British Journal of Clinical Pharmacology
`
`DOI:10.1111/j.1365-2125.2006.02590.x
`
`Br J Clin Pharmacol
`
`61
`
`:4 414–419 414 © 2006 Blackwell Publishing Ltd
`
`Correspondence
`
`Walter E. Haefeli MD,
`
` Department of
`Internal Medicine VI, Clinical
`Pharmacology and
`Pharmacoepidemiology, University of
`Heidelberg, Im Neuenheimer Feld
`410, D-69120 Heidelberg, Germany.
`
`Tel:
`
`
`
`+
`
` 49 62 2156 8740
`
`Fax:
`
`
`
`+
`
` 49 62 2156 4642
`
`E-mail:
`
` walter_emil_haefeli@med.
`uni-heidelberg.de
`
`Keywords
`
`neurokinin-1 receptor antagonist,
`pharmacokinetics, SLV317, substance
`P, vein
`
`Received
`
`4 July 2005
`
`Accepted
`
`24 October 2005
`
`Published
`
`OnlineEarly
`
`20 January 2006
`
`Kinetics and dynamics of the peripheral neurokinin-1
`
`receptor antagonist SLV317 in healthy individuals
`
`Christiane Hesse, Steffen P. Luntz,
`
`1
`
` Heike Siedler, Kristina Unnebrink,
`
`1
`
` Gerd Mikus, Marianne de Bruijn,
`
`2
`
` Edu Zondag,
`
`2
`
`
`Michiel de Vries,
`
`2
`
` Monika Seibert-Grafe
`
`1
`
` & Walter E. Haefeli
`
`Department of Internal Medicine VI, Clinical Pharmacology and Pharmacoepidemiology and
`
`1
`
`Coordination Centre for Clinical Trials,
`Medical Faculty, University of Heidelberg, Heidelberg, Germany, and
`
`2
`
`Solvay Pharmaceuticals B.V ., DA Weesp, the Netherlands
`
`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 col-
`lected for analysis of SLV317 plasma concentrations and the inhibition of the
`venodilator response to substance P was evaluated using the hand vein compli-
`ance 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% confi-
`dence 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.
`
`Introduction
`
`Neurokinin-1 (NK-1) receptors have been identified in
`the central nervous system as well as in peripheral
`organs including the gastrointestinal and respiratory sys-
`tem, the genitourinary tract and the vascular endothe-
`lium [1]. The undecapeptide substance P, a member of
`the tachykinin family, is the natural agonist with the
`highest affinity to the NK-1 receptor and is a mediator
`of emesis, pain transmission, neurogenic inflammation
`and endothelium-dependent vasodilation [1, 2]. Further-
`more, substance P mediates the transmission of afferent
`perceptional signals from the gastrointestinal tract and
`mediates neuromuscular transmission in the enteric ner-
`vous system, resulting in the activation of gastrointesti-
`HELSINN EXHIBIT 2065
`Azurity Pharmaceuticals, Inc. v. Helsinn Healthcare S.A.
`IPR2025-00945
`Page 1 of 6
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`NK-1 antagonism of SLV317 in humans
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`Br J Clin Pharmacol
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`61
`
`:4 415
`
`nal motility [1]. Hence, there is considerable potential
`for neurokinin modulation in the treatment of sensory
`or motor disorders in inflammatory bowel disease or
`irritable bowel syndrome [3].
`3-[((2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-{[5-
`(morpholinomethyl)-2H-1,2,3-triazol-4 yl]methyl} pip-
`erazinyl)methyl]-1H-indole dihydrochloride (SLV317)
`is a potent and highly selective NK-1 receptor antagonist
`
`in vitro
`
` and
`
`in vivo
`
`. Preclinical data have revealed that
`the compound acts
`
`in vivo
`
` mainly as a peripheral NK-1
`receptor antagonist. SLV317 reduced visceral hypersen-
`sitivity to colonic distension in rats with a maximal
`inhibition of visceral hypersensitivity of 70% [4].
`SLV317 had weak, but significant effects on gastrointes-
`tinal transit. It reduced faecal output in rats and exhib-
`ited antidiarrhoeal activity in rats and mice. In a model
`of inflammatory bowel disease in guinea-pigs, oral
`doses of SLV317 significantly reduced various parame-
`ters of trinitrobenzenesulphonic acid (TNBS)-induced
`ileitis [5]. Based on these data, SLV317 is a promising
`compound potentially counteracting visceral pain and
`inflammation in hypersensitive patients with inflamma-
`tory bowel disease or irritable bowel syndrome.
