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Pharmaceutical Research

, Volume 33, Issue 7, pp 1602–1614 | Cite as

In Silico Modelling of Transdermal and Systemic Kinetics of Topically Applied Solutes: Model Development and Initial Validation for Transdermal Nicotine

  • Tao Chen
  • Guoping Lian
  • Panayiotis Kattou
Research Paper

Abstract

Purpose

The purpose was to develop a mechanistic mathematical model for predicting the pharmacokinetics of topically applied solutes penetrating through the skin and into the blood circulation. The model could be used to support the design of transdermal drug delivery systems and skin care products, and risk assessment of occupational or consumer exposure.

Methods

A recently reported skin penetration model [Pharm Res 32 (2015) 1779] was integrated with the kinetic equations for dermis-to-capillary transport and systemic circulation. All model parameters were determined separately from the molecular, microscopic and physiological bases, without fitting to the in vivo data to be predicted. Published clinical studies of nicotine were used for model demonstration.

Results

The predicted plasma kinetics is in good agreement with observed clinical data. The simulated two-dimensional concentration profile in the stratum corneum vividly illustrates the local sub-cellular disposition kinetics, including tortuous lipid pathway for diffusion and the “reservoir” effect of the corneocytes.

Conclusions

A mechanistic model for predicting transdermal and systemic kinetics was developed and demonstrated with published clinical data. The integrated mechanistic approach has significantly extended the applicability of a recently reported microscopic skin penetration model by providing prediction of solute concentration in the blood.

KEY WORDS

diffusion disposition percutaneous absorption physiologically-based pharmacokinetic modelling toxicokinetics 

ABBREVIATIONS

3Rs

Replacement refinement and reduction

CVODE

C-language variable-coefficients ODE solver

MW

Molecular weight

ODE

Ordinary differential equation

PDE

Partial differential equation

QSPR

Quantitative structure–property relationship

SUNDIALS

SUite of nonlinear and differential/algebraic equation solvers

SWIG

Simplified wrapper and interface generator

Notes

ACKNOWLEDGMENTS AND DISCLOSURES

This work was supported by the UK Royal Academy of Engineering (grant number: ISS1415\7\46), the Biotechnology and Biological Sciences Research Council (grant number: BB/L502042/1), and Unilever Research Colworth, UK. We would like to thank Drs Stephen Glavin and Ian Sorrell at the Safety and Environmental Assurance Centre, Unilever, for useful discussions on dermal pharmacokinetic modelling and safety assessment.

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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Department of Chemical and Process EngineeringUniversity of SurreyGuildfordUK
  2. 2.Unilever Research ColworthBedfordshireUK

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