Therapeutic drug monitoring of azathioprine in myositis

Mme Dorra JARRAYAa, Dr. Patrick HINDLETb, Dr. Aude RIGOLETc, Pr. Olivier BENVENISTEc, Pr. Christian FUNCK-BRENTANOa, Pr. Christine FERNANDEZb, Pr. Serge HERSONc, Dr. Noël ZAHRa

a Service de Pharmacologie - Groupe Hospitalier Pitié Salpêtrière-Charles Foix, b Service de Pharmacie - Groupe Hospitalier Pitié Salpêtrière-Charles Foix, c Service de médecine interne I - Groupe Hospitalier Pitié Salpêtrière-Charles Foix

Introduction: Azathioprine is an immunosuppressive drug prescribed in second line treatment for myositis. Because of its pharmacokinetic inter individual variability and its haematopoietic and liver toxicity, therapeutic drug monitoring is important. Interindividual differences in therapeutic efficiency might be explained by the polymorphism of thiopurine S-methyltransferase (TPMT), the enzyme involved in the metabolism of azathioprine.

Objective: The aim of our work was to study the  relation between azathioprine blood level, patient TPMT genotype and tolerance.

Patients, materials and methods: 6 thioguanine (6TG) and 6 methylmercaptopurine (6MMP) were quantified in erythrocytes from patients treated with azathioprine and corticoids for myositis. Both metabolites were quantified using reversed-phase high-performance chromatography (HPLC) with UV detection at two different wavelengths: 303 nm and 342 nm. Biological parameters (liver enzymes and blood count) were used for hemato and hepatotoxicity assessment. Patients were genotyped for TPMT*3A, TPMT*3B, TPMT*3C and TPMT*2 wich are the most frequently reported genetic variants.

Results: Five patients (4 female and 1 male) with myositis and long term antimetabolite therapy were included in the study. Blood sampling was performed between 4 months and 4 years after treatment initiation. Patients (aged from 36 to 78 years, mean 59 ± 12.5) were treated with 75mg to 150 mg by oral route. Double TPMT variants were detected in one subject (TPMT*3C et B). Mean trough metabolite concentrations in erythrocytes ranged from 131 to 365 (mean 241) pmol/3.108RBC and from 63 to 5623 (mean 3211) pmol/3.108RBC for 6TG and 6MMP respectively. Moreover, the full blood count and the hepatic function tests were within normal ranges.

Discussion and conclusion: These preliminary results show no haematopoietic and liver toxicity in our patients. In addition, no major toxicity was detected in patient with the double TPMT variations. However, 6TG concentrations are interpreted with therapeutic range used in IBD. Therefore, future studies will be set up in order to establish a therapeutic range for azathioprine metabolites in the treatment of myositis.


Keywords : Therapeutic drug monitoring, Azathioprine, Myositis