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Aim  Dual enkephalinase inhibitors (DENKIs) are involved in the regulation of nociception via opioid receptors. The novel compound STR‐324 belongs to the DENKI pharmacological class. This first‐in‐human study evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of STR‐324 in healthy male participants.    Methods  This was a randomised, double‐blind, placebo‐controlled ascending dosing study in two parts: in part 1, 30 participants received 0.004‐11.475 mg h −1  of STR‐324 or placebo (ratio 4:1) by 4 h intravenous infusion in a two‐group, partial crossover design with four treatment periods separated by 1 month wash‐out, and in part 2, 48 participants divided into three groups received either the active drug (1.25‐11.25 mg h −1 ) or placebo (ratio 3:1) by 48 h intravenous infusion. Safety and tolerability parameters, pharmacokinetics and pharmacodynamic effects on neurocognitive and neurophysiological tasks and on a nociceptive test battery were evaluated.    Results  No clinically relevant changes in safety parameters were observed. All treatment‐emergent adverse events were mild and transient. The pharmacokinetics of STR‐324 could not be determined due to most concentrations being below quantifiable limits. STR‐324 metabolite concentrations were measurable, showing dose proportionality of  C  max  and AUC inf  with an estimated  t  1/2  of 0.2‐0.5 h. Significant changes in pharmacodynamic parameters were observed, but these were not consistent or dose‐dependent.    Conclusion  STR‐324 displayed favourable safety and tolerability profiles at all doses up to 11.475 mg h −1 . Although pharmacokinetic characterisation of STR‐324 was limited, dose proportionality could be assumed based on major metabolite data assayed as proxy. No clear effects on nociceptive thresholds or other pharmacodynamic measures were observed.  Trial registry: EudraCT (2014‐002402‐21) and toetsingonline.nl (63085).

british journal of clinical pharmacology

First‐in‐human trial to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of STR‐324, a dual enkephalinase inhibitor for pain management