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Randomized Controlled Trial
. 2006 Apr;61(4):414-9.
doi: 10.1111/j.1365-2125.2006.02590.x.

Kinetics and dynamics of the peripheral neurokinin-1 receptor antagonist SLV317 in healthy individuals

Christiane Hesse  1 , Steffen P Luntz, Heike Siedler, Kristina Unnebrink, Gerd Mikus, Marianne de Bruijn, Edu Zondag, Michiel de Vries, Monika Seibert-Grafe, Walter E Haefeli
Affiliations
Randomized Controlled Trial

Kinetics and dynamics of the peripheral neurokinin-1 receptor antagonist SLV317 in healthy individuals

Christiane Hesse et al. Br J Clin Pharmacol. 2006 Apr.

Abstract

Aims: To investigate the pharmacokinetics and the pharmacodynamic effects in dorsal hand veins of the neurokinin-1 receptor antagonist SLV317.

Methods: In a randomized, double-blind, placebo-controlled cross-over study 19 healthy men received a single oral dose of SLV317 or placebo. Blood samples were collected for analysis of SLV317 plasma concentrations and the inhibition of the venodilator response to substance P was evaluated using the hand vein compliance method.

Results: Administration of 250 mg SLV317 as an oral solution was well tolerated and resulted in mean peak plasma concentrations (+/- SEM) of 77 +/- 9 ng ml(-1) within 47 +/- 3 min; the mean half-life was 9.9 +/- 1.6 h. In hand veins preconstricted with phenylephrine, local infusion of substance P resulted in a mean venodilation of 56 +/- 8% and 49 +/- 6% (P = 0.91) before administration of SLV317 or placebo, respectively. SLV317 caused a substantial inhibition of substance P-induced venodilation, whereas placebo had no effect (P < 0.001). The maximum antagonizing effect of SLV317 averaged 95 +/- 8% and was observed after 1.47 +/- 00.24 h. Correspondingly, the mean area under the effect curve after administration of SLV317 [278 +/- 67% h(-1); 95% confidence interval (CI) 198, 358] was significantly higher compared with placebo (49 +/- 12% h(-1); 95% CI -24, 122; P < 0.001).

Conclusions: This study demonstrates that the neurokinin-1 receptor antagonist SLV317 is an orally active and highly effective antagonist of substance P-induced effects in humans.

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Figures

Figure 1
Figure 1
Semilogarithmic plot of plasma concentrations of the NK-1 receptor antagonist SLV317 in 18 healthy participants (mean ± SEM) after administration of 250 mg SLV317 as an oral solution
Figure 2
Figure 2
Substance P-induced venodilation expressed as percent reversal of phenylephrine-induced preconstriction after oral administration of the NK-1 receptor antagonist SLV317 (•) or placebo (○) in 17 healthy participants (mean ± SEM)
Figure 3
Figure 3
Antagonism of substance P-induced venodilation after oral administration of the NK-1 receptor antagonist SLV317 (•) or placebo (○) in 17 healthy participants over time (mean ± SEM). Data are expressed as a percentage of the initial individual response to substance P, which was set to 100%
Figure 4
Figure 4
Antagonism of substance P-induced venodilation plotted against the corresponding SLV317 plasma concentrations. Data are from 17 participants; mean ± SEM. The arrows indicate the time course of the data points (counter-clockwise hysteresis)
See this image and copyright information in PMC

References

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