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

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Abstract

Background and Objectives

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.

Methods

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.

Results

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.

Conclusions

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.

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Acknowledgements

The authors wish to thank Verisfield UK Ltd for providing the C‐t data to perform this computational analysis.

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Authors and Affiliations

  1. Laboratory of Biopharmaceutics, Pharmacokinetics, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, 15784, Athens, Greece

    Eleni Karatza & Vangelis Karalis

  2. Institute of Applied and Computational Mathematics (IACM)/Foundation of Research and Technology Hellas (FORTH), Heraklion, Crete, Greece

    Eleni Karatza & Vangelis Karalis

Authors
  1. Eleni Karatza
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  2. Vangelis Karalis
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Corresponding author

Correspondence to Vangelis Karalis.

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Funding

The authors have not received any funding for this study

Conflict of interest

All authors declare no conflict of interest and approved this submission

Availability of data and material

The concentration–time data of losartan and its metabolite are confidential and belong to Verisfield UK Ltd.

Code availability

The developed codes in Matlab® and R are available upon request.

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Karatza, E., Karalis, V. Investigating the Impact of Gastric Emptying on Pharmacokinetic Parameters Using Delay Differential Equations and Principal Component Analysis. Eur J Drug Metab Pharmacokinet 46, 451–458 (2021). https://doi.org/10.1007/s13318-021-00683-3

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  • DOI: https://doi.org/10.1007/s13318-021-00683-3

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