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Assessment of the predictive capability of modelling and simulation to determine bioequivalence of inhaled drugs: A systematic review

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Abstract

Objectives

There are a multitude of different modelling techniques that have been used for inhaled drugs. The main objective of this review was to conduct an exhaustive survey of published mathematical models in the area of asthma and chronic obstructive pulmonary disease (COPD) for inhalation drugs. Additionally, this review will attempt to assess the applicability of these models to assess bioequivalence (BE) of orally inhaled products (OIPs).

Evidence acquisition

PubMed, Science Direct, Web of Science, and Scopus databases were searched from 1996 to 2020, to find studies that described mathematical models used for inhaled drugs in asthma/COPD.

Results

50 articles were finally included in this systematic review. This research identified 22 articles on in silico aerosol deposition models, 20 articles related to population pharmacokinetics and 8 articles on physiologically based pharmacokinetic modelling (PBPK) modelling for inhaled drugs in asthma/COPD. Among all the aerosol deposition models, computational fluid dynamics (CFD) simulations are more likely to predict regional aerosol deposition pattern in human respiratory tracts. Across the population PK articles, body weight, gender, age and smoking status were the most common covariates that were found to be significant. Further, limited published PBPK models reported approximately 29 parameters relevant for absorption and distribution of inhaled drugs. The strengths and weaknesses of each modelling technique has also been reviewed.

Conclusion

Overall, while there are different modelling techniques that have been used for inhaled drugs in asthma and COPD, there is very limited application of these models for assessment of bioequivalence of OIPs. This review also provides a ready reference of various parameters that have been considered in various models which will aid in evaluation if one model or hybrid in silico models need to be considered when assessing bioequivalence of OIPs.

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Data availability

All data generated or analyzed during this study are included in this published article.

Abbreviations

ACI:

Andersen Cascade Impactor

BE:

Bioequivalence

CFD:

Computational fluid dyanamics

COPD:

Chronic Obstructive Pulmonary Disease

IVIVC/E:

In vitro in vivo Correlation/extrapolation

IP:

Induction port

NGI:

New generation impactor

OFV:

Objective function value

PBPK:

Physiologically based pharmacokinetics

PD:

Pharmacodynamics

PK:

Pharmacokinetics

VPC:

Visual predictive checks

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Acknowledgements

The authors humbly thank Megha Kale (Librarian, Cipla Ltd) for immense support in referencing literature.

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  1. Clinical Research Division, Cipla Ltd, Mumbai, Maharashtra, India

    Juliet Rebello & Bill Brashier

  2. Symbiosis Statistical Institute (SSI), Symbiosis International University, Pune, Maharashtra, India

    Sharvari Shukla

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Juliet Rebello was responsible for the conducting searches as per the search strategy, collecting the data and summarizing it. Dr. Sharvari Shukla reviewed the information. Dr. Bill Brashier helped improve the clarity of the manuscript in presentation and reviewed the technical content. He was employed at Cipla Ltd at the time of submission of this manuscript.

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Rebello, J., Brashier, B. & Shukla, S. Assessment of the predictive capability of modelling and simulation to determine bioequivalence of inhaled drugs: A systematic review. DARU J Pharm Sci 30, 229–243 (2022). https://doi.org/10.1007/s40199-021-00423-7

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