Bosentan, an endothelin receptor antagonist, has been widely used as a first-line medication for the treatment of pulmonary arterial hypertension (PAH). However, liver dysfunction is a major side effect of bosentan treatment that could hamper the optimal management of patients with PAH. Previously, we demonstrated, using drug metabolism enzymes and transporters (DMET) analysis, that the carbohydrate sulfotransferase 3 (CHST3) and CHST13 alleles are significantly more frequent in patients with elevated amino-transferases during therapy with bosentan than they are in patients without liver toxicity. In addition, we constructed a pharmacogenomics model to predict bosentan-induced liver injury in patients with PAH using two single nucleotide polymorphisms (SNPs) and two non-genetic factors. The purpose of the present study was to externally validate the predictive model of bosentan-induced liver toxicity in Japanese patients. We evaluated five cases of patients treated with bosentan, and one presented with liver dysfunction. We applied mutation alleles of CHST3 and CHST13, serum creatinine, and age to our model to predict liver dysfunction. The sensitivity and specificity were calculated as 100% and 50%, respectively. Considering that PAH is a rare disease, multicenter collaboration would be necessary to validate our model.
Background:Though several studies showed the efficacy of tacrolimus (TAC) in patients with rheumatoid arthritis (RA) in a dose-depending manner [1], the relationship between efficacy and concentration of TAC remained unclear. Genetic polymorphisms of cytochrome P450 (CYP) 3A5 were reported not only to play an important role in pharmacokinetics of TAC but also to have an influence on clinical outcomes in patients of rheumatic diseases. Several reports showed that the blood concentration of TAC in patients with a CYP3A5 *1 allele (EX, expressor) was lower than that of patients with a CYP3A5 *3/*3 (NEX, non-expressor) [2].Objectives:To assess the relationship between efficacy and concentration of TAC in patients with RA, and to examine the usefulness of CYP3A5 genotype screening to detect outpatients suitable for TAC treatment.Methods:We examined the relationship between disease activity score (DAS) 28-CRP and concentration of TAC in patients with RA. TAC was taken after the evening meal and blood samples were taken 12±4h after TAC administration. Next we investigated the relationship between genotype frequencies of CYP3A5 and concentration of TAC in patients with rheumatic disease without having renal dysfunction (eGFR<60) and also investigated the influence of concomitant drugs, such as strong inhibitors of CYP3A4/5 or metabolized by CYP3A4/5, to C/D value in each NEX and EX group. 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. Furthermore we investigated the relationship between genotype frequencies of CYP3A5 and concentration of TAC in patients with rheumatic disease at first visit and second visit after starting TAC administration to assess the possibility for making rapid attainment of enough concentrations of TAC in early stage of treatment.Results:The concentration of TAC tended to be negatively correlated with the disease activity of RA. The C/D value in the NEX group (n=16) was 124.7±62.1, which was significantly higher than that in the EX group (n=23; 67.7±29.8;P<0.001). When comparing patients using concomitant drugs which are strong inhibitors of CYP3A4/5 or metabolized by CYP3A4/5 with patients not using those drugs, the each C/D value of NEX group was 122.9±52.3 (n=9) and 126.9±77.3 (n=7), and that of EX group was 71.3±32.2 (n=12) and 63.8±28.0 (n=11). There were no significant differences between these groups. In NEX group, when comparing concentration of TAC at first visit and second visit after starting TAC administration, the each concentration of TAC was 3.14±2.06 ng/ml and 3.80±2.20 ng/ml in NEX group (n=10), and that of TAC was 1.82±0.82 ng/ml and 2.69±1.52 ng/ml (n=11) in EX group (Figure).Conclusion:TAC showed efficacy in patients with RA in a concentration-dependent manner. EX patients may be impossible to achieve enough concentration of TAC even though using TAC of 3mg/day, approved dose for patients with RA in Japan, and NEX patients could make rapid attainment of enough concentrations of TAC in early stage of treatment, suggesting that we should consider induction of TAC only in NEX outpatients. Furthermore, drugs only slightly affected concentration of TAC in this study, suggesting that we can use TAC without any special attention to concomitant drugs.References:[1]Furst DE et al. Arthritis Rheum 2002;46:2020-28.[2]Y. Muraki et al. Exp Ther Med 2018;15:532-38.Acknowledgments:noneDisclosure of Interests:Soshi Takahashi: None declared, Shinji Horibata: None declared, Saori Hatachi: None declared, Miho Takahashi: None declared, Motoko Katayama: None declared, Saki Mukohara: None declared, Norihiko Amano: None declared, Katsuyuki Yoshida: 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
Background:Tacrolimus (TAC), an immunosuppressant, can be used in second-line maintenance therapy for interstitial lung disease (ILD) in patients with dermatomyositis (DM) [1]. Although some studies reported the clinical efficacy of initial high-trough levels of TAC in combination with GC and IVCY in induction therapy for severe DM-ILD [2], there have been no useful clinical tools for deciding suitable initial dose of TAC. Genotype of polymorphisms in cytochrome P450 (CYP) 3A5 enzyme was reported to play an important role in pharmacokinetics of TAC [3], and we made a formula for deciding initial dose of TAC according to CYP3A5 genotypes in our previous study.Objectives:In our previous study (retrospective study), we set the target trough according to the severity for nine DM-ILD patients, six of whom were CYP3A5 *3/*3 and investigated the dose of TAC that could attain the trough using their CYP3A5 genootyping. Using these results, we developed a formula for deciding initial daily dose of TAC (target trough*weight / [(151.1, if CYP3A5 *3/*3) or (86.5, if CYP3A5 *1 allele)]). In this study, we prospectively examined the usefulness and accuracy of this formula.Methods:We introduced TAC for new six DM-ILD patients who visited our hospital between November 2019 and May 2020 (prospective study). The starting dose of TAC was decided by using the formula. We assessed the association between predicted and observed trough concentration of TAC at first measurement date (from day 2 to day4), using linear regression analysis. We also assessed the days for attaining the target trough concentration between the patients using the formula (prospective group) and six patients with CYP3A5 *3/*3 (retrospective group).Results:CYP3A5 genotype of all six DM-ILD patients were *3/*3 and underwent the TAC treatment by using the formula. The predicted and observed trough concentration of first measurement date were significantly correlated in the patients (r 2= 0.897, p=0.0041) (Fig.1). Compared with our retrospective study, target trough was more quickly attained in patients of the prospective study (Fig.2).Conclusion:The formula which we made for attainment target trough concentration based on CYP3A5 genotype was useful for deciding the starting dose of TAC. We also showed that we could attain the target trough concentration at early stage of initial treatment by using the formula.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.Figure 1.Correlation of predicted and observed tacrolimus trough concentration at first measurement in the prospective studyFigure 2.Days to attain the target trough concentration of tacrolimus in the prospective group and the retrospective groupDisclosure of Interests:None declared
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