DeVane C L, Grasela T H, Antal E J, Miller R L
Department of Pharmacy Practice, University of Florida, Gainesville.
Clin Pharmacol Ther. 1993 May;53(5):521-8. doi: 10.1038/clpt.1993.65.
The feasibility of incorporating blood sampling for population pharmacokinetic analysis into postmarketing surveillance was evaluated. Demographic and drug disposition data, consisting of two blood samples collected at a random time during two different dose intervals, was prospectively collected for 94 psychiatric inpatients (mean age, 48 +/- 13 years) receiving alprazolam. Mixed-effect modeling was used to estimate population pharmacokinetic parameters. The mean alprazolam clearance, volume of distribution, and absorption rate constant were 0.05 L/hr/kg, 0.7 L/kg, and 1.1 hr-1, respectively. Clearance was increased by 59% in women, decreased by 26% in patients with multiple organ disease, and decreased by 23% in patients older than 60 years of age. These estimates are similar to those determined from rigorous premarketing clinical trials. Interindividual variability in alprazolam clearance was relatively small (40%) after adjustment for significant patient covariates. Population pharmacokinetic analysis represents a reasonable approach to assessment of pharmacokinetic variability in a large, heterogenous patient population.
评估了将用于群体药代动力学分析的血样采集纳入上市后监测的可行性。前瞻性收集了94名接受阿普唑仑治疗的精神科住院患者（平均年龄48±13岁）的人口统计学和药物处置数据，这些数据包括在两个不同剂量间隔的随机时间采集的两份血样。采用混合效应模型来估计群体药代动力学参数。阿普唑仑的平均清除率、分布容积和吸收速率常数分别为0.05L/（小时·千克）、0.7L/千克和1.1小时⁻¹。清除率在女性中升高59%，在多器官疾病患者中降低26%，在60岁以上患者中降低23%。这些估计值与严格的上市前临床试验确定的值相似。在对显著的患者协变量进行调整后，阿普唑仑清除率的个体间变异性相对较小（40%）。群体药代动力学分析是评估大型异质性患者群体中药代动力学变异性的一种合理方法。
