摘要
目的在淋巴瘤化疗患者中建立大剂量甲氨蝶呤(MTX)的群体药动学模型,评价病生理和临床因素对药物分布和消除的影响,并利用Bayesian方法预测药物浓度达到目标值(0.2μmol·L-1)所需要的时间。方法82名恶性淋巴瘤病人接受了大剂量甲氨蝶呤化疗并入组。利用NONMEM法建立药动学模型。考察病生理因素、临床合用药对药动学行为的影响。利用交错确认法和自举法对模型进行验证。结果大剂量甲氨蝶呤化疗符合二室模型分布特征。药动学参数及其个体间变异如下:清除率CL7.45L·h-1(个体间变异51.4%),中心室表观分布容积V125.9L(22.4%),外周室分布容积V29.23L(42.3%),室间转运系数Q0.333L·h-1(70.7%)。血清肌苷浓度对清除率、体重对表观分布容积表现出明显的影响。Bayesian方法能够预测给药后44h药物浓度及达到安全阈值(0.2μmol·L-1)所需要的时间。结论血清肌苷和体重分别对甲氨蝶呤体内清除率和表观分布容积有影响。利用Bayesian估计和44h药物浓度可以预测个体的药动学参数和达到0.2μmol·L-1所需要的时间。
OBJECTIVE To develop a population pharmacokinetic model of high dose methotrexate （HD-MTX） infusion in patients with lymphoid malignancy, to investigate the biological and clinical covariates related to the drug distribution and elimination, and to propose a limited sampling strategy（LSS） for the estimation of the time above the threshold （0.2μmol·L-1）. METHODS A total 82 patients with lymphoid malignancy receiving high dose methotrexate treatment were involved in the study. A pharmacokinetic model was developed using nonlinear mixed-effect model. The influence of demographic characteristics, biological factors, and concurrent administration were investigated. The final predictive performance was validated by bootstrap and cross-validation. Bayesian estimation was evaluated. RESULTS The pharmacokinetics of high dose methotrexate were described by a two-compartment model. The pharmacokinetic parameters and the inter-individual variability were as follows： the clearance CL 7.45 L·h-1 （inter-individual variability 51.4%）, the volume of the central and peripheral compartment V1 25.9 L （22.4%）, F2 9.23 L （42.3%）, respectively, and the transfer constant Q 0.333 L·h-1 （70.7%）. The influence of serum creatinine on CL and weight on V1 was remained in the final model. The protocol involved one sampling time, 44 h after the beginning of the infusion, allowed to predict the time at which the methotrexate concentration reached the expected threshold （0.2 μmol·L-1）. CONCLUSION Serum creatinine and weight showed significant influence on methotrexate CL and V1, respectively. Furthermore, a Bayesian estimation based the covariates and 44 h sample was developed, allowing predict the individual methotrexate pharmacokinetic parameters and the time to 0.2 μmol·L-1.
出处
《中国药学杂志》
CAS
CSCD
北大核心
2009年第5期367-372,共6页
Chinese Pharmaceutical Journal
