By Kevin Warner
Your project team is tasked with developing a topical semisolid product for a dermatological disease. The site of action for this dermal disease is thought to be at the epidermal/dermal junction. You develop a panel of prototype formulations for an in vitro skin penetration study. The study results show measurable amounts of API in the skin tissues (epidermis and dermis) and steady-state skin flux that is maintained for several hours. However, these results don’t address the key question: “Will the formulation provide adequate exposure at the site of action to elicit the desired pharmacodynamics outcome?” Developing a strategy to address this question will help de-risk clinical trials. At this point, what clinical de-risking strategies would you employ? When answering this question, consider the following when defining a non-clinical pharmacology strategy:
- Identify relevant skin disease models that enable identification and validation of targets. Target validation may require a panel of different models to establish the relevance of the pathway and/or target for the disease indication of interest. When establishing models that establish relevance of the target, understand the limitation of the model. For example, in vitro model systems are limited to providing results in a static system (i.e., don’t account for physiological parameters such as blood flow, how the immune system responds, etc.).
- With targets identified, consider how to establish a dose response in the models identified above. Dose response evaluation includes development of appropriate analytical methods to show that the drug is present at the site of action.
- What in vitro models are available and are the effective concentrations in these models known or can they be measured?
- What in vivo non-clinical models are available that show pharmacology (target expression, affinity, etc.) comparable to humans. Can the effective concentrations of drug(s) be accurately quantified at the site of action in an in vivo model? Are dermal pharmacokinetics in the model (e.g. mouse) likely different from human skin? If so, can dermal pharmacokinetics be studied in a model relevant to the human-disease state (e.g. minipig)?
- How might this data be used to assess the risk that inadequate levels of the drug would be reached in a clinical study with the formulation?
It is unlikely that there is one single model that mimics the pathogenesis of a dermatological disease. The approach outlined here is to get product development teams to think about an appropriate nonclinical strategy in order to select the right compound, formulation, and/or formulation strength to set clinical trials up for success.