(Hypertension. 1995;25:14-21.)
© 1995 American Heart Association, Inc.
Articles |
Characterization of the Angiotensin II Receptor Antagonist TCV-116 in Healthy Volunteers
From the Division of Hypertension and the Division of Clinical Pharmacology (J.B.), University Hospital, Lausanne, Switzerland.
Correspondence to Hans R. Brunner, Division of Hypertension, CHUV, 1011 Lausanne, Switzerland.
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Abstract The purpose of this study was to assess the inhibitory effect of TCV-116, an orally active angiotensin II (Ang II) antagonist, on the pressor action of exogenous Ang II and to determine the compensatory rise in plasma renin activity and Ang II levels. Twenty-three male volunteers were treated for 8 days in a double-blind fashion with either placebo or TCV-116 (1, 2, or 4 mg PO daily) and challenged on the first, fourth, and eighth days with repeated bolus injections of Ang II. An additional 4 subjects received 8 mg PO daily in a single-blind fashion. The inhibitory effect on the systolic blood pressure response to Ang II was long lasting and clearly dose related. Six hours after 4 mg TCV-116, the systolic blood pressure response to a given dose of Ang II was reduced to 40±4% and 35±8% of baseline value on days 1 and 8, respectively. TCV-116 induced a dose-related increase in plasma renin activity and Ang II levels that was more pronounced on the eighth than on the first day of drug administration. Despite this compensatory mechanism, the relation between the time-integrated systolic blood pressure response to Ang II and the time-integrated CV-11974 levels, the active metabolite of TCV-116, was not different between days 1 and 8. In conclusion, TCV-116 appears to be a well-tolerated, orally active, potent, and long-lasting antagonist of Ang II in men.
Key Words: angiotensin II • aldosterone • renin • dose-response relationship, drug
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Introduction |
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Blockade of the renin-angiotensin system has turned out to be a very effective treatment of hypertension and congestive heart failure.1 2 3 4 Today, angiotensin-converting enzyme (ACE) inhibitors are used as therapeutic agents, but originally the concept was established with angiotensin receptor antagonists. Saralasin ([Sar1,Ala8]angiotensin II)5 was the first receptor antagonist of angiotensin II (Ang II) administered to humans.6 7 8 Since this peptide is not orally active, long-term antihypertensive treatment was not possible. Furthermore, the antagonist exhibited significant inherent agonist activity.9 Therefore, most patients did not respond with a decrease in blood pressure. Furukawa and coworkers10 have synthesized some imidazole derivatives that specifically block the Ang II–induced vasoconstriction. Important chemical modification of these initial molecules has led to the synthesis of new orally active Ang II receptor antagonists.11 12 Although most of the compounds specifically block the angiotensin type 1 (AT1) receptor responsible for all hitherto known Ang II actions, including vascular smooth muscle contraction,13 14 some compounds that specifically bind to the AT2 receptors were also synthesized.13 15 16 17 The first orally active AT1 receptor antagonist, DuP 753 (losartan), was shown to effectively block the pressor effect of exogenous Ang II18 19 and to reduce blood pressure of patients in a manner similar to ACE inhibitors.20 21 Although losartan is a potent Ang II receptor antagonist, its therapeutic effect is probably mostly due to its active metabolite, EXP3174, which exhibits about 10-fold higher affinity to the receptor.22
TCV-116, a new AT1 receptor antagonist, and its active metabolite (CV-11974) have been shown in different pharmacological studies to be approximately 10-fold more potent than losartan and to have a long elimination half-life. The objectives of the present study were to assess the inhibitory effect of TCV-116 on the pressor action of exogenous Ang II in healthy volunteers, to determine the dose dependency and duration of the inhibitory effect, to evaluate the correlation of the inhibitory effect with serum levels of the active metabolite CV-11974, and to determine the effect of the compound on plasma Ang II, aldosterone, and catecholamine levels.
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Methods |
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Subjects
Twenty-seven male volunteers aged 20 to 36 years (mean, 26.0 years) and weighing between 48 and 85 kg (mean, 69.9 kg) were enrolled in the randomized, double-blind, placebo-controlled parallel design dose-ranging study. Volunteers underwent a complete physical evaluation, electrocardiogram, and routine blood and urine analyses before being included in the study. The study was conducted in accordance with the principles of the Declaration of Helsinki. The protocol was reviewed and approved by the institutional review committee before the study was started. The nature, purpose, and potential risks of the study were explained to each volunteer, and written consent was obtained.
Blood Pressure Measurement
The pressor effect of exogenous challenges of Ang II was
measured on the finger using a photoplethysmograph (Finapres, Ohmeda).