`However, the presumed mechanism of action (NK-1-
`antagonism of SLV317) has not been demonstrated in
`humans so far. Proof of mechanism in humans is of
`particular importance for the further development of the
`compound because the primary sequence of the human
`NK-1 receptor protein differs from the sequence of ani-
`mal NK-1 receptors. Although these differences do not
`affect agonist responses, it has been shown that they
`may markedly reduce the potency of antagonists [6].
`We aimed to investigate the pharmacokinetics after a
`single oral dose of SLV317 in healthy male volunteers,
`confirm the preclinical effects of this compound in
`humans (proof of mechanism) and investigate the rela-
`tionship between pharmacodynamic effects and SLV317
`plasma concentrations. Pharmacodynamic effects were
`evaluated by measuring the antagonism of substance P-
`induced venodilation using the hand vein compliance
`technique. We have shown previously that NK-1 recep-
`tors are present in human hand veins [7] and that sub-
`stance P produces potent, efficient and reproducible
`venodilation, provided that the occurrence of tolerance
`is avoided [8]. Venodilation can therefore be considered
`as an adequate biomarker for effects mediated through
`the human NK-1 receptor.
`
`Methods
`
`Participants
`
`Nineteen healthy male nonsmokers participated in a ran-
`domized, double-blind, placebo-controlled, cross-over
`study after each gave written informed consent. After
`review and approval of the study by the responsible
`Ethics Committee of the Medical Faculty of the Univer-
`sity of Heidelberg, Germany, the study was conducted
`in accordance with the Declaration of Helsinki and its
`subsequent amendments. Only healthy volunteers with-
`out concurrent drug use were included in the study. All
`volunteers had a physical examination, a 12-lead ECG
`and a laboratory examination to exclude haematologi-
`cal, renal or hepatic dysfunction. Further exclusion cri-
`teria were: a history of allergies, known conditions
`causing endothelial dysfunction such as diabetes, hyper-
`lipidaemia, arterial hypertension, hyperhomocystein-
`aemia and smoking, regular medication or treatment
`with drugs within the last 2 weeks, acute or chronic
`illness, and drug or alcohol abuse.
`
`Hand vein compliance technique
`
`The participants abstained from alcohol for at least 24 h
`and from methylxanthine-containing beverages for at
`least 12 h before the measurements of hand vein com-
`pliance were made. Two hours before investigations
`were started they had a standardized light breakfast.
`Venodilator responses were investigated in a quiet room
`maintained at a constant temperature between 23 and
`25
`
`°
`
`C using the dorsal hand vein compliance technique
`according to Aellig [9], with modifications as described
`previously [10]. Hand vein compliance measurements
`always started in the morning and the participants were
`asked to remain in a supine position throughout the
`study.
`In brief, the hand under investigation was placed on
`a vacuum pillow sloping upwards at an angle of 30
`
`°
`
`from the horizontal. All vasoactive compounds were
`administered through a butterfly needle at a constant
`flow rate (0.25 ml min
`
`−
`
`1
`
`) into the vein under investiga-
`tion. In each participant, the same hand vein was used
`for both study phases. Changes of the diameter of the
`vein were recorded using a linear variable differential
`transformer (Schaevitz
`
`®
`
`, Type 100 MHR, Pennsauken,
`NJ, USA) with a freely movable core (weight 0.5 g)
`resting over the centre of the vein under investigation.
`Transformer signals were amplified by a Schaevitz
`
`®
`
`CAS series signal conditioner and the output was
`recorded on a strip-chart recorder (LKB 2210 recorder,
`LKB Produkter AB
`
`®
`
`, Bromma, Sweden) at a paper
`speed of 0.5 cm min
`
`−
`
`1
`
`. The difference between the posi-
`tion of the core before and during inflation of a sphyg-
`momanometer cuff on the same upper arm to 40 mmHg
`gave a measure of the diameter changes under a given
`congestion pressure. Peak heights on the strip-chart
`recorder were linearly proportional to the movement of
` 13652125, 2006, 4, Downloaded from https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/j.1365-2125.2006.02590.x by Test, Wiley Online Library on [28/08/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
`Page 2 of 6
`
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`
`
`
`C. Hesse et al.
