Clinical Pharmacology Unit (UPC)

Development of New Tools for Pharmacological Profiling of Immunosuppressants in Children

Study Rational

Treatment through immunosuppressant drugs has changed the prognosis of patients who suffer from autoimmune diseases or receive an organ transplant. However, drug use protocols place little importance on sensitivity variability among individuals relating to patient age. Consequently, the degree of induced immunosuppression (pharmacodynamics) may differ from one patient to another and result in an under- or overdose, despite a blood concentration of the therapeutic drug (pharmacokinetics). These two situations lead to major deleterious effects, namely treatment failure and drug toxicity. This, in turn, means higher costs for patient care. Better treatment adaptation would not only benefit the patient, but also the health system economy. Until now, the adjustment of administered immunosuppressant doses has been based solely on residual concentrations. However, it should be individualized by also taking into account pharmacodynamic variability. We can distinguish “predictive” pharmacodynamics from “effective” pharmacodynamics. The first predicts the patient’s response to treatment, in vitro, while the second evaluates treatment effectiveness, ex vivo. There are few articles on studies relating to immunosuppressant pharmacodynamics. The few studies that exist focus on the effective pharmacodynamics of immunosuppressants prescribed to adults following an organ transplant.

Hypothesis

Immunosuppressant susceptibility varies according to age and individual. This variability is attributable to polymorphisms (interindividual variability) and modifications observed during the ontogeny (age-related variability) of target receptors, as well as biotransformation and signaling pathways. Our hypothesis is that the analysis of the in vitro sensibility (predictive pharmacodynamics done following the addition of immunosuppressants in the culture medium) and ex vivo sensibility (effective pharmacodynamics carried out following oral immunosuppressant intake by patient) of T lymphocytes can be used to design individualized treatment.

Objectives

Primary: Develop a pharmacological profile, including criteria drawn from predictive pharmacodynamics (immunosuppressant activity tested in vitro prior to treatment) and effective pharmacodynamics (immunosuppressant activity tested ex vivo following treatment) in association with pharmacokinetic data (administered dose vs. blood concentrations). The immunosuppressive agents studied will be nucleotide synthesis route inhibitors (6-mercaptopurine, mycophenolate mofetil and methotrexate) and calcineurin inhibitors (tacrolimus and cyclosporine A).

Secondary: These pharmacodynamics studies, in association with the pharmacokinetics study currently in wide use at the CHU Ste-Justine (Dr. Yves Théoret) will constitute the pharmacological profile that will enable Sainte-Justine researchers to (1) propose an algorithm to individualize immunosuppressant treatments for patients in order to optimize drug efficacy while reducing their deleterious effects, (2) develop a new standard of care affecting a great number of patients, (3) reduce patient care costs by limiting the deleterious effects due to under- or overdosage of immunosuppressants, (4) describe pediatric aspects related to immunosuppressant pharmacodynamics, and (5) target a future pharmacogenetic study on factors that may be responsible for interindividual susceptibility.