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 healthy volunteers

Abstract

Aims: The objective of this study was to evaluate the tolerability of a novel dual ACE-NEP inhibitor, Z13752A, after the oral administration of rising single doses in healthy volunteers. This study was also a preliminarily investigation of Z13752A pharmacodynamics (PD) and pharmacokinetics (PK).

Methods: In this randomized, placebo-controlled, sequential study, two alternating panels of eight healthy male volunteers each (six subjects receiving the active treatment + two subjects receiving placebo) were treated with increasing oral doses of Z13752A: 10, 50, 200, and 600 mg were given to panel I and 20, 100, 400 and 800 mg were given to panel II. The study was double-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 tolerated. Only six mild-to-moderate adverse events mainly headache, were reported and appeared to be of little clinical relevance. After administration of 200, 400, 600 and 800 mg of Z13752A, a nonsignificant fall in diastolic blood pressure was detected, in both the standing and supine position. After single oral doses of Z13752A, ACE inhibition appeared to be significant at all the doses tested, linearly correlated with the dose and was almost complete at doses > or = 100-200 mg. NEP inhibition was indicated 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 plasma cGMP levels and a 50-80% elevation in urinary cGMP concentrations. Detectable plasma levels of Z13752A were found in all the treated subjects. Z13752A was well and rapidly absorbed, with peak concentrations reached approximately 2.5 h after administration. The mean apparent elimination half-life from plasma was approximately 12 h. The pharmacokinetics of Z13752A after single oral doses were characterized by low intersubject variability and appeared 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 humans. The relatively slow clearance indicates that a once-a-day dose regimen could be considered for Z13752A.

Figure 1

Chemical structure of Z13752A(N-[(s)-2(mercaptomethyl)-1-oxo-3-phenylpropyl]-4-(2-thiazolyl)-l-phenyl-alanine).

Figure 2

Time course of systolic (SBP) and diastolic (DBP) blood pressure, recorded in the supine position, over the first 12 h after administration of placebo (▪ group 1; • group 2) or after the highest administered doses of Z13752A (▴ 600 mg, group 1; ♦ 800 mg, Group 2. Values are expressed as changes from baseline (▵ mmHg). The mean curves for six subjects are shown (eight for placebo).

Figure 3

Mean plasma concentration-time profiles after oral administration of Z13752A tablet at eight dose levels (▪ 10 mg; □ 20 mg; ▾ 50 mg; ▿ 100 mg; ♦ 200 mg; ◊ 400 mg; • 600 mg; ○ 800 mg) in healthy volunteers.

Figure 4

Relationship between Z13752A dose and individual C_max (a) or AUC (b) values at the eight doses tested. The best-fitted linear regression line (solid line) and the 95% confidence region (dotted lines) are also shown.

Figure 5

(a) Time course of inhibition of serum ACE activity over 48 h after single oral administration of placebo (▪ group 1; □ group 2) or Z13752A (• 10 mg; ○ 20 mg; ▴ 50 mg; ▵ 100 mg; ▾ 200 mg; ▿ 400 mg; ♦ 600 mg; ◊ 800 mg).Values are expressed as percentage changes from predose values. The mean curves for six subjects are shown (eight for placebo). (b) Relationship between mean Z13752A plasma concentration at C_max and mean ACE activity inhibition after single oral administration of Z13752A at eight dose levels in healthy volunteers.Standard deviation of mean ACE activity and Z13752A concentration are shown by vertical and horizontal bars, respectively.

Figure 6

Time course of plasma ANP variation over 24h after single oral administration of placebo (a) ▪ group 1; b) □ group 2) or Z13752A (▴ 10 mg; ▾ 50 mg; • 200 mg; ♦ 600 mg; ▵ 20 mg; ▿ 100 mg; ○ 400 mg; ◊ 800 mg). Values are expressed as percentage changes from predose values. The mean curves for six subjects/panel are shown (eight for placebo).

Figure 7

Time course of plasma cGMP variation over 24h after single oral administration of placebo (a) ▪ group 1; b) □ group 2) or Z13752A (▴ 10 mg; ▾ 50 mg; • 200 mg; ♦ 600 mg; ▵ 20 mg; ▿ 100 mg; ○ 400 mg; ◊ 800 mg). Values are expressed as percentage changes from predose values. The mean curves for six subjects/panel are shown (eight for placebo).