The measurement technique, which is a noninvasive method measuring
digital artery blood pressure continuously through a cuff wrapped
around the finger, was first described by Penaz in 1973.23
The monitor provides beat-to-beat blood pressure values (systolic,
diastolic, and mean) and heart rate. This device has been demonstrated
to correlate well with intra-arterial pressure24 25 and to
be accurate for the study of short-lasting blood pressure changes by
vasoactive agents in humans.26 Blood pressure and heart
rate were continuously recorded on graduated paper 10 minutes before
and at least 15 minutes after injection of each Ang II challenge. Peak
blood pressure changes were calculated using these tracings.
Study Design
Throughout the study, volunteers were on a free sodium intake.
No medication other than the study drug was allowed, neither were
cigarette smoking and consumption of alcohol or caffeine-containing
beverages and food. One week before the first study day, a
dose-response curve to intravenous bolus injections of Ang II was
established for each subject. The goal was to obtain a test dose able
to increase systolic blood pressure (SBP) by 25 to 40 mm Hg. Ang II
(Clinalfa) was dissolved in 0.9% NaCl to achieve a concentration of 1
µg/mL. After a polytetrafluoroethylene cannula was placed in the
antecubital vein and after a 30-minute resting period to reach a steady
baseline blood pressure and heart rate, bolus injections were started
at a dose of 10 ng/kg and increased thereafter every 15 to 20 minutes
by increments of 10 ng/kg until the required blood pressure increase
was reached. This individual final test dose was then repeated at least
twice and was subsequently used to assess the inhibitory effects of
TCV-116 during the entire study. The median dose determined for Ang II
challenges was 30 ng/kg (range, 10 to 60 ng/kg). The corresponding
baseline responses (increase of SBP after Ang II challenges) were on
average 31.1 mm Hg (range, 28.3 to 38.7 mm Hg).
TCV-116 [(±)-1-(cyclohexyloxycarbonyloxy)ethyl-2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1-H-benzimidazole-7-carboxylate] (Fig 1) is the active metabolite of CV-11974. In fact, CV-11974 was synthesized first, but its bioavailability was less than 5% in animals. Therefore, the prodrug, TCV-116, was developed by esterizing the carboxylic group of CV-11974 at position 7 of the benzimidazole ring (see Fig 1). After oral administration, 14C-labeled TCV-116 is not detected in plasma, whereas radiolabeled CV-11974 is present.27 In vitro studies have shown that the inhibitory effect of TCV-116 on the Ang II (10-8 mol/L)–induced contraction of rabbit aorta was approximately one thirtieth that of CV-11974.27 Accordingly, it appears that the inhibitory activity resides almost exclusively in CV-11974. TCV-116 is absorbed and converted to the active metabolite CV-11974 (Fig 1). Results of in vitro studies with 14C-labeled CV-11974 showed that the protein binding of the compound was concentration independent over the range of 10 to 104 ng/mL. In rats, dogs, and humans, 99.6% to 99.8%, 96.7% to 97.5%, and 99.4% to 99.6% of CV-11974 is bound to protein.
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TCV-116 was provided by Takeda Europe R&D Centre in the form of 1-, 2-, 4-, and 8-mg film-coated tablets. Placebo tablets were identical in appearance. The tablets were administered with 200 mL tap water.
Volunteers received on the mornings of 8 consecutive days one dose of TCV-116 (1, 2, or 4 mg) or placebo. Thus, each dose or placebo was given in a double-blind fashion to 6 volunteers, except the 1-mg dose, which was given to only 5 volunteers because of a dropout at entry screening. The 8-mg dose was administered subsequently to 4 additional volunteers in a single-blind fashion, when it had become evident that doses up to 4 mg may not produce maximal inhibition of the Ang II pressor response. During study days 1 through 9, the volunteers came every day at 6:30 AM to the research facility having fasted overnight (from 10 PM). Supine blood pressure and heart rate were measured after a 45-minute supine resting period. On study days 1 through 8, the dose of TCV-116 or placebo was administered at 8 AM. On days 1 and 8, systolic and diastolic pressor effects of Ang II challenges were measured before and after drug or placebo intake. Venous cannulas were inserted into a vein in each forearm, one line for angiotensin injections and the other for blood sampling. The blood pressure–monitoring cuff was wrapped around the third or fourth finger on the side used for blood sampling. After a period of bed rest of at least 45 minutes and approximately 45 minutes before TCV-116 or placebo was given to the volunteers, the established test dose of Ang II (selected according to the predetermined dose-response curve) was administered. The effect of the drug was then monitored on days 1 and 8 using bolus injections of the Ang II test dose at 1, 2, 3, 4, 6, 8, 12, 24, and 36 hours after drug intake. Additional Ang II challenges were also performed on day 4 before and 2, 6, and 12 hours after TCV-116 or placebo administration. The volunteers remained fasting and in a supine position for 6 hours after drug administration; they then received a light meal and remained resting in bed or seated for 6 more hours (supine for 1 hour before each blood sampling). Between hours 12 and 22.5, they were allowed to leave the hospital. At the end of the study, all volunteers underwent routine and laboratory safety evaluation.
