(T1230-09-61) Physiologically Based Pharmacokinetic Simulations Using Transdermal Compartmental Absorption and Transit Model (TCAT) for RLS-1496 Dermal Preparations

Purpose: RLS-1496 is a senolytic drug formulated as a cream for topical administration and currently in Phase 1 clinical trials for dermatological conditions. A 1% cream strength was determined to be a safe starting dose for first-in-human studies, based on IND-enabling toxicology studies. In this work, we present the application of PBPK modelling, employing a transdermal compartmental absorption and transit (TCAT) model in GastroPlus^®, to support formulation changes and simulate concentrations in the skin compartments, resulting from the administration of the 1% cream in a clinical setting.

Methods: The TCAT model was developed utilizing in vitro permeation and penetration data (IVPT) from an early development cream formulation CR-16 (1% w/w), alongside physicochemical properties of RLS-1496 and formulation-related parameters. Where experimental data were lacking, in silico values obtained from ADMET Predictor were incorporated. The cream formulation was treated as an oil-in-water emulsion. The subsequently developed TCAT model, coupled with in silico whole-body clearance estimates, was then employed to simulate RLS-1496 concentrations across various skin layers for the clinical formulation CR-24 (1% w/w). Model input parameters, including dispersed phase volume, partition coefficient, and solubility, were systematically evaluated to assess the impact of application time and skin surface area on RLS-1496 levels.

Results: The TCAT model, incorporating the Wang-Kasting-Nitsche full hydration model with dermis fraction bound at 99.9% and 99% for epidermis, reasonably explained the flux observed in the IVPT experiment for CR-16 at 1% w/w (observed 0.491 ng/cm2 and simulated 0.454 ng/cm2, at 24 hours). The simulated RLS-1496 concentrations for CR-24 1% w/w after a single application of 3g/1500 cm² over an application period of 3, 12, and 24h were well above the target concentration of 140 nM in dermis for at least 7 days post-application, regardless of application period (Figure 1).

Conclusion: Overall, a whole body PBPK model was developed for simulating the drug delivery of RLS-1496 from topical formulations. Based on the results, it is predicted that the concentration in dermis, when 3g of the 1% strength is applied in a surface area of 1500cm2 of normal healthy skin, will be above the target concentration for RLS-1496 which is expected to provide maximal target engagement and senolytic response based on preclinical data, for at least a week after a single dose.

References: Predicting Human Dermal Drug Concentrations Using PBPK Modelling and Simulation: Clobetasol Propionate Case Study. AAPS PharmSciTech (2024) 25:39. Van Osdol et al, 2024.

Acknowledgements: We are also thankful to Dr. William van Osdol of Simulations Plus for his expertise and discussions on PBPK modeling and simulation for topical systems.