Over the last twenty years there has been a significant change in the approach taken to the early stages of clinical development. Early studies with a new compound are no longer focused purely on safety, tolerability and PK but are layering in techniques to better understand and characterise a molecule in terms of putative efficacy, wanted and undesired side effects, time course of pharmacodynamic effects and competitive performance to existing therapies.
A key method that has been developed to provide this additional information is the application of clinical pharmacodynamic (PD) models of disease states. In their most basic form PD models simulate the symptoms of a disease state in a healthy volunteer, enabling drug effects to be characterised under controlled, laboratory conditions. PD models have gained acceptance across a wide variety of therapeutic states (e.g. affective disorders, cognitive impairment, diabetes and metabolic disease). It is however in the areas of pain and inflammation where these models are of particularly relevance offering the diversity and range of parameters needed to characterise the complex and varied conditions that come under these labels.
Initial work in the pain area was focused on simple models of nociception such as the cold pain model. In this model subjects immerse their hand in water at 2°C for two minutes and continuously record their pain for the duration of the test. Healthy volunteers have been shown to report nociceptive pain to this stimulus in a very consistent manner. Treatment of subjects with compounds with known efficacy in treating nociceptive pain produces significantly lower pain responses in a dose dependent and reproducible manner. The technique is now widely used in cross-over designs including placebo and a positive control to rapidly assess the analgesic potential of putative novel treatments for pain.
More complex pain conditions such as neuropathic pain characterised by the development of painful hyperalgesia and allodynia can also be modelled in healthy volunteers using challenge agents such as capsaicin. Intradermal injection of capsaicin produces pain, hyperalgesia and allodynia that can persist for up to 8 hours giving a wide window to test the therapeutic potential of compounds.
In addition to providing an indication of potential efficacy, the pharmaceutical industry is also using these techniques to demonstrate target engagement and expected pharmacological response. Specific challenge agents have been tested to differentiate between compounds acting at various transient receptor protein (TRP) sites e.g. Menthol for TRPM8, Mustard Oil for TRPA1 and Capsaicin for TRPV1.
Appropriate application of well-validated PD models can help accelerate the decision making process and the selection of appropriate drug-candidates from development, providing benefits in terms of both cost and time. Pivotal to these models is to establish a pain signal that is strong enough to be measured and has a pharmacodynamic range that is large enough to be manipulated by drug intervention. Common to all the models described above is that they have to induce significant effects for a short period of time that does not persist beyond the experimental setting. To achieve this, the one thing they must be is quite painful… as without this pain there can be no development gain!
ICON will be hosting a webinar on this topic on September 13th 2012.
For more information and to register please click below