Hormone and Drug Measurements
On days 1 and 8, plasma renin activity (PRA), Ang II,
aldosterone, norepinephrine, and epinephrine were measured immediately
before and 2, 4, 6, 12, and 24 hours after drug or placebo intake. The
same parameters were also measured on day 4 immediately before drug or
placebo intake. Additional samples for the measurement of plasma
concentrations of CV-11974, the active metabolite of TCV-116, were
drawn on every day of the study immediately before drug intake and
repeatedly on days 1 and 8 (days 1 and 8: 1, 2, 2.5, 3, 3.5, 4, 6, 8,
12, and 24 hours; day 8: 30 and 36 hours after drug or placebo intake).
Blood sampling was always performed immediately before the next
angiotensin challenge. Volunteers remained in a supine position for 60
minutes before all these blood samples.
Blood samples (5 mL) for measurement of plasma CV-11974 concentration were collected into heparinized tubes, and plasma was stored at -70°C until analyzed. The active metabolite CV-11974 (molecular weight, 610.67) was analyzed by reversed-phase high-performance liquid chromatography (HPLC) after extraction from acidified serum into ethyl ether. Briefly, 0.5 mL serum was acidified with 0.5 mL of 0.2 mol/L hydrochloric acid. After mixing, 5.0 mL ethyl ether was added to extract CV-11974 by shaking for 15 minutes. One hundred microliters of 10% propylene glycol in methanol was added to the organic extract before evaporation under nitrogen. The residue was taken up in 200 µL of mobile phase A (acetonitrile/KH2PO4 [20 mmol/L], pH adjusted to 3.5 with 85% H3PO4). One hundred microliters was injected. A column-switching HPLC method was used. A fraction containing CV-11974 from column A was eluted by mobile phase A into column B. CV-11974 was separated from the coeluting endogenous compounds using mobile phase B (acetonitrile/KH2PO4 [20 mmol/L], 34:66). A 10-port column-switching valve was used to control the time events. The detection limit of CV-11974 was 0.8 ng/mL or 1.3 nmol/L in human serum. The extraction recovery of CV-11974 from serum was 70% and was consistent over the entire standard curve range.
For the measurement of PRA, generated Ang I was trapped and quantitated by high-affinity antibodies.28 29 Immunoreactive Ang II was quantitatively extracted from plasma by reversible adsorption to phenylsilyl silica and estimated by radioimmunoassay using monoclonal antibodies against Ang II.30 Plasma aldosterone was determined by a direct radioimmunoassay.31 Plasma norepinephrine and epinephrine levels were determined using the radioenzymatic method of Peuler and Johnson32 as modified for our laboratory.33 Subjects remained in a supine position for 30 minutes before blood sampling.
The percent of baseline pressor response to Ang II was time-integrated up to 24 hours in calculating the area under the curve according to a trapezoidal rule for each individual volunteer. The same was done for time integration of CV-11974 concentration and PRA and Ang II plasma levels up to 24 hours.
Pharmacokinetic Calculations
A one-compartment model after extravascular administration was
fitted to the plasma data by extended least-squares nonlinear
regression with the error model=v(1) (homoscedastic model). In two
subjects, a two-compartment model had to be used. The area under the
time versus concentration time curve (AUC) was calculated using the
trapezoidal rule in the ascending portion of the curve and the
log-trapezoidal rule for the descending concentrations and was
extrapolated to infinity at day 1 and up to 24 hours at day 8 (one
dosing interval). The (apparent) clearance (CL') was calculated
assuming complete absorption and transformation of TCV-116 into
CV-11974 as dose/AUC and the terminal half-life (t1/2) as
Ln(2)/
z. The mean residence time (MRT) was calculated as
(AUMC/AUC)-MAT, where AUMC represents the area under the first
moment of the concentration versus time curve (to infinity) and MAT the
mean formation time.
Statistical Analysis
All values are mean±SEM. Blood pressure and heart rate
responses to the Ang II challenge were defined as the difference
between the values before and after individual challenges and expressed
as percent of the mean baseline response to the individual final test
dose of Ang II. Statistical analysis was performed using ANOVA for
repeated measures and paired t test with the Bonferroni
adjustment for multiple comparisons (SUPERANOVA 1.1,
Abacus Concepts, Inc). The time-integrated parameters (SBP response to
Ang II, PRA, plasma drug, and Ang II concentrations) were analyzed by a
two-factor ANOVA followed when required by a Fischer's protected least
significant difference test. The correlation coefficients were
calculated when indicated by the least-squares method. A probability
value of less than .05 was considered significant.
