Laboratory of Biopharmaceutics, Pharmacokinetics, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, 15784, Athens, Greece.
Institute of Applied and Computational Mathematics (IACM)/Foundation of Research and Technology Hellas (FORTH), Heraklion, Crete, Greece.
Eur J Drug Metab Pharmacokinet. 2021 May;46(3):451-458. doi: 10.1007/s13318-021-00683-3.
Losartan presents multiple peaks after single oral administration, which can be attributed to gastric emptying. The aim of this study was to describe the multiple peak phenomenon of losartan using a delay differential model and a model with sine function. The impact of gastric emptying on pharmacokinetic parameters was investigated by applying principal component analysis to the individual parameter estimates.
Using Monolix, two population pharmacokinetic models were developed to describe the multiple peak phenomenon; the first using delay differential equations and the second using a sine function. Matlab delay differential equation solver was used to arithmetically solve both functions. Principal component analysis and all statistical analyses were performed in the R language.
The description of losartan multiple peaks can be achieved by the use of either delay differential equations or typical sine wave functions. Principal component analysis unveiled the impact of gastric emptying on the pharmacokinetic parameters. In the case of the delay differential equation model, a negative relationship was found between the constant delay tau1 and the parameters reflecting rate and extent of absorption (i.e., area under the curve [AUC], peak plasma concentration [C], and the absorption rate constant). Similar results were obtained from the sine model, where a higher amplitude and lower period (i.e., higher frequency) of gastric emptying were associated with higher AUC and C values.
The observed multiple peaks for certain drugs like losartan can be attributed to gastric emptying. Parameters describing gastric emptying can be associated with pharmacokinetic metrics like AUC and C.
氯沙坦经单次口服后呈现多重峰，这归因于胃排空。本研究旨在使用延迟微分模型和正弦函数模型来描述氯沙坦的多重峰现象。通过对个体参数估计进行主成分分析，研究了胃排空对药代动力学参数的影响。
使用 Monolix，建立了两个群体药代动力学模型来描述氯沙坦的多重峰现象；第一个模型使用延迟微分方程，第二个模型使用正弦函数。使用 Matlab 延迟微分方程求解器对这两个函数进行了数值求解。主成分分析和所有统计分析均在 R 语言中进行。
可以使用延迟微分方程或典型的正弦波函数来描述氯沙坦的多重峰。主成分分析揭示了胃排空对药代动力学参数的影响。在延迟微分方程模型中，发现常数延迟 tau1 与反映吸收速率和程度的参数（即曲线下面积 [AUC]、血浆峰浓度 [C] 和吸收速率常数）呈负相关。在正弦模型中也得到了类似的结果，其中胃排空的更高振幅和更低周期（即更高频率）与更高的 AUC 和 C 值相关。
某些药物（如氯沙坦）出现的多重峰可以归因于胃排空。描述胃排空的参数可以与 AUC 和 C 等药代动力学指标相关联。