`
`416
`
`61
`
`:4
`
`Br J Clin Pharmacol
`
`the core and were measured manually in units according
`to the Department’s standard operating procedures.
`
`Drug administration and assessment of effects
`
`After having installed the tripod for hand vein compli-
`ance technique and having established a stable initial
`baseline with 4% gelatine solution defined as 100%
`relaxation, increasing dose rates of the selective
`
`α
`
`1
`
`-
`adrenoceptor agonist phenylephrine (Neo-Synephrine
`
`®
`
`;
`Abbott Laboratories, North Chicago, IL, USA; dosages
`1.25–8000 ng min
`
`−
`
`1
`
`) were locally infused to constrict
`the vein by about 80%. This preconstriction baseline
`was defined as 0% and the effect of subsequently admin-
`istered vasodilators was expressed in percentage
`changes from the difference between the initial baseline
`diameter during normal saline and the diameter during
`stable preconstriction.
`Once preconstriction was stable, substance P (Calbi-
`ochem/Novabiochem AG, Läufelfingen, Switzerland)
`was coadministered until the maximal venodilation was
`reached (approximately 7–10 min). To prevent the pep-
`tide from sticking to tubing and syringes, substance P
`was dissolved in a 4% gelatine solution. Based on the
`experience of previous experiments in this setting, a
`substance P dose rate was selected that is at the upper
`end of the steep part of the dose–response curve [8]
`(1.5 pmol min
`
`−
`
`1
`
`) and thus is already able to detect small
`antagonistic effects. If a participant reacted with less
`than 50% venodilation to the dose of 1.5 pmol min
`
`−
`
`1
`
`, the
`dose was doubled to 3 pmol min
`
`−
`
`1
`
`.
`SLV317 (250 mg and 25 mg quinine sulphate) or pla-
`cebo (25 mg quinine sulphate), both dissolved in water
`for injection and mint syrup, were then administered as
`an oral solution. A SLV317 dose of 250 mg was chosen
`because this was the highest dose used in preliminary
`experiments in healthy participants and was well toler-
`ated. For blinding, quinine was added to mimic the bitter
`taste of SLV317 and mint syrup to disguise the slightly
`yellowish colour as well as bitter taste of SLV317. The
`infusion of substance P (same dose as before study drug
`administration) was repeated at the following time
`points: 0.5, 1.25, 2, 2.75, 3.5 and 4.25 h after dosing.
`Each peptide application was separated by a wash-out
`phase of 45 min to avoid the occurrence of tolerance [8].
`Before the end of the experiment, immediately fol-
`lowing the last substance P infusion, a single high dose
`(2
`
`µ
`
`g min
`
`−
`
`1
`
`) of the vasodilator sodium nitroprusside
`(SNP) (Nipruss
`
`®
`
`; Schwarz Pharma AG, Monheim, Ger-
`many) was administered into the hand vein for at least
`6 min, to demonstrate that the vein was still fully
`responsive and that full vasodilation could still be
`achieved.
`Dose rates administered locally into the hand vein
`were intended not to result in any systemic effects,
`which were monitored by repeated measurements of
`heart rate and blood pressure. Blood pressure was taken
`before and after every infusion of drugs or solvents
`(sodium chloride, phenylephrine, substance P); a 12-
`lead ECG was monitored continuously up to the end of
`the hand vein compliance measurements.
`
`SLV317 pharmacokinetics
`
`Venous blood samples for SLV317 kinetics were taken
`0.25 h before as well as 0.25, 0.5, 0.75, 1, 1.25, 2.0,
`2.75, 3.5, 4.25, 6, 8, 12 and 24 h after administration of
`SLV317. Blood was drawn into vials containing dry
`heparin, immediately stored on ice (4
`
`°
`
`C) and plasma
`was separated within 30 min at 3000
`
`g
`
` for 10 min. The
`samples were stored at
`
`−
`
`20
`
`°
`
`C until analysis. When time
`points of pharmacodynamic (hand vein compliance
`method) and pharmacokinetic measurements coincided,
`the pharmacodynamic measurements were first finished
`before blood samples were taken, accepting a delay in
`pharmacokinetic sampling of about 5 min.
