Development and validation of a physiologically-based pharmacokinetic model for dermal absorption

Student thesis: Doctoral ThesisPhD

Abstract

Measurement of the bioavailability of a drug in the skin after topical application is an important objective when attempting to assess whether the target-site concentrations are satisfactory to treat the disease. However, determining the amount of drug that reaches the different skin layers is still a challenge. Self-evidently, this challenge requires knowledge of both the drug input rate into the skin ‘compartment’ and its subsequent clearance therefrom.
The Chapter 2 of this thesis focused on characterising experimentally (using in vitro permeation tests) the input functions of two transdermal drugs, buprenorphine and nicotine, from commercially available patches. In addition, the input-rate of diclofenac from a medicated plaster was determined using the same approach as demonstrated for the transdermal drugs. A good agreement between the experimentally determined input-rates of the two transdermal drugs and their labelled performance in vivo was found, lending support to the potential utility of the in vitro approach proposed to define topical drug input-rates more broadly.
The Chapter 3 described an investigation of the behaviour of diclofenac in the stratum corneum. The uptake of diclofenac into the stratum corneum and its clearance therefrom following application of a medicated plaster was investigated in vivo in human. The results presented in this chapter have utility with respect to the application of stratum corneum tape-stripping to derive useful skin pharmacokinetic parameters related to drug partitioning into and diffusion across the stratum corneum.
The results described in chapter 3 suggested that diclofenac uptake into the stratum corneum may be modified by the presence of excipient(s). Therefore, the work described in Chapter 4 focused on exploring the uptake of two excipients/co-solvents, propylene glycol and butylene glycol, into the stratum corneum in vivo in human, following application of the diclofenac medicated plaster. The results obtained from the uptake of propylene and butylene glycol suggests that these volatile solvents were rapidly taken into the stratum corneum. In parallel, evaporation of the solvents was identified.
The work described in Chapter 5 investigated the hypothesis that information about clearance from the skin can be derived from available systemic pharmacokinetic data for drugs administered via transdermal delivery systems. A statistical mathematical model describing drug clearance from the skin in terms of drug molecular descriptors was developed. The model showed a good predictive ability. It has been further demonstrated that the empirical model closely predicts the results obtained in in vitro skin experiments. Overall, this thesis has provided useful information on the application of different strategies to predict topical skin delivery upon which further development and optimisation might be based.
Date of Award19 Apr 2019
LanguageEnglish
Awarding Institution
  • University of Bath
SupervisorRichard Guy (Supervisor), Begona Delgado-Charro (Supervisor) & Jane White (Supervisor)

Cite this

Development and validation of a physiologically-based pharmacokinetic model for dermal absorption
Maciel Tabosa, M. (Author). 19 Apr 2019

Student thesis: Doctoral ThesisPhD