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Refereed/Peer-reviewed Pharmacokinetic (PK) models are widely used to describe drug permeation across the epidermal membrane barrier, the stratum corneum (SC). Here, we extend our previously reported diffusion and compartment-in-series models to describe plasma concentrations, urinary excretion-time profiles and exposure estimates after topically applied finite doses of solvent deposited solids. In vivo models were derived by convolution of a skin absorption input function for finite dosing with that for in vivo disposition PK. In vitro skin permeation test (IVPT) and in vivo urinary excretion data for cortisone, desoxycorticosterone, and testosterone were extracted from literature for model validation and establishment of in vitro - in vivo relationships (IVIVR). Both SC diffusion and SC 3-compartment-in-series PK models adequately described experimental in vitro and in vivo permeation data, with similar model parameter estimates for SC diffusion time and bioavailability. A satisfactory IVIVR was generated for cortisone, whereas testosterone and desoxycorticosterone showed higher bioavailability in vitro compared to in vivo. In recognising that future prospective studies need to both have an adequate sampling schedule and be harmonized for robust IVIVRs, we developed expressions for predicting extent of absorption and time for peak absorption for both in vitro and in vivo studies. Other study parameters, such as application site, applied dose, and application techniques, can also affect drug permeability through skin during dosage form metamorphosis after finite dose application, and a lack of correlation may result if these are poorly matched.

Refereed/Peer-reviewed Topical products, widely used to manage skin conditions, have evolved from simple potions to sophisticated delivery systems. Their development has been facilitated by advances in percutaneous absorption and product design based on an increasingly mechanistic understanding of drug-product-skin interactions, associated experiments, and a quality-by-design framework. Topical drug delivery involves drug transport from a product on the skin to a local target site and then clearance by diffusion, metabolism, and the dermal circulation to the rest of the body and deeper tissues. Insights have been provided by Quantitative Structure Permeability Relationships (QSPR), molecular dynamics simulations, and dermal Physiologically Based PharmacoKinetics (PBPK). Currently, generic product equivalents of reference-listed products dominate the topical delivery market. There is an increasing regulatory interest in understanding topical product delivery behavior under ‘in use’ conditions and predicting in vivo response for population variations in skin barrier function and response using in silico and in vitro findings.

This paper demonstrates how to use distorted Gaussian copula functions to produce a heavy tailed portfolio loss distribution in the context of synthetic Collateralized Debt Obligations (CDOs). Distortion functions have not previously been used in this area. Hence, we demonstrate that it is possible to simulate realistic tranche prices by incorporating distorted copula functions within a well established CDO pricing system, such as that of JP Morgan. Furthermore, we only require a single dependence parameter for the entire portfolio rather than one per tranche. Thus, we are providing practitioners with a simpler and more flexible alternative to current CDO pricing methods.