`
`SLV317 assay
`
`The plasma samples were analysed using a validated
`analytical method (Solvay, internal file). This method
`consists of extraction of SLV317 and its internal stan-
`dard from plasma with diethylether, concentration and
`injection into a high-performance liquid chromatogra-
`phy system with MS/MS detection. Accuracy and pre-
`cision were within specifications; bias was
`
`<
`
`12%; the
`interday coefficient of variation was
`
`<
`
`14%. The lower
`limit of quantification was set at 0.2 ng ml
`
`−
`
`1
`
`.
`
`Safety
`
`Safety was assessed by measuring ECG, pulse rate,
`blood pressure, haematology, blood chemistry, urinaly-
`sis, and by occurrence of adverse events.
`
`Data analysis and statistics
`
`Source verification of all data documented in case report
`forms was performed by an independent clinical moni-
`tor. Nineteen individuals were randomized and thus
`included in the safety analysis. Only the randomized
`participants who completed both dosing sessions
`according to protocol were included in the pharmacody-
`namic analysis (
`
`n
`
`
`
`=
`
` 17). Two participants had to be
`withdrawn due to methodological problems during hand
`vein measurements. One of these two was exposed to
`SLV317 and complete pharmacokinetic data were
`obtained, leading to datasets of 18 participants for phar-
`macokinetic analysis.
` 13652125, 2006, 4, Downloaded from https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/j.1365-2125.2006.02590.x by Test, Wiley Online Library on [28/08/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
`Page 3 of 6
`
`
`
`
`
`
`
`
`NK-1 antagonism of SLV317 in humans
`
`Br J Clin Pharmacol
`
`61
`
`:4 417
`
`The effect of SLV317 was expressed as percentage
`antagonism of substance P-induced venodilation, calcu-
`lated as follows:
`where SP
`
`=
`
` substance P-induced venodilation (units),
`SP0
`
`=
`
` initial substance P-induced venodilation (predos-
`ing) (units) and PC
`
`=
`
` preconstriction baseline (units).
`The area under the effect–time curve (AUC
`
`e
`
`) was
`calculated according to the trapezoidal rule. Statistical
`analysis of AUC
`
`e
`
` was performed using a mixed model
`analysis of variance (
`
`ANOVA
`
`) including the factors sub-
`ject, sequence, period and treatment. Pharmacokinetic
`calculations were performed using WinNonlin Pro-
`fessional 4.0.1 for Windows (Pharsight Corporation,
`Mountain View, CA, USA). Differences in vital signs
`and dose rates were assessed with Wilcoxon signed rank
`test, unless stated otherwise. Data are expressed as mean
`
`±
`
` SEM. A
`
`P
`
`-value of
`
`<
`
`0.05 was considered significant.
`
`Results
`
`The participants had a mean age of 25
`
`±
`
` 1 years (range
`19–32 years), a mean weight of 78.0
`
`±
`
` 1.8 kg (range
`68.5–95.8 kg), a mean height of 183
`
`±
`
` 2 cm (range 171–
`197 cm) and a mean body mass index of 23.4
`
`±
`
`1.4 kg m
`
`−
`
`2
`
` (range 21.1–26.0 kg m
`
`−
`
`2
`
`).
`
`Pharmacokinetics
`
`After oral administration SLV317 was rapidly absorbed
`and plasma concentrations reached peaks of 77
`
`±
`
` 9 ng
`ml
`
`−
`
`1
`
` within 47
`
`±
`
` 3 min (Figure 1). The mean AUC
`
`0–
`
`∞
`
`was 183
`
`±
`
` 22 h ng−1 ml−1; the mean half-life was 9.9
`± 1.6 h. In the terminal phase of concentration–time
`curves 24 h after dosing, SLV317 was still detectable at
`low concentrations in all participants. Large interindi-
`vidual variability was observed for C
`max and AUC, with
`the ratio between maximal and minimal value being 6.5
`for C
`max and 6.3 for AUC.
`Pharmacodynamics
`Phenylephrine dose rates used to preconstrict hand
`veins were similar in both study phases (SLV317
`1370 ± 297 ng min
`−1; placebo 1491 ± 286 ng min−1; P =
`0.75), as was the preconstriction expressed as a percent-
`age from the initial vein diameter recorded during infu-
`sion of solvent (SLV317 21 ± 2%; placebo 25 ± 4%;
`P = 0.81). Substance P dose rates were equal for both
`study treatments (SLV317 2.0 ± 0.2 ng min
`−1; placebo
`2.1 ± 0.2 ng min−1; P = 1.00 for the sign test) and the
`mean venodilation induced by substance P was similar
`immediately before oral administration of SLV317
`(56 ± 8%) or placebo (49 ± 6%; P = 0.64).
