Platelet aggregation assays for preclinical assessment of 5-HT4 agonists

The 5-HT4 agonist tegaserod has been withdrawn since 2007, except for emergency use, leaving indications such as constipation and irritable bowel disease poorly served by medications.
Tegaserod was withdrawn due to an excess of ischaemic events noted in meta-analysis of clinical trials, although the mechanism causing this is unknown. With other 5-HT4 receptor agonists in development, the FDA has discussed how best to assess any potential ischaemic risk in preclinical development.
This may include the use of in vitro platelet aggregation assays in preclinical development. However, not all platelet aggregation assays are equal. Platelet aggregation assayUsing this approach to detect possible side effects of small magnitude in this sort of setting requires careful consideration of optimal reagents and customisation of the assay conditions. Java Clinical Research has considerable expertise in this area. For instance, 5-HT is a weak platelet agonist, and use of a co-agonist can identify subtle platelet-activating effects in this pathway. Other assays, such as measurement of urinary thromboxane, may also be useful.
The FDA Briefing Document (pdf) notes that finding no effect in preclinical platelet aggregation studies does not rule out a potential effect in vivo, but finding such a signal would warrant close monitoring in clinical studies. However, rare adverse effects need to be balanced against the potential beneficial effects of the drug. Sensitive platelet aggregation studies can help place the magnitude of any effect into context.
While platelet aggregation is often considered the ‘gold’ standard’ of platelet function assessments, the FDA also notes that while suggestive, these results are not validated markers and their clinical implications are unknown.