Use of Physiologically-Based Kinetics Modelling to Reliably Predict Internal Concentrations of the UV Filter, Homosalate, After Repeated Oral and Topical Application

Abstract

Ethical and legal considerations have led to increased use of non-animal methods to evaluate the safety of chemicals for human use. We describe the development and qualification of a physiologically-based kinetics (PBK) model for the cosmetic UV filter ingredient, homosalate, to support its safety without the need of generating further animal data. The intravenous (IV) rat PBK model, using PK-Sim^®, was developed and validated using legacy in vivo data generated prior to the 2013 EU animal-testing ban. Input data included literature or predicted physicochemical and pharmacokinetic properties. The refined IV rat PBK model was subject to sensitivity analysis to identify homosalate-specific sensitive parameters impacting the prediction of C_max (more sensitive than AUC_(0-∞)). These were then considered, together with population modeling, to calculate the confidence interval (CI) 95% C_max and AUC_(0-∞). Final model parameters were established by visual inspection of the simulations and biological plausibility. The IV rat model was extrapolated to oral administration, and used to estimate internal exposures to doses tested in an oral repeated dose toxicity study. Next, a human PBK dermal model was developed using measured human in vitro ADME data and a module to represent the dermal route. Model performance was confirmed by comparing predicted and measured values from a US-FDA clinical trial (Identifier: NCT03582215, https://clinicaltrials.gov/). Final exposure estimations were obtained in a virtual population and considering the in vitro and input parameter uncertainty. This model was then used to estimate the C_max and AUC_{(0-24 h)} of homosalate according to consumer use in a sunscreen. The developed rat and human PBK models had a good biological basis and reproduced in vivo legacy rat and human clinical kinetics data. They also complied with the most recent WHO and OECD recommendations for assessing the confidence level. In conclusion, we have developed a PBK model which predicted reasonably well the internal exposure of homosalate according to different exposure scenarios with a medium to high level of confidence. In the absence of in vivo data, such human PBK models will be the heart of future completely non-animal risk assessments; therefore, valid approaches will be key in gaining their regulatory acceptance. Clinical Trial Registration: https://clinicaltrials.gov/, identifier, NCT03582215.

Keywords: UV filter; dermal application; homosalate; physiologically-based kinetics models; plasma concentration.

FIGURE 1

Predicted versus observed (blue circles) concentration-time profile of homosalate after an IV dose of 0.5 mg/ kg. Profiles were generated using (A) default values and (B) optimized values. The blue circles represent measured values and the red line denoted a simulated profile.

FIGURE 2

The output of the sensitivity analyses of C_max values for the (A) rat-IV PBK model (Dose: 0.5 mg/ kg, single) and (B) human dermal PBK model (dose 103 μg/ cm², single). The y-axis represents the ratio of the relative change of C_max and the relative variation of the input parameter denoted in the x-axis. Parameters with sensitivities less than absolute 0.1 are not listed. Blood to plasma P = blood to plasma permeability; Fu = fraction unbound; K = partition coefficient; Periportal-pls-int P = Periportal-plasma-interstitial permeability; plasma to blood P = plasma to blood permeability; SBFR = specific blood flow rate; SF = scale factor.

FIGURE 3

Predicted mean (closed circles) and CI95% (crosses) versus observed (open circles) C_max (A) and AUC_(0-∞) (B) of homosalate after IV doses of 0.5, 2 and 5 mg/ kg to rats. Predictions were generated using optimized input values. The CI95% (red lines) and CI5% (blue lines) are also included.

FIGURE 4

Simulated concentration-time profile of homosalate (A) over 24 h after a single application, where the dermal penetration was estimated to be 2.5% (this scenario mimics that tested by Matta et al. (2020)), and (B) over 30 days of repeated dermal exposure, where the dermal penetration was estimated to be 5.3% of the applied dose (this scenario mimics the dosing for the safety assessment). Values are shown for the mean and the CI (5–95)%. The application was of 10% homosalate applied to the human whole-body.

FIGURE 5

An overview of the development of the PBK models, together with the associated assessments for model qualification and the derivation of the MoIE.