Modeling percutaneous absorption for successful drug discovery and development

ABSTRACT

Introduction

Skin has been used as an administration route for local or systemic action since ancient times. The efficacy and toxicity of any product applied to the skin is determined by the chemical composition and physicochemical properties of the active(s) and excipients, which in turn govern their percutaneous absorption and effects.

Areas covered

This review addresses market trends, skin physiology, solute permeability, formulation properties and effects that are most relevant to a drug discovery scientist designing potentially active solutes for topical application. It also summarizes in silico model strategies, strengths, and limitations associated with the drug delivery design of topical products, with relevant examples.

Expert opinion

From a drug discovery perspective, many factors can determine the percutaneous absorption of an active solute. Current in silico models are limited by their dependence on data generated from the permeation of solutes across normal human skin from aqueous solutions. In practice, the choice of formulation, the pertinent skin physiology, and the solute properties, including its clearance, potency, and enhancement, also define dermal delivery. Consequently, there is an emerging trend of using in silico methods to inform effective drug design and development that are based on a combination of QSAR/QSPR with physiologically based pharmacokinetic and pharmacodynamic (PBPKPD) models.

KEYWORDS:

• Clearance
• exposure
• in silico modeling
• PBPKPD
• percutaneous absorption
• physicochemical properties
• potency
• QSAR/QSPR
• skin irritancy
• toxicity

Article highlights

• This review summarizes some key factors a drug discovery scientist should consider for designing drugs suitable for topical application.

• The efficacy of any drug applied to the skin is dependent on its ability to reach its site of action in sufficient concentrations, its potency, and clearance from various sites in the body.

• The transport of drugs through skin is, in turn, dependent on the nature of the skin barrier, physicochemical properties of the solutes and the nature of the formulated product with its excipients, and their interactions with the skin.

• Physiologically based pharmacokinetic-pharmacodynamic (PBPKPD) modeling provides useful tools to predict drug percutaneous absorption, clearance in the body and drug effects, which can guide the selection of suitable drug candidates for topical delivery.

• Strategies used to model percutaneous absorption are discussed, with a focus on their strengths and limitations.

This box summarizes key points contained in the article.

Declaration of interest

This work was undertaken at the Translational Research Institute, Woolloongabba, QLD, Australia. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

HS Cheruvu was supported by an Australian Government RTP (International) scholarship awarded by the University of Queensland. MS Roberts was the recipient of a National Health and Medical Research Council of Australia Fellowship (#1107356).