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
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
OBJECTIVES
Suggest AZA dose for children
Evaluate efficacy, toxicity in function
of AZA dose and 6TGN level
AZA METABOLISM
AZA
6MP
6-MeMP
Inactive
metabolite,
TOXICITY
6-TGMP
Mono P
6-TGDP
6-TGN
Active metabolite
6-TUA
Di P
6-TGTP
Tri P
Most
active
1st year
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
RESULTS
-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
Now
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
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
Next
years
STUDY ON AZA THERAPY IN CHILDREN
WITH SOME OTHER AUTOIMMUNE DISEASES

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