Jin Seok-Joon, Jung Jin Ah, Cho Sang-Heon, Kim Un-Jib, Choe Sangmin, Ghim Jong-Lyul, Noh Yook-Hwan, Park Hyun-Jung, Kim Jung-Chul, Jung Jin-A, Lim Hyeong-Seok, Bae Kyun-Seop
Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, University of Ulsan College of Medicine, Pungnap-2-dong, Seoul, Repubic of South Korea.
Int J Clin Pharmacol Ther. 2012 Aug;50(8):557-65. doi: 10.5414/CP201709.
To characterize the pharmacokinetics (PK) of letrozole by noncompartmental and mixed effect modeling analysis with the exploration of effect of body compositions on the PK.
The PK data of 52 normal healthy male subjects with intensive PK sampling from two separate studies were included in this analysis. Subjects were given a single oral administration of 2.5 mg letrozole (Femara®), an antiestrogenic aromatase inhibitor used to treat breast cancer. Letrozole concentrations were measured using validated high-performance liquid chromatography with tandem mass spectrometry. PK analysis was performed using NONMEM® 7.2 with first-order conditional estimation with interaction method. The association of body composition (body mass index, soft lean mass, fat free mass, body fat mass), CYP2A6 genotype (*1/*1, *1/*4), and CYP3A5 genotype (*1/*1, *1/*3, *3/*3) with the PK of letrozole were tested.
A two-compartment model with mixed first and zero order absorption and first order elimination best described the letrozole concentration-time profile. Body weight and body fat mass were significant covariates for central volume of distribution and peripheral volume of distribution (Vp), respectively. In another model built using more readily available body composition measures, body mass index was also a significant covariate of Vp. However, no significant association was shown between CYP2A6 and CYP3A5 genetic polymorphism and the PK of letrozole in this study.
Our results indicate that body weight, body fat mass, body mass index are associated with the volume of distribution of letrozole. This study provides an initial step toward the development of individualized letrozole therapy based on body composition.
通过非房室模型和混合效应模型分析来表征来曲唑的药代动力学（PK），并探究身体组成对PK的影响。
本分析纳入了来自两项独立研究的52名正常健康男性受试者的PK数据，这些受试者进行了密集的PK采样。受试者单次口服2.5mg来曲唑（芙瑞®），这是一种用于治疗乳腺癌的抗雌激素芳香化酶抑制剂。使用经过验证的高效液相色谱串联质谱法测量来曲唑浓度。使用NONMEM® 7.2采用带交互作用的一阶条件估计法进行PK分析。测试了身体组成（体重指数、瘦软组织质量、去脂体重、体脂肪量）、CYP2A6基因型（*1/*1、*1/*4）和CYP3A5基因型（*1/*1、*1/*3、*3/*3）与来曲唑PK的相关性。
具有混合一阶和零阶吸收以及一阶消除的二室模型最能描述来曲唑的浓度-时间曲线。体重和体脂肪量分别是中央分布容积和外周分布容积（Vp）的显著协变量。在另一个使用更容易获得的身体组成测量值建立的模型中，体重指数也是Vp的显著协变量。然而，在本研究中，未显示CYP2A6和CYP3A5基因多态性与来曲唑的PK之间存在显著相关性。
我们的结果表明，体重、体脂肪量、体重指数与来曲唑的分布容积相关。本研究为基于身体组成开发个体化来曲唑治疗迈出了第一步。
