PII-010 - THE REPLACEMENT, REDUCTION AND REFINEMENT PRINCIPLE APPLIED TO THE VINTAGE ORAL TYRAMINE CHALLENGE TEST OF MAO INHIBITORS; EVALUATION OF A REFINED AND REDUCED DESIGN WITH TYRAMINE CMAX REPLACING BLOOD PRESSURE RESPONSE.

E. van Hoogdalem¹, J. Hartstra¹, K. Smith², J. Constant³; ¹ICON, Groningen, The Netherlands, ²ICON, Reading, United Kingdom, ³ICON, Vancouver, Canada.

Background: The need exists for a modified oral tyramine challenge design that focusses on the primary concern of mono-amino oxidase (MAO) inhibition, i.e. increase of tyramine exposure, and that operates at lower tyramine doses, to avoid poorly predictable systolic blood pressure (SBP) excursions.

Methods: A retrospective analysis was performed on a completed double-blind, placebo- and active-controlled, oral tyramine challenge study in healthy participants (7 groups of n=16-24 each), receiving escalating tyramine doses at baseline, and after repeated dosing of reference or test treatments or placebo. Tyramine Cmax, tyramine dose leading to SBP increase ≥ 30 mmHg (TYR30), and dose to Cmax ≥ 10 ng/mL (TYRC10) were assessed. Dose- and concentration-response, and variation in estimates were evaluated post-hoc.

Results: Effects of active treatments and placebo were similar or identical for TYRC10 and TYR30, whilst TYRC10 was typically 2-4 fold below TYR30. Phenelzine proved an exception, with stronger SBP effect than reflected by tyramine Cmax, possibly due to a direct effect on SBP. Tyramine Cmax increased approximately linearly with tyramine dose, with high CVinter, from around 80% to above 200%. Within-subject variation of Cmax was substantial, up to 50-fold in an individual case. Tyramine showed a sigmoidal dose – SBP response relationship, with substantial inter-subject variation, i.e. 40-100 mm Hg difference in change in SBP between subjects at any tyramine dose.

Conclusion: Tyramine Cmax proved as informative as SBP for assessing tyramine sensitivity, allowing a safer and more efficient study at lower doses with smaller SBP excursions. The safer and more efficient performance of TYRC10 over TYR30 will be further evaluated by trial simulation.