Abstract P131: The Acute Effect of the Creatine Kinase Inhibitor Beta-GPA in Healthy Man (ABC-Trial): A Randomized Placebo Controlled First-in-human Trial

Abstract

Aim: Increasing evidence indicates that the ATP-generating enzyme creatine kinase is involved in hypertension. Creatine kinase rapidly regenerates ATP from creatine phosphate and ADP. Recently, we showed that beta-guanidinopropionic acid (GPA), a kidney-synthesized creatine analogue and competitive inhibitor of creatine kinase, effectively and safely reduced blood pressure in spontaneously hypertensive rats. To further develop the substance as a potential blood pressure-lowering agent, we assessed the tolerability of a sub-therapeutic GPA dose in healthy men. Methods: In this active and placebo-controlled, triple-blind, single-center trial, we recruited 24 healthy men (18 to 50 years old, BMI 18.5 to 29.9 kg/m 2 ) in the Netherlands. Participants were randomized (1:1:1) to one week daily oral administration of GPA 100 mg, creatine 5 gram, or matching placebo. The primary outcome was the tolerability of GPA, in an intent-to-treat analysis. Results: Twenty four randomized participants received the allocated intervention and 23 completed the study. One participant in the placebo arm dropped out for personal reasons. GPA was well tolerated, without serious or severe adverse events. No abnormalities were reported with GPA use in clinical safety parameters, including physical examination, laboratory studies, or 12-Lead ECG (Table1). At day 8, mean plasma GPA was 213.88 (SE 0.07) in the GPA arm vs. 32.75 (0.00) nmol/L in the placebo arm, a mean difference of 181.13 (95% CI 26.53 to 335.72). Conclusion: In this first-in-human trial, low-dose GPA was safe and well-tolerated when used during 1 week in healthy men. Therefore, GPA is suitable for dose escalation trials