entails a fundamental knowledge of the individual characteristics of the recipient and its graft in relation to the pharmacodynamic and -kinetic properties of the agent.

A complex and often interdependent set of factors appears relevant in determining drug exposure. These include recipient characteristics such as age, race, body composition, organ function (intestine-liver-kidney), food and concomitant medication intake, but also graft-related characteristics such as: seize, donor-age, and time after transplantation. Longitudinal and cross-sectional analysis of clinical and genetic co-variables in allograft recipient cohorts has identified several single nucleotide polymorphisms (SNPs) in genes encoding for enzymes and transporters involved in drug metabolism(CYP3A4, CYP3A5, MDR1), which were associated with differences in dosing and toxicity (4-10). In particular carriers of a common polymorphism in CYP3A5 (designated CYP3A5*1) demonstrate a 25-40% increase in tacrolimus clearance and a 2-3 fold increase in dose requirements.

In children the dose requirements per kg bodyweight to attain desired blood concentrations are approximately 2.7 fold higher for patients under 5 years and 1.9 fold higher for patients aged 5 to 12 years when compared to older patients11-14. Age-related differences in expression of enzymes or transporters involved in drug metabolism might play an important role. Fakhoury et al demonstrated an increase in intestinal CYP3A4/5 mRNA and protein expression from childhood to adulthood (15). In addition other factors such as intestinal transit time and length, body composition, protein binding, body metabolism and organ function, might be important in determining dose requirements in children (16-18). The importance of the aforementioned genetic polymorphisms on long-term dose requirements have not been studied in children.

Objective: