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

« MONITORING OF AZATHIOPRINE THERAPY IN

PEDIATRIC POPULATION: RELATION

PHARMACOKINETIC/PHARMACODYNAMIC IN

AUTOIMMUNE DISEASES »

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

OBJECTIVES

Suggest AZA dose for children

Evaluate efficacy, toxicity in function of AZA dose and 6TGN

level

INTRODUCTION - OBJECTIVES

AZA METABOLISM

AZA

6MP

6-MeMP 6-TGMP

6-TGDP

6-TGTP6-TGN

Active metabolite

TPMT

Inactive metabolit

e, TOXICITY

Most active

Mono P

Di P

Tri P

6-TUA

XOD

AZA DOSE FOR IBD CHILDREN Objective: - Suggest AZA dose for pediatric IBD patients

- Investigate efficacy, toxicity in function of AZA dose and 6-TGN level

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

1st year

-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

Further Studies

RESULTS

INFLUENCE OF AGE ON

UTILITY OF AZA DOSE IN IBD CHILDREN

Our 1st study: suggest dose for IBD children less than 19 years

AZA dose less than 2 mg/kg/d is effective

1 published study: suggest dose greater than 3 mg/kg/d for children 6

years old or younger

Now

Investigate influence of age on AZA

efficacy and toxicity in function of AZA

dose and 6-TGN level

Method: -Divide studied population into 2 age groups: the adolescent

( more than 11 years), the young children (11 years and younger)

- 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

STUDY ON AZA THERAPY IN CHILDREN

WITH SOME OTHER AUTOIMMUNE DISEASES

Autoimmune Hepatitis (AIH) and Dermatology diseases

Next years

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)

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

Previous studies determinedtotal 6-TGN levels