Ma Yanjiao, Xue Ling, Chen Xin, Kang Yingbo, Wang Yong, Wang Liqing
Department of Pharmacy, Zhujiang Hospital of Southern Medical University, Guangzhou, 510282, Guangdong, China.
Department of Clinical Pharmacology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, Jiangsu, China.
Int J Clin Pharm. 2018 Oct;40(5):1010-1018. doi: 10.1007/s11096-018-0636-6. Epub 2018 May 18.
Background Theophylline has a narrow therapeutic range and large interindividual variability in blood levels, so a thorough understanding of its pharmacokinetic characteristics is essential. Population pharmacokinetic (PPK) approaches could achieve it and many PPK studies of theophylline have been reported in infants. However, none was conducted in Chinese adults and none has explored the effect of CYP1A2 genotypes on the PPK characteristics of theophylline in adults. Objective To evaluate the PPK characteristics of theophylline and to assess the possible influence of covariates, including CYP1A2 genotypes, on theophylline clearance in Chinese adult patients. Setting The study is conducted at the department of respiration in Zhujiang Hospital, Guangzhou, China. Methods Theophylline concentrations were obtained from eligible patients and were measured by high performance liquid chromatography. The polymorphisms of - 3860G > A, - 163C > A, C5347T (CYP1A21B) and G-3113A were genotyped using a direct sequencing method. Then, CYP1A2 genotypes, age, fat-free mass (FFM) and other covariates were used to develop a PPK model by NONMEM software. Bootstrap analysis was used to asses the accuracy and prediction of the PPK model. Main outcome measure The concentration and clearance of theophylline. Results A total of 134 theophylline concentrations from 95 patients were obtained. The final model was as follows: CL/F(L/h) = 4.530 × (FFM/56.1) × 0.713, the inter-individual variability in clearance/bioavailability (CL/F) was 44.0%, and the residual variability was 9.8%. The final model was proved to be reliable by bootstrap analysis. Conclusion Theophylline clearance was significantly associated with FFM and CYP1A21B genotypes in Chinese adult patients.
背景 氨茶碱治疗窗窄，血药浓度个体差异大，因此深入了解其药代动力学特征至关重要。群体药代动力学（PPK）方法可以实现这一点，并且已有许多关于婴儿氨茶碱的PPK研究报道。然而，尚未有针对中国成年人的此类研究，也没有人探讨CYP1A2基因多态性对成年人氨茶碱PPK特征的影响。目的 评估氨茶碱在中国成年患者中的PPK特征，并评估包括CYP1A2基因多态性在内的协变量对氨茶碱清除率的可能影响。地点 本研究在中国广州珠江医院呼吸科进行。方法 从符合条件的患者中获取氨茶碱浓度，并通过高效液相色谱法进行测定。采用直接测序法对-3860G＞A、-163C＞A、C5347T（CYP1A21B）和G-3113A的基因多态性进行基因分型。然后，使用NONMEM软件，将CYP1A2基因多态性、年龄、去脂体重（FFM）和其他协变量用于建立PPK模型。采用自抽样法分析评估PPK模型的准确性和预测能力。主要观察指标 氨茶碱的浓度和清除率。结果 共获得95例患者的134个氨茶碱浓度数据。最终模型如下：CL/F（L/h）=4.530×（FFM/56.1）×0.713，清除率/生物利用度（CL/F）的个体间变异为44.0%，残差变异为9.8%。自抽样法分析证明最终模型可靠。结论 在中国成年患者中，氨茶碱清除率与FFM和CYP1A21B基因多态性显著相关。
