(T1230-11-70) Application of Physiologically Based Pharmacokinetic Modeling to the Prediction of In Vitro and In Vivo Permeation of the UV Filter Octocrylene

Purpose: Dermal physiologically based pharmacokinetic (PBPK) models incorporate human skin physiology, formulation characteristics, and trial design parameters to enable mechanistic predictions of skin absorption [1]. Sunscreen products contain single or combined UV filters as actives to protect the human skin from UV radiation. In 2019, the US FDA proposed that additional skin absorption data be provided for twelve UV filters, including octocrylene, for which the public record does not contain sufficient data to support GRASE (Generally Recognized as Safe and Effective) determination [2]. Additionally, the US FDA recommends conducting Maximal Usage Trials (MUsT) for sunscreen products, which involve the application of the formulation to 75% of the body surface area [3]. In the present study, a dermal PBPK model was developed and verified against the in vitro permeation of the UV filter, which was subsequently extrapolated to simulate in vivo MUsT of the same commercial lotion and spray sunscreen formulations.

Methods: The Simcyp simulator’s Multi-Phase Multi-Layer (MPML) MechDermA model was employed to simulate the IVPT studies of octocrylene from spray, lotion, and cream sunscreen formulations reported by Yang et al. in 2020 and 2022 [4, 5]. The physiochemical properties of octocrylene were obtained from the literature, while the formulation parameters and trial design were informed by the published data where available. The partition and diffusion coefficients were either predicted using QSARs models in the MPML MechDermA model or optimised and verified against the experimental IVPT data. Additionally, the same spray and lotion formulations were investigated in two MUsT studies conducted in 2019 and 2020 [6, 7]. The octocrylene model was subsequently extrapolated to simulate the in vivo absorption. Volume of distribution and clearance were predicted from ADMETLab 2.0 [8] due to the absence of experimental data. The trial design in the in vivo simulation was parameterised based on the information provided in the published studies. The multiple-application site function was used to simulate the nine body sites on the face, torso, arms and legs simultaneously. No further optimisation was performed in the in vivo simulation.

Results: During the first stage of the study, the model accurately predicted the in vitro permeation of octocrylene from all the assessed formulations under both finite and infinite dose conditions. Furthermore, the majority of the observed permeation profiles from individual donors fell within the 5^th and 95^th percentiles of the model’s predictions. Good predictions of skin retention from the lotion and cream formulations were also obtained. Overprediction was obtained for the in vitro permeation through human epidermis from the spray formulation under finite dose conditions, however, an extremely low mass balance recovery was reported in the experiment. Without further information, this was disregarded in the current study. In the second stage of the study, the model was extrapolated to simulate the in vivo absorption of octocrylene following the application of the same lotion and spray formulations to more than 75% of the body surface area of six or twelve subjects, up to four times per day, for four consecutive days. The simulations recapitulate the clinical study design. The simulated plasma profile of octocrylene is presented in Figure 1, overlaid with the observed data. The prediction of octocrylene absorption from the lotion was considered satisfactory, with most observed data falling within the 5^th and 95^th percentiles of the prediction for both the 2019 and 2020 studies (Figure 1A and B). The spray was only investigated in the 2019 study and the model also captured the initial phase of its plasma profile. Nonetheless, an overprediction of the systemic concentration was observed after the initial phase throughout the study. This could be attributed to the uncertainty in the in silico predicted octocrylene clearance.

Conclusion: This is the first application of a dermal PBPK model to predict the in vivo absorption of UV filters following application of commercial sunscreens in MUsT studies. This study provides a framework to simulate MUsT trials which applies the drug to nine body sites simultaneously. The case study demonstrated that dermal PBPK modelling is useful for both in vitro assessments of UV filters' skin absorption, which are integral to the design of MUsT trials, and for predicting its systemic absorption in clinical studies.

References: 1. Patel N., Clarke J.C., Salem F., Abdullah T., Martins F., Arora S., Tsakalozou E., Hodgkinson A., Arjmandi-Tash O., Cristea S., Ghosh P., Alam K., Raney S. G., Jamei M. and Polak S., CPT Pharmacometrics Syst. Pharmacol., 2022, 11(8): 1060-1084
2. FDA. Sunscreen drug products for over-the-counter human use. https://www.federalregister.gov/documents/2019/02/26/2019-03019/sunscreen-drugproducts-for-over-the-counter-human-use; 2019. (accessed May 3, 2023).
3. FDA. Maximal usage trials for topical active ingredients being considered for
inclusion in an over-the-counter monograph: study elements and considerations. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/maximal-usage-trials-topically-applied-active-ingredients-being-considered-inclusion-over-counter; 2019. (accessed May 3, 2023).
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6. Matta MK, Florian J, Zusterzeel R, Pilli NR, Patel V, Volpe DA, Yang Y, Oh L, Bashaw E, Zineh I, Sanabria C, Kemp S, Godfrey A, Adah S, Coelho S, Wang J, Furlong LA, Ganley C, Michele T, Strauss DG. Effect of Sunscreen Application on Plasma Concentration of Sunscreen Active Ingredients: A Randomized Clinical Trial. JAMA. 2020 Jan 21;323(3):256-267.
7. Matta MK, Zusterzeel R, Pilli NR, Patel V, Volpe DA, Florian J, Oh L, Bashaw E, Zineh I, Sanabria C, Kemp S, Godfrey A, Adah S, Coelho S, Wang J, Furlong LA, Ganley C, Michele T, Strauss DG. Effect of Sunscreen Application Under Maximal Use Conditions on Plasma Concentration of Sunscreen Active Ingredients: A Randomized Clinical Trial. JAMA. 2019 Jun 4;321(21):2082-2091.
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Acknowledgements:The authors have no conflicts of interest to declare.

Figure 1 The simulated and observed plasma concentration of octocrylene following application of lotion (A and B) and spray (C).