Multi‐phase multi‐layer mechanistic dermal absorption (MPML MechDermA) model to predict local and systemic exposure of drug products applied on skin

Patel, Nirmal; Clarke, James F.; Salem, Farzaneh; Abdulla, Tariq; Martins, Frederico Severino; Arora, Sumit; Tsakalozou, Eleftheria; Hodgkinson, Arran B. J.; Arjmandi‐Tash, Omid; Cristea, Sinziana; Ghosh, Priyanka; Alam, Khondoker; Raney, Sam G.; Jamei, Masoud; Polak, Sebastian

doi:10.1002/psp4.12814

Cited by 17 publications

(16 citation statements)

References 93 publications

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“…The Multi-Phase Multi-Layer Mechanistic Dermal Absorption (MPML-MechDermA) model implemented in the Simcyp Simulator (Version 20, Release 1; Certara UK Limited) was used to simulate the metronidazole permeation across and within different skin layers following topical application of various drug products. , …”

Section: Methodsmentioning

confidence: 99%

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Mechanistic Modeling of In Vitro Skin Permeation and Extrapolation to In Vivo for Topically Applied Metronidazole Drug Products Using a Physiologically Based Pharmacokinetic Model

et al. 2022

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Physiologically based pharmacokinetic (PBPK) modeling has increasingly been employed in dermal drug development and regulatory assessment, providing a framework to integrate relevant information including drug and drug product attributes, skin physiology parameters, and population variability. The current study aimed to develop a stepwise modeling workflow with knowledge gained from modeling in vitro skin permeation testing (IVPT) to describe in vivo exposure of metronidazole locally in the stratum corneum following topical application of complex semisolid drug products. The initial PBPK model of metronidazole in vitro skin permeation was developed using infinite and finite dose aqueous metronidazole solution. Parameters such as stratum corneum lipid–water partition coefficient (Ksclip/water) and stratum corneum lipid diffusion coefficient (D sclip) of metronidazole were optimized using IVPT data from simple aqueous solutions (infinite) and MetroGel (10 mg/cm2 dose application), respectively. The optimized model, when parameterized with physical and structural characteristics of the drug products, was able to accurately predict the mean cumulative amount permeated (cm2/h) and flux (μg/cm2/h) profiles of metronidazole following application of different doses of MetroGel and MetroCream. Thus, the model was able to capture the impact of differences in drug product microstructure and metamorphosis of the dosage form on in vitro metronidazole permeation. The PBPK model informed by IVPT study data was able to predict the metronidazole amount in the stratum corneum as reported in clinical studies. In summary, the proposed model provides an enhanced understanding of the potential impact of drug product attributes in influencing in vitro skin permeation of metronidazole. Key kinetic parameters derived from modeling the metronidazole IVPT data improved the predictions of the developed PBPK model of in vivo local metronidazole concentrations in the stratum corneum. Overall, this work improves our confidence in the proposed workflow that accounts for drug product attributes and utilizes IVPT data toward improving predictions from advanced modeling and simulation tools.

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Section: Methodsmentioning

confidence: 99%

“…The model accounts for the microstructure of the stratum corneum and other skin layers by simulating diffusion and partitioning processes between different phases. More information on the structure and verification of the model can be found in a recently published article Patel et al …”

Section: Methodsmentioning

confidence: 99%

Mechanistic Modeling of In Vitro Skin Permeation and Extrapolation to In Vivo for Topically Applied Metronidazole Drug Products Using a Physiologically Based Pharmacokinetic Model

et al. 2022

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“…The premise for the presented database was to provide a detailed repository for the anatomical and physiological parameters of the porcine skin. The literature search encompassed 20 parameters that describe skin in the MPML MechDermA Model ( 21 ). Six of these were not included in the final data set, namely, corneocyte pH, lipid and sebum viscosity, density of lipids and proteins and tortuosity, due to a lack of quantitative data in the literature.…”

