Population pharmacokinetic meta-analysis method was used in order to obtain the pharmacokinetic characteristics of risperidone and its active metabolite. Eighteen studies were selected from published papers from 1995 to 2011. A model consisted of two compartments for parent drug and one compartment for its active metabolite combined with a flexible absorption process was developed based on the meta-dataset. The population-predicted apparent clearance for risperidone and 9-hydroxyrisperidone, the active metabolite was 7.66 L/h and 7.38 L/h, and the apparent volume of distribution in the central compartment was 70.6 L and 117 L, respectively. The final model was evaluated by visual predictive check（VPC） based on 1000 times model simulation. This model was adequately used to predict clinical therapeutic drug monitoring（TDM） data from 42 Chinese inpatients. Bias（mean prediction errors, MPE） and precision（root mean squared prediction errors, RMSE） were calculated to statistically analysis the population prediction error. It was demonstrated that the model developed from the meta-dataset was reliable and can be used to facilitate the individualized treatment for a target population.
The epidermal growth factor receptor（EGFR）—tyrosine kinase inhibitors（TKIs） monotherapies have limited efficacy in the treatment of EGFR mutation-negative non-small cell lung cancers（NSCLCs）. In the present study, we aimed to investigate the combined effect of erlotinib（ER） and cabozantinib（CAB） on NSCLC cell lines harboring wild-type EGFR and to optimize the dosage regimens using pharmacodynamic（PD） modeling and simulation. Therefore, we examined the combined effect of ER and CAB on cell viability, cloning, apoptosis induction, migration and growth dynamics in H1299 and A549 cells. PD modeling and simulation were also performed to quantitatively describe the H1299 cells growth dynamics and to optimize the dosage regimens as well. Our results showed that CAB effectively enhanced the sensitivity of both cell lines to ER. The PD models fitted the data well, and some important parameters were obtained. The exponential（λ_0） and linear（λ_1） growth rates of H1299 cells were 0.0241 h^（–1） and 360 cells？h^（–1）, respectively. The Emax of ER and CAB was 0.0091 h^（–1） and 0.0085 h^（–1）, and the EC50 was 0.812 μM and 1.16 μM, respectively. The synergistic effect observed in the experiments was further confirmed by the estimated combination index φ（1.37）,（95% confidence interval： 1.24–1.50）, obtained from PD modeling. Furthermore, the dosage regimens were optimized using simulations. In summary, both the experimental and modeling results demonstrated the synergistic interaction between ER and CAB in NSCLCs without EGFR mutations. Sequential combinations of ER and CAB provided an option for the therapy of the NSCLCs with wild-type EGFR, which would provide some references for preclinical study and translational research as well.
目的研制开发成年病人的万古霉素治疗药物监测软件,帮助临床进行万古霉素个体化用药。方法系统地检索PubMed数据库中发表于2012年9月前的文献,提取成年病人万古霉素群体药动学模型并结合笔者建立的模型构建万古霉素治疗药物监测模型集。根据建立的群体药动学模型和Bayesian原理,在Microsoft Visual Studio 2005集成开发环境中采用C++语言研发治疗药物监测软件。结果构建的治疗药物监测模型集包含14个群体药动学模型。基于模型开发的软件可根据病人信息的多寡分别进行群体、亚群体和个体预测,为临床万古霉素个体化给药提供帮助。结论本实验研发的软件涵盖了当前报道的万古霉素药动学模型,医生可以根据病人的实际情况选择适当的模型,具有较广的适用性。
