PhD Student : NGUYEN Thi Van Anh Supervisor: Prof. Roselyne BOULIEU EA 4169

1. « MONITORING OF AZATHIOPRINE THERAPY IN PEDIATRIC POPULATION: RELATION PHARMACOKINETIC/PHARMACODYNAMIC IN AUTOIMMUNE DISEASES » PhD Student: NGUYEN Thi Van Anh Supervisor: Prof. Roselyne BOULIEU EA 4169 Department of Clinical Pharmacy Pharmacokinetics and Drug Evaluation Laboratory Lyon 1 University 11.2010 – 11.2013

2. INTRODUCTION - OBJECTIVES • Autoimmune diseases:arise from an overactive immune response of the body against its cell. • Inflammatory bowel disease (IBD):a group of disorders in which the intestines become inflamed • Autoimmune hepatitis (AIH): the immune systems attacks liver cells • Dermatology diseases: Skin diseases • Azathioprine (AZA):-an immunosuppressive drug, complex metabolism 6-TGN: an active metabolite, 250-450 pmol/8.108 RBCs: therapeutic range Limited data: on AZA dose for children Suggest AZA dose for children OBJECTIVES Evaluate efficacy, toxicity in function of AZA dose and 6TGN level

3. AZA METABOLISM AZA 6MP TPMT XOD 6-MeMP 6-TUA 6-TGMP Mono P Inactive metabolite, TOXICITY 6-TGDP Di P 6-TGN Active metabolite Most active 6-TGTP Tri P

4. 1st year AZA DOSE FOR IBD CHILDREN • Method: 64 patients less than 19 years • received AZA mono-therapy for at least 3 months • - 3 dose groups: below 2, 2-2.5 (standard dose), greater than 2.5 mg/kg/d - Remission: PCDAI <10 - Toxicity: Leukopenia; Lymphopenia; Hepatotoxicity, Pancreatotoxicity - Metabolite assay (6-TGN, Me6-MPN): HPLC • Objective: - Suggest AZA dose for pediatric IBD patients - Investigate efficacy, toxicity in function of AZA dose and 6-TGN level • AZA dose below 2 mg/kg/d appears effective in pediatric patients (94%) • Children may achieve remission when 6-TGN level below 250 nmol/h/mL RBCs (85%) • Therapeutic range 250-450 pmol/8.108 RBCs seems not appropriate RESULTS Further Studies

5. INFLUENCE OF AGE ON UTILITY OF AZA DOSE IN IBD CHILDREN Now • Our 1st study: suggest dose for IBD children less than 19 years AZA dose less than 2 mg/kg/d is effective • 1published study: suggest dose greater than 3 mg/kg/d for children 6 years old or younger Investigate influence of age on AZA efficacy and toxicity in function of AZA dose and 6-TGN level • Divide studied population into 2 age groups: the adolescent • ( more than 11 years), the young children (11 years and younger) Method: • Data of each groups is subdivided into groups of AZA dose: • Below 2 mg/kg/d, 2-2.5 mg/kg/d, more than 2.5 mg/kg/d

6. STUDY ON AZA THERAPY IN CHILDREN WITH SOME OTHER AUTOIMMUNE DISEASES Next years • Autoimmune Hepatitis (AIH) and Dermatology diseases Collect pediatric patients treated with AZA Evaluate efficacy, toxicity - Investigate therapeutic range of 6-TGN level - Optimize AZA dose for children with these diseases • 6TGN:-correspond to the mono, di, tri-phosphate forms of 6-Thioguanosine • (Tri phosphate form was considered to be the major active compound) • Previous studies determined • total 6-TGN levels Contradictory data on relation between 6-TGN level and efficacy • Develop a method to determine levels of these 6-TGN forms in children • Investigate the relation between each form of 6-TGN and efficacy in children