Section: Data Collectionmentioning

confidence: 99%

“…Physiologically based pharmacokinetic (PBPK) modelling accounts for physiology and geometry of the skin in a mechanistic modelling framework ( 21 ). One powerful feature of PBPK models is the ability to extrapolate between systems, such as from healthy individuals to a diseased population ( 22–24 ), adult to paediatric ( 25–27 ) or animal to human ( 28–30 ).…”

Section: Introductionmentioning

confidence: 99%

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An open-access data set of pig skin anatomy and physiology for modelling purposes

et al. 2022

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The use of animal as opposed to human skin for in vitro permeation testing (IVPT) is an alternative, which can reduce logistical and economic issues. However, this surrogate also has ethical considerations and may not provide an accurate estimation of dermal absorption in humans due to physiological differences. The current project aimed to provide a detailed repository for the anatomical and physiological parameters of porcine skin, with the aim of parametrizing the Multi-phase Multi-layer Mechanistic Dermal Absorption (MPML MechDermA) Model in the Simcyp Simulator. The MPML MechDermA Model is a physiologically based pharmacokinetic (PBPK) model that accounts for the physiology and geometry of skin in a mechanistic mathematical modelling framework. The database provided herein contains information on 14 parameters related to porcine skin anatomy and physiology, namely, skin surface pH, number of stratum corneum (SC) layers, SC thickness, corneocyte thickness, corneocyte dimensions (length and width), volume fraction of water in corneocyte (where SC is divided into four parts with different water contents), intercellular lipid thickness, viable epidermis thickness, dermis thickness, hair follicle and hair shaft diameter, hair follicle depth and hair follicle density. The collected parameters can be used to parameterize PBPK models, which could be further utilized to bridge the gap between animal and human studies with interspecies extrapolation or to predict dermatokinetic properties typically assessed in IVPT experiments. Database URL: https://data.mendeley.com/datasets/mwz9xv4cpd/1

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Physiologically‐based pharmacokinetic model of in vitro porcine ear skin permeation for drug delivery research

Krumpholz,

Polak,

Wiśniowska

2024

J of Applied Toxicology

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In silico techniques, such as physiologically based pharmacokinetic modeling (PBKP), are recently gaining importance. Computational methods in drug discovery and development and the generic drugs industry enhance research effectiveness by saving time and money and avoiding ethical issues. One key advantage is the ability to conduct toxicology studies without risking harm to living beings. This study aimed to repurpose the multi‐phase multi‐layer mechanistic dermal absorption (MPML MechDermA) PBPK model for simulation permeation through porcine ear skin under in vitro conditions. The work was divided into four steps: (1) the development of a pig ear skin model based on a previously collected dataset; (2) testing the model's ability to discriminate permeation between pig ear, human abdomen, and human back skin; (3) development of a caffeine permeation model; and (4) testing the caffeine model's performance against in vitro generated data sourced from the scientific literature. Data from 31 manuscripts were used for the development of the pig skin model. Based on these data, values specific to pig skin were found for 22 parameters of the MPML MechDermA model. The model was able to discriminate permeation between pig and human skin. A caffeine model was developed and used to simulate seven experiments identified in the literature. The model's performance was assessed by comparing simulated to observed results. Based on a visual check, all simulations were considered acceptable, whereas three out of seven experiments met the twofold difference criterion. The variability of the experimental data was considered the biggest challenge for reliable model assessment.

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Multi‐phase multi‐layer mechanistic dermal absorption (MPML MechDermA) model to predict local and systemic exposure of drug products applied on skin

Cited by 17 publications

References 93 publications

Mechanistic Modeling of In Vitro Skin Permeation and Extrapolation to In Vivo for Topically Applied Metronidazole Drug Products Using a Physiologically Based Pharmacokinetic Model

Mechanistic Modeling of In Vitro Skin Permeation and Extrapolation to In Vivo for Topically Applied Metronidazole Drug Products Using a Physiologically Based Pharmacokinetic Model

An open-access data set of pig skin anatomy and physiology for modelling purposes

Physiologically‐based pharmacokinetic model of in vitro porcine ear skin permeation for drug delivery research

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