Monitoring of azathioprine metabolites in pediatric patients with autoimmune hepatitis.
Azathioprine is commonly used in the treatment of autoimmune hepatitis (AIH). Few data are available on drug monitoring of azathioprine metabolites in patients with AIH, especially in pediatric patients. The purpose of this study was to investigate intracellular thiopurine metabolites in children with AIH and to assess the relevance of drug monitoring compared with the efficacy and toxicity. Data from 28 patients with AIH treated by azathioprine for at least 3 months were recorded. 6-Thioguanine nucleotides (6-TGN) and 6-methyl mercaptopurine nucleotides (6-MeMPN) concentrations and TPMT activity were determined by high-performance liquid chromatography. Blood cell counts and liver function tests were also collected and the clinical outcome was documented. A wide interindividual variability in 6-TGN and 6-MeMPN concentrations was observed with values ranging from 51 to 1966 pmol/8 x 10(8) red blood cells (RBCs) for 6-TGN and from 42 to 8189 pmol/8 x 10(8) RBCs for 6-MeMPN. A total of 61.4% of the patients achieved remission and only 32.6% of these children had 6-TGN values within the target range proposed for inflammatory bowel disease (250-450 pmol/8 x 10(8) red blood cells). No difference in metabolite concentrations was observed between children in remission and those with active disease. Azathioprine dosage was significantly related to 6-TGN and 6-MeMPN levels (r = 0.308, P < 0.001 and r = 0.405, P < 0.001, respectively). A significant negative correlation was observed between 6-TGN concentrations and erythrocyte and lymphocyte counts, whereas 6-MeMPN was not related to blood cell counts. Although leukocyte counts were not related to 6-TGN concentrations, patients with leucopenia exhibited higher 6-TGN values than those without leucopenia (median values 438 pmol/8 x 10(8) RBCs versus 405 pmol/8 x 10(8) RBCs, respectively). Thiopurine metabolite monitoring appears useful in identifying the myelotoxicity and the hepatotoxicity as a result of azathioprine with disease recurrence and to assess adherence to therapy. A further larger study will be required to confirm the optimal recommended target for thiopurine metabolites to achieve remission in patients with AIH.
Nguyen
Thi-Mai-Hoang
TM
Université de Lyon, Département de Pharmacie Clinique, de Pharmacocinétique et d'Evaluation du Médicament, Lyon, France.
Daubard
Marina
M
Le Gall
Catherine
C
Larger
Magali
M
Lachaux
Alain
A
Boulieu
Roselyne
R
D000293:Adolescent; D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D001379:Azathioprine / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D001711:Biotransformation; D001772:Blood Cell Count; D002648:Child; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D016903:Drug Monitoring; D004359:Drug Therapy, Combination; D005260:Female; D019693:Hepatitis, Autoimmune / Q000097:blood* / Q000188:drug therapy*; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D008111:Liver Function Tests; D008297:Male; D015122:Mercaptopurine / Q000031:analogs & derivatives / Q000097:blood; D013866:Thioguanine / Q000097:blood
D000305:Adrenal Cortex Hormones; D000893:Anti-Inflammatory Agents; D007166:Immunosuppressive Agents; C010240:6-methylthiopurine; D015122:Mercaptopurine; D013866:Thioguanine; D001379:Azathioprine