A double-blind, placebo-controlled study to assess tolerability, pharmacokinetics and preliminary pharmacodynamics of single escalating doses of Z13752A, a novel dual inhibitor of the metalloproteases ACE and NEP, in healthyvolunteers

Aims The objective of this study was to evaluate the tolerability of a nove l dual ACE-NEP inhibitor, Z13752A, after the oral administration of rising single doses in healthy volunteers. This study was also a preliminarily inv estigation of Z13752A pharmacodynamics (PD) and pharmacokinetics (PK). Methods In this randomized, placebo-controlled, sequential study, two alter nating panels of eight healthy male volunteers each (six subjects receiving the active treatment + two subjects receiving placebo) were treated with i ncreasing oral doses of Z13752A: 10, 50, 200, and 600 mg were given to pane l I and 20, 100, 400 and 800 mg were given to panel II. The study was doubl e-blind relative to placebo or active treatment, and was open with respect to the dose levels. The same volunteer received placebo only once. Results Single oral doses of Z13752A, as high as 800 mg, were well tolerate d. Only six mild-to-moderate adverse events mainly headache, were reported and appeared to be of little clinical relevance. After administration of 20 0, 400, 600 and 800 mg of Z13752A, a nonsignificant fall in diastolic blood pressure was detected, in both the standing and supine position. After sin gle oral doses of Z13752A, ACE inhibition appeared to be significant at all the doses tested, linearly correlated with the dose and was almost complet e at doses greater than or equal to 100-200 mg. NEP inhibition was indicate d by elevation of ANP and cGMP plasma concentrations in almost all subjects . In the 200-800 mg dose range, Z13752A produced a 50-100% increase of plas ma cGMP levels and a 50-80% elevation in urinary cGMP concentrations. Detec table plasma levels of Z13752A were found in all the treated subjects. Z137 52A was well and rapidly absorbed, with peak concentrations reached approxi mately 2.5 h after administration. The mean apparent elimination half-life from plasma was approximately 12 h. The pharmacokinetics of Z13752A after s ingle oral doses were characterized by low intersubject variability and app eared to be dose-independent. Conclusions Z13752A showed a good single dose tolerability profile at doses up to 800 mg. The pharmacokinetic data indicate that Z13752A administered orally is rapidly absorbed and available to the systemic circulation in hum ans. The relatively slow clearance indicates that a once-a-day dose regimen could be considered for Z13752A.