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Variance based global sensitivity analysis of physiologically based pharmacokinetic absorption models for BCS I–IV drugs

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Abstract

Regulatory agencies have a strong interest in sensitivity analysis for the evaluation of physiologically-based pharmacokinetic (PBPK) models used in pharmaceutical research and drug development and regulatory submissions. One of the applications of PBPK is the prediction of fraction absorbed and bioavailability for drugs following oral administration. In this context, we performed a variance based global sensitivity analysis (GSA) on in-house PBPK models for drug absorption, with the aim of identifying key parameters that influence the predictions of the fraction absorbed and the bioavailability for neutral, acidic and basic compounds. This analysis was done for four different classes of drugs, defined according to the Biopharmaceutics Classification System, differentiating compounds by permeability and solubility. For class I compounds (highly permeable, highly soluble), the parameters that mainly influence the fraction absorbed are related to the formulation properties, for class II compounds (highly permeable, lowly soluble) to the dissolution process, for class III (lowly permeable, highly soluble) to both absorption process and formulation properties and for class IV (lowly permeable, lowly soluble) to both absorption and dissolution processes. Considering the bioavailability, the results are similar to those for the fraction absorbed, with the addition that parameters related to gut wall and liver clearance influence as well the predictions. This work aimed to give a demonstration of the GSA methodology and highlight its importance in improving our understanding of PBPK absorption models and in guiding the choice of parameters that can safely be assumed, estimated or require data generation to allow informed model prediction.

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Notes

  1. Let us consider the model Y = X1 · X2, with X1 distributed normally with mean equal to 1 and variance equal to 1 and X2 distributed normally with mean equal to 0 and variance equal to 1. The main effect of X1 is equal to 0, because X2 has mean 0. Thus, by limiting the analysis on the main effect, one may conclude that X1 has no impact on V(Y). Intuitively, this conclusion is wrong. In fact, X1 impact can be observed if X2 is allowed to vary from its mean value. Thus, X1 impact on V(Y) is due to interaction effect with X2.

  2. The codes used to perform the analysis are available at the following link: http://aimed11.unipv.it/JPKPDMelillo18/.

  3. Atenolol is a BCS class III drug with a mean in vivo Peff of 0.5 × 10−4 cm/s and a standard deviation of 0.2 × 10−4 cm/s [5, 34]. Supposing that Peff is distributed log-normally, the 95th percentile is equal to 0.47 and the 5th percentile is below the inferior limit in Table 1. So, for Atenolol the range of variability of Peff, from the lower limit in Table 1 to its 95th percentile, represents around 30% of the whole range of variation considered for class III drugs.

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Acknowledgements

This work is an in-kind contribution to the OrBiTo Project (http://www.imi.europa.eu/content/orbito).

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Authors and Affiliations

  1. Laboratory of Bioinformatics, Mathematical Modelling and Synthetic Biology, Department of Electrical, Computer and Biomedical Engineering, Università degli Studi di Pavia, Via Ferrata 5, 27100, Pavia, Italy

    Nicola Melillo & Paolo Magni

  2. Centre for Applied Pharmacokinetic Research, Division of Pharmacy & Optometry, The University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT, UK

    Nicola Melillo, Leon Aarons & Adam S. Darwich

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Melillo, N., Aarons, L., Magni, P. et al. Variance based global sensitivity analysis of physiologically based pharmacokinetic absorption models for BCS I–IV drugs. J Pharmacokinet Pharmacodyn 46, 27–42 (2019). https://doi.org/10.1007/s10928-018-9615-8

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