Naito Takafumi, Ohshiro Junya, Sato Hikaru, Torikai Eiji, Suzuki Motohiro, Ogawa Noriyoshi, Kawakami Junichi
Department of Hospital Pharmacy, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Department of Hospital Pharmacy, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Clin Biochem. 2019 Jul;69:8-14. doi: 10.1016/j.clinbiochem.2019.05.003. Epub 2019 May 8.
This study aimed to evaluate the relationships between concomitant biologic disease-modifying anti-rheumatic drugs (DMARDs) and prednisolone administration and blood tacrolimus exposure or serum CYP3A4/5-related markers in rheumatoid arthritis (RA) patients without severe disease activity.
Forty-six RA patients treated with oral tacrolimus once daily for maintenance of clinical remission to moderate disease activity were enrolled. The blood concentrations of tacrolimus and its major metabolite were determined at 12 h after the evening dosing. Blood samples for determination of serum markers including 4β-hydroxycholesterol (4β-OHC), 25-hydroxyvitamin D (25-OHD) and interleukin-6 (IL-6), and CYP3A5 genotype were collected.
Most enrolled patients had RA with clinical remission to mild disease activity. Concomitant tocilizumab or low-dose prednisolone administration did not alter the blood tacrolimus exposure. Serum 4β-OHC level was lower in tocilizumab co-treated patients than in the biologic DMARD non-treated patients. The blood tacrolimus concentration was inversely correlated with the serum level of 25-OHD, but not 4β-OHC and IL-6. The serum level of 4β-OHC was positively associated with that of 25-OHD. No correlations were observed between the serum levels of CYP3A4/5 activity markers and IL-6. The patients with the homozygous CYP3A53 had the higher blood tacrolimus concentration, while CYP3A53 allele was not associated with the serum levels of 4β-OHC and 25-OHD.
Concomitant use of tocilizumab or low-dose prednisolone had no effect on the pharmacokinetics of tacrolimus, while tocilizumab lowered serum 4β-OHC. Blood tacrolimus exposure was negatively associated with serum 25-OHD in RA patients with clinical remission to moderate disease activity.
本研究旨在评估在无严重疾病活动的类风湿关节炎（RA）患者中，联合使用生物性改善病情抗风湿药（DMARDs）和泼尼松龙与血液中他克莫司暴露量或血清CYP3A4/5相关标志物之间的关系。
纳入46例接受每日一次口服他克莫司治疗以维持临床缓解至中度疾病活动的RA患者。在晚上给药后12小时测定他克莫司及其主要代谢物的血药浓度。采集用于测定血清标志物（包括4β-羟基胆固醇（4β-OHC）、25-羟基维生素D（25-OHD）和白细胞介素-6（IL-6））以及CYP3A5基因型的血样。
大多数纳入患者的RA处于临床缓解至轻度疾病活动状态。联合使用托珠单抗或低剂量泼尼松龙并未改变血液中他克莫司的暴露量。托珠单抗联合治疗患者的血清4β-OHC水平低于未接受生物性DMARD治疗的患者。血液中他克莫司浓度与25-OHD血清水平呈负相关，但与4β-OHC和IL-6无关。4β-OHC血清水平与25-OHD血清水平呈正相关。未观察到CYP3A4/5活性标志物血清水平与IL-6之间存在相关性。携带纯合CYP3A53的患者血液中他克莫司浓度较高，而CYP3A53等位基因与4β-OHC和25-OHD血清水平无关。
联合使用托珠单抗或低剂量泼尼松龙对他克莫司的药代动力学无影响，而托珠单抗可降低血清4β-OHC。在临床缓解至中度疾病活动的RA患者中，血液中他克莫司暴露量与血清25-OHD呈负相关。
