Novel Skin PBPK model in Action: Clindamycin and Tazarotene Modeling

Authors: Krishnatry AS, Damian-Iordache V, Lloyd R, Lenn J, Kang G, Hussey B, Chaudhuri S, Spires J, Lukacova V
Conference: AAPS
Keywords: ADMET, dermal, PBPK, skin, tcat, topical, topical application, Transdermal Compartmental Absorption & Transit (TCAT™)
Software: ADMET Predictor®, GastroPlus®
Division: PBPK

Introduction

  • Skin is the major organ in the human body with a complex barrier that serves as protection from the external environment.
  • Predicting dermal and systemic exposures of drug following topical application is especially challenging when considering the impact of formulations.
  • Scientists from GlaxoSmithKline, Stiefel (a GSK Company) and Simulations Plus have collaborated to develop a mathematical model, Transdermal Compartmental Absorption & Transit (TCAT™) that allows better understanding of drug penetration through the skin while accounting for the formulation characteristics, evaporation and precipitation effects that influence dermal delivery.

Methods:

  • TCAT model was used to predict systemic exposures upon topical administration of different Clindamycin formulations after single dose (Dalacin T Topical Solution and DUAC gel) and multiple dose (Evoclin foam and Clindagel) administration, as well as two Tazarotene formulations (Tazorac gel and Fabior foam) to evaluate the ability of TCAT model in differentiating the drug exposures from different topical dermal formulations.
  • For details on the TCAT model please also visit poster # W5289.
  • Compound specific physicochemical parameters were either predicted using ADMET Predictor v6.0 experimental values were used for model building.
  • Models describing systemic disposition were calibrated against plasma concentration-time profiles after intravenous administration for each compound.
  • The formulation characteristics including type, volatile content, volume, evaporation rate, solubility, application area / region/ time and appropriate skin physiology were accounted for in each case.
  • Vehicle /Water partition coefficient and systemic uptake rate was optimized for different formulations.
  • Diffusivity and partition coefficients in the Stratum Corneum were calculated using Wang-Kasting Nitsche equation 1 , in viable epidermis were calculated using Krestos equation2 and in sebum were calculated according to the equation derived from Valiveti et al., data3 .

American Association of Pharmaceutical Scientists (AAPS), November 2-6, 2014, San Diego, CA

By Anu Shilpa Krishnatry, Valeriu Damian-Iordache, Richard Lloyd, Jon Lenn, Grace Kang, Betty Hussey, Siladitya Ray Chaudhuri, Jessica Spires, Viera Lukacova