A topical skin PBPK pipeline for natural-product-inspired therapeutics: Dancik 4-layer ODE, SkinPiX-trained LGBM logKp head, NPASS 2026 ADME records, and a 102-compound 4-vehicle finite-dose evaluation with IVRT / IVPT readiness anchor

Topical (transdermal) drug delivery is the dominant route fordermatological therapeutics, yet most AI drug-discovery pipelinesomit physiologically-based pharmacokinetic (PBPK) modeling for skin.We present a fully open-source pipeline combining: (1) **Dancik 4-layerskin PBPK** (stratum corneum → viable epidermis → dermis → systemic);(2) LightGBM logKp head trained on SkinPiX (n=2,326, OECD 428) +NPASS 2026 ADME records (n=9,713); (3) **integration with cofoldingoutput** to produce per-compound topical bioavailability + skin layerconcentration estimates. We validate against legacy Potts-Guy 1992regression and demonstrate use on a 102-compound natural-productlibrary targeting 14 skin disease proteins. Code is released underApache-2.0; the pipeline is the first to combine modern ML-based logKpwith multi-layer ODE in a commercial-safe stack.