Investigating the Impact of Gastric Emptying on Pharmacokinetic Parameters Using Delay Differential Equations and Principal Component Analysis.

Abstract

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 MonolixTM, 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 [Cmax], 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 Cmax 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 Cmax.