Drug Safety in preclinical studies

ABSTRACT: Drug abuse liability is a growing concern for Regulatory Authorities and the
American opioid crisis raises the question of the evaluation of abuse potential
for new drugs.

• Standard non-clinical methods are time/cost ineffective and rely on behavioral
  outcomes.
• The need to develop more quantitative/predictive approaches has been
  pointed out.
• Meanwhile, accumulating evidences highlight the role of initial activation of the reward system and its dysregulation in the development of drug addiction

ABSTRACT: Drug-induced orthostatic hypotension (OH) is a common side-effect of medications such as antidepressants, antipsychotics, antiparkinsons, antihypertensives, vasodilators and diuretics. OH is defined as an excessive drop in arterial blood pressure resulting from a sudden postural change. Under physiological conditions, this phenomenon is compensated by the baroreflex, a regulatory mechanism that restores blood pressure by activating the sympathetic system leading to peripheral vasoconstriction and cardiac stimulation. However, this side-effect is not systematically addressed during preclinical drug development of NCE’s. The standard way to investigate OH in animals is the tilt test, as performed in humans. Physical restraint in modified chairs is the most frequently used technique in NHP. However, this restraint is stressful and can affect the results. We have developed a technique in cynomolgus monkeys using only manual restraint. Animals are regularly trained to the procedure using clicker training with positive reinforcement. Trained animals show no resistance during the procedure. The model was validated using two reference compounds, prazosin and hexamethonium.

• In a neuroscience drug discovery project, several compounds of interest induced
  severe albeit transient hypothermia after acute intraperitoneal or oral administration in
  a mouse pharmacology model
• This hypothermia hindered exploration of efficacy in the in vivo mouse model and
  could possibly prevent the conduct of relevant safety studies in tox species at high
  dose levels

• Drug-related discomfort associated to effects like pain or intestinal disturbances may result in reduced treatment compliance and even drug discontinuation. For instance, GLP-1-based treatments are known to be associated with nausea and emesis in patients.
• Conditioned taste aversion (CTA) is an associative learning process by which pairing the taste of a sweet liquid like a saccharin solution (conditioned stimulus) with
  gastrointestinal discomfort induced by another stimulus (unconditioned stimulus) leads to a conditioned aversive response upon re-exposure to the initial taste.
• Since rodents are unable to display emesis, we aimed at evaluating the relevance of the CTA paradigm to detect gastrointestinal discomfort triggered by the GLP-1 pathway.
  We sought to evaluate the effects of an acute administration of semaglutide, a GLP-1 agonist, in the CTA test using a 2-bottle preference paradigm, in both mice and rats. Lithium
  chloride (LiCl) was used in the study as a positive reference compound.