FRI0246 GENOTYPING OF CYP3A5 IS USEFUL FOR TREATMENT WITH TACROLIMUS IN INTERSTITIAL LUNG DISEASE IN DERMATOMYOSITIS
Authors: M. Katayama, S. Horibata, S. Takahashi, M. Takahashi, S. Mukohara, N. Amano, K. Yoshida, S. Hatachi, K. Yorifuji, S. Kumagai
Journal: Annals of the Rheumatic Diseases (2020)

Background: Tacrolimus (TAC), an immunosuppressant, can be used in second-line maintenance therapy of interstitial lung disease (ILD) in patients with dermatomyositis (DM) [1]. In Japan, TAC is approved for DM-ILD and often used as induction therapy for severe cases, especially in patients with anti-MDA5-Ab (melanoma differentiation-associated gene 5 antibody) positive, in combination with glucocorticoids (GC) and intravenous cyclophosphamide (IVCY). Some studies reported the clinical efficacy of initial high-trough level TAC for DM-ILD in combination with GC and IVCY [2]. Adjustment to target concentration of TAC in early stage of treatment is important for controlling disease activity. The concentration of TAC depends on genetic polymorphisms in cytochrome P450 (CYP) 3A5 enzyme expression and several reports showed that the bioavailability and concentration of TAC in patients with a CYP3A5 *1 allele (*1) was lower than those with a CYP3A5 *3/*3 (*3/*3) [3]. Objectives: To examine the usefulness of CYP3A5 polymorphisms in decision of initial dose to achieve the target concentration of TAC and to evaluate the clinical efficacy in patients of DM-ILD who achieved the enough concentration of TAC in early stage of treatment. Methods: We investigated CYP3A5 polymorphisms and TAC concentration in 9 patients of DM-ILD without renal dysfunction (eGFR&gt;60). TAC was taken after both morning and evening meals and blood samples were taken 12h after TAC administration. The blood concentration of TAC normalized to the corresponding dose per body weight (C/D, ng/ml per mg/kg) was analyzed according to genetic variation in CYP3A5. Based on the retrospective analyzation, we chose proper dose of TAC in initial treatment for an anti-MDA5-Ab positive DM-ILD patient, whose genotype was *3/*3. Results: The C/D value in the *3/*3 group (n=6) was 154.6±25.6, which was significantly higher than that in the *1 group (n=3;79.0±2.8; P =0.028). When the target concentration was set at 5-10 ng/ml, the required dose was (0.0316 to 0.0633) mg/kg in the *1 group and (0.0162 to 0.0324) mg/kg in the *3/*3 group. The *1 group needs more dose than that of the *3/*3 group to achieve the same target trough of TAC, suggesting that the examination of CYP3A5 genotype is useful for deciding initial dose of TAC (Fig.1). We started TAC 6mg/day with setting target concentration at 15-20 ng/ml to a *3/*3 patient of DM-ILD with anti-MDA5-Ab positive, resulting in good clinical course with making rapid attainment of target concentration in early stage of treatment (Fig.2). Conclusion: To examine the CYP3A5 genotype is valuable for deciding the initial dose of TAC, especially in patients who need achievement to target concentration rapidly. References: [1]Oddis CV and Aggarwal R. Nat Rev Rheumatol 2018;14(5):279-89. [2]Suzuka T et al. Int J Rheum dis 2019;22: 303-13. [3]Y. Muraki et al. Exp Ther Med 2018;15:532-38. Acknowledgments: none Disclosure of Interests: motoko katayama: None declared, Shinji Horibata: None declared, Soshi Takahashi: None declared, Miho Takahashi: None declared, Saki Mukohara: None declared, Norihiko Amano: None declared, Katsuyuki Yoshida: None declared, Saori Hatachi: None declared, Kennosuke Yorifuji: None declared, Shunichi Kumagai Grant/research support from: Astellas, Chugai, Mitsubishi Tanabe Co.Ltds, Consultant of: Sysmex Co.Ltd, Speakers bureau: many companies