`%%antagonism SP PC
`SP PC=- -
`- ◊100 0 100
`After administration of 250 mg SLV317, substance P-
`induced venodilation markedly decreased while vasodi-
`lation during placebo was unchanged ( P < 0.001;
`Figure 2). Correspondingly, the antagonizing effect of
`SLV317 markedly increased after administration of
`250 mg SLV317 compared with placebo (Figure 3). The
`maximum antagonizing effect of SLV317 ( E
`max) aver-
`aged 95 ± 8% [95% confidence interval (CI) 78, 111]
`and was observed after 1.47 ± 00.24 h (median 01.25 h;
`95% CI 0.96, 1.98). At the time point of Emax under
`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
`Time [hrs]
`0
`SLV317 [ng/ml]
`1
`10
`100
`4 81 2 2 4
`Figure 2
`Substance P-induced venodilation expressed as percent reversal of
`phenylephrine-induced preconstriction after oral administration of the NK-
`1 receptor antagonist SLV317 (/H17033) or placebo ( /H17034) in 17 healthy
`participants (mean ± SEM)
`Time [hrs]
`0
`Substance P-induced venodilation
`[% dilation]
`0
`20
`40
`60
`123 4
` 13652125, 2006, 4, Downloaded from https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/j.1365-2125.2006.02590.x by Test, Wiley Online Library on [28/08/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
`Page 4 of 6
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`
`
`
`
`
`
`C. Hesse et al.
`418 61:4 Br J Clin Pharmacol
`active treatment the antagonism of venodilation under
`placebo averaged 19 ± 14% (95% CI −11, 49; P <
`0.001). Also, the mean AUC e after administration of
`SLV317 (278 ± 67% h−1; 95% CI 198, 358) was signif-
`icantly higher compared with placebo (49 ± 12% h−1;
`95% CI −24, 122; P < 0.001). There were no carry-over
`effects ( P = 0.33) and no period effects ( P = 0.22) as
`tested with ANOVA. The response to SNP at the end of
`the experiment was pronounced and not different for
`either study treatment (SLV317 92 ± 9%; placebo
`96 ± 7%; P = 0.69).
`Concentration–effect relationship
`Figure 4 shows mean substance P-induced venodilation
`(% antagonism) plotted against the corresponding
`SLV317 plasma concentrations. High SLV317 plasma
`concentrations and maximum effects were reached
`already at the time of the first pharmacodynamic assess-
`ment and the antagonistic effect persisted throughout the
`study while plasma concentrations declined (counter-
`clockwise hysteresis).
`Safety
`Oral administration of 250 mg SLV317 was well toler-
`ated by all participants. Neither SLV317 nor placebo
`induced significant changes in heart rate, blood pressure
`or ECG parameters. At baseline and 4.5 h after admin-
`istration of SLV317 blood pressure values (systolic/
`diastolic) were 124 ± 3/68 ± 3 vs. 127 ± 2/72 ± 2 mmHg
`(P = 0.10/P = 0.12) and heart rate was 60 ± 2 vs. 63 ±
`2 beats min
`−1 (P = 0.14). The respective values after pla-
`cebo administration were 125 ± 3/69 ± 2 vs. 127 ± 2/
`71 ± 2 mmHg ( P = 0.14/P = 0.17) and 62 ± 3 vs. 63 ±
`2 beats min−1 (P = 0.64).
`No serious adverse event occurred. Six adverse events
`during placebo [mild headache ( n = 4), cloudy urine,
`mild orthostatic dysregulation] and three adverse events
`during SLV317 (mild headache, severe headache,
`cloudy urine) were reported and classified as possibly
`related to the study drug. All resolved without any
`sequelae within the following hours. Cardiovascular,
`laboratory and physical investigations showed no clini-
`cally relevant changes.
`Discussion
`This double-blind placebo-controlled study is the first
`to show that SLV317 is an orally active and highly
`effective antagonist of substance P-induced effects in
`humans. SLV317 was rapidly absorbed and well toler-
`ated. It caused a substantial reduction of substance P-
`induced venodilation, which was already almost fully
`established at the time of the first measurement (30 min
`after dosing) and which was still pronounced at the end
`of the measurements (after 4.25 h).
