Original ArticleMonitoring of Azathioprine Metabolites in Pediatric Patients With Autoimmune HepatitisNguyen, Thi-Mai-Hoang PharmD*; Daubard, Marina PharmD*; Le Gall, Catherine MD†; Larger, Magali PhD*‡; Lachaux, Alain PhD†; Boulieu, Roselyne PhD*‡Author Information From the *Université de Lyon, Département de Pharmacie Clinique, de Pharmacocinétique et d'Évaluation du Médicament, Lyon, France; †Hospices Civils de Lyon, Hôpital Femme Mère Enfant, Service de Pédiatrie, Bron, France; and ‡Hospices Civils de Lyon, Hôpital Cardio-vasculaire et Pneumologique Louis Pradel, Laboratoire de Pharmacocinétique Clinique, Université de Lyon, Lyon, France. Received for publication August 28, 2009; accepted March 3, 2010. Correspondence: Roselyne Boulieu, PhD, Université Lyon 1-ISPB, Département de Pharmacie Clinique, de Pharmacocinétique et d'Evaluation du Médicament, 8 avenue Rockefeller, 69373 Lyon Cedex 08, France (e-mail: [email protected]). Therapeutic Drug Monitoring: August 2010 - Volume 32 - Issue 4 - p 433-437 doi: 10.1097/FTD.0b013e3181dbd712 Buy Metrics Abstract 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 × 108 red blood cells (RBCs) for 6-TGN and from 42 to 8189 pmol/8 × 108 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 × 108 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 × 108 RBCs versus 405 pmol/8 × 108 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. © 2010 Lippincott Williams & Wilkins, Inc.