`Because substance P is by definition the natural NK-
`1 receptor agonist with the highest affinity [11], this
`peptide is best suited to study NK-1 receptor effects in
`humans. We have shown previously that NK-1 receptors
`are present in human hand veins [7] and that substance
`P produces potent, efficient and reproducible venodila-
`tion, provided that the occurrence of tolerance is
`avoided [8]. Substance P-induced changes in hand vein
`compliance may therefore constitute a surrogate for
`effects mediated by the human NK-1 receptor. Thus, this
`Figure 3
`Antagonism of substance P-induced venodilation after oral administration
`of the NK-1 receptor antagonist SLV317 (/H17033) or placebo (/H17034) 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%
`Time [hrs]
`0
`Antagonism of substance
`P-induced venodilation [%]0
`20
`40
`60
`80
`100
`1234
`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)
`SLV317 [ng/ml]
`00 10 1
`Antagonism of substance
`P-induced venodilation [%]
`0
`20
`40
`60
`80
`100
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`NK-1 antagonism of SLV317 in humans
`Br J Clin Pharmacol 61:4 419
`study shows that SLV317 substantially antagonizes sub-
`stance P-induced venodilation, suggesting peripheral
`NK-1-antagonistic activity of SLV317 in humans. We
`obtained only limited information on the selectivity of
`SLV317 for the NK-1 receptor in the present study
`because we administered only one dose of only one
`additional vasodilator acting through an independent
`second messenger pathway (sodium nitroprusside).
`However, SLV317 has been shown to be highly selective
`for the NK-1 receptor in animal models [4] and the
`preserved full relaxation of the hand vein through acti-
`vation of the nitric oxide–cGMP pathway by SNP is in
`line with these findings. Changes in substance P
`responses were not caused by counter-regulatory reflex
`activation or altered vascular smooth muscle reactivity,
`as indicated by the absence of haemodynamic effects of
`SLV317 and the similar response to SNP after both
`SLV317 and placebo treatment.
`Rapid onset and the persistence of the antagonistic
`effect precluded assessment of SLV317 potency by con-
`struction of the expected sigmoidal concentration–effect
`relationship. During the evaluation of hand vein
`responses SLV317 plasma concentrations declined from
`a mean maximum of 77 ng ml
`−1 (109 nmol l −1) to a
`mean of 7 ng ml−1 (10 nmol l−1), whereas no substantial
`change in its effect occurred. The sustained antagoniz-
`ing effect at low concentrations might suggest that
`SLV317 is a potent NK-1 receptor antagonist and that
`maximum receptor blockade in vivo might already be
`reached with much lower doses. Information on plasma
`concentrations required to induce the maximum effect
`is of interest to define dose ranges for subsequent
`studies.
`As an oral solution, SLV317 kinetics was highly vari-
`able with respect to absorption and elimination of the
`compound. If the potency of the compound were to be
`defined in this model, future pharmacodynamic studies
`should be planned with smaller doses or repetitive
`administration of fractions of the total dose to be able
`to quantify vascular effects in the steep part of the con-
`centration–effect relationship. Moreover, because of the
`rapid absorption, pharmacodynamic measurements
`should start already 15 min after dosing. A solid galenic
`formulation or even a slow-release formulation might
`allow the pharmacodynamic evaluation during the
`absorption process.
`In conclusion, this study in healthy participants
`revealed clear evidence of a profound inhibition of sub-
`stance P-induced venodilation by a single oral dose of
`SLV317. This is in complete agreement with the concept
`that SLV317 acts as a potent inhibitor of human NK-1
`receptors in vivo. Future studies are required to establish
`the dose–response relationship in man and to assess a
`potential therapeutic effect in patients with diseases
`probably linked to NK-1 receptor stimulation such as
`visceral pain and inflammation in patients with inflam-
`matory bowel disease or visceral pain in irritable bowel
`syndrome patients.
`We are grateful to Brigitte Tubach and Reinhard Ding
`for their excellent study support. Solvay Pharmaceuti-
`cals, the Netherlands, the manufacturer of SLV317, has
`contributed funds to perform this study at Heidelberg
`University.
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` 13652125, 2006, 4, Downloaded from https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/j.1365-2125.2006.02590.x by Test, Wiley Online Library on [28/08/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
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