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Results |
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Safety of Oral Administration of TCV-116
No clinically significant adverse reaction was observed in any volunteer during the study. TCV-116 had no effect on (resting) supine or upright blood pressure and heart rate after the first administration or during the 8-day treatment. TCV-116 did not modify blood cell counts, routine laboratory tests, urine analyses, or electrocardiograms. Of the 24 volunteers collected for the initial randomization, 2 had to be withdrawn before administration of the medication because of abnormal laboratory findings and only 1 of them could be replaced in time.
Blood Pressure Response to Ang II
The Table and Fig 2 show the
dose-related inhibition of the SBP response to exogenous Ang II. Doses
of 1, 2, 4, and 8 mg induced a dose-related inhibition of the response
to Ang II. On day 1, the peak inhibitory effect was reached between 4
and 8 hours after drug intake; 4 hours after the 4-mg dose, the blood
pressure response to Ang II decreased to 41±9% and 21±7% of the
baseline response on days 1 and 8, respectively. The mean blood
pressure response to Ang II of the 4 volunteers treated with the 8-mg
dose in a single-blind fashion decreased to 22±3% and 16±6% 4 hours
after drug intake. On day 1, a significant attenuation of the blood
pressure response to Ang II was still present 24 hours after intake
of the 2-, 4-, and 8-mg doses of TCV-116 (75±5%, P<.01;
58±11%, P<.05; 49±6%, P<.01, respectively,
versus predrug blood pressure response). The integral of SBP response
over 24 hours is represented in Fig 2B. The trough effect on day 8
showed no statistically significant difference compared with the trough
effect on day 1. Except for the 1-mg dose on day 1, any dose of TCV-116
significantly reduced the SBP response to Ang II, and this reduction
was dose related. The time-integrated SBP response tended to decrease
slightly more on day 8 than on day 1.
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P<.01.
Pharmacokinetics
Plasma concentrations of TCV-116 were not detected. After the
administration of TCV-116, its active metabolite CV-11974 appeared
after a mean lag time of 1.0 hour (days 1 and 8) and reached a peak
(Tmax) between 3.5 and 6 hours. Its mean formation
time was 1.2 and 1.3 hours on days 1 and 8, respectively. The mean
concentrations of CV-11974 are described in the Table and plotted in
Fig 3 (day 1: Fig 3A, left; day 8: Fig 3A, right).
Maximal concentrations (Tmax) and AUC values increased in
proportion to the dose after the three low doses but less than expected
at the high dose. Except once in 2 subjects, the plasma concentrations
declined monoexponentially with half-life periods of 3.5 hours (day 1)
and 4.0 hours (day 8). Plasma levels were still measurable at 24
hours, and trough concentrations remained unchanged from day 2 through
day 8 for all doses of TCV-116. MRT values were 8.1 and 9.7 hours on
days 1 and 8, respectively. The apparent clearance of CV-11974, its
maximal possible clearance given the assumptions made in its
calculation, were 0.25 L · h-1 · kg-1
on day 1 and 0.20 L · h-1 · kg-1 on
day 8.
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P<.001.
Dose-Effect Relations
In Fig 4A, the mean inhibition of the pressure
response to exogenous Ang II challenge is plotted against the
respective concentrations of CV-11974 for each dose and each time point
(up to 24 hours) on day 1. The dose-effect relation shows a
considerable dispersion of individual values (not shown) and mean
values (Fig 4A, left), which accounts for an anticlockwise hysteresis
loop (Fig 4A, right) on day 1. This loop characterizes a slow onset of
the inhibitory effect of the drug on blood pressure while plasma
concentrations of CV-11974 are increasing, and a sustained effect when
drug concentrations are falling. The time necessary to collapse both
arms of the curve varies between 1 and 2 hours. This loop in
dose-effect relations exists for each individual volunteer (data not
shown). On day 8, the loop is flattened (data not shown). Furthermore,
for a given plasma drug level, the degree of inhibition of the SBP
response to Ang II seems to be higher on day 8 than on day 1. Fig 4B
illustrates the same relation for the time-integrated data of
individual subjects on days 1 and 8 taking into account the duration of
the drug effect (the integral of the percentage of inhibition over 24
hours was related to the AUC of CV-11974 during the same period). This
time-integrated dose-effect relation showed a linear pattern without
any plateau, although the maximal inhibition is reached with the higher
CV-11974 plasma concentrations. Although the magnitude of the
inhibition of the blood pressure response to Ang II does not change,
its duration is prolonged, leading to a linear increase of the
time-integrated hemodynamic effect.
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Neurohumoral Variables
The Table and Fig 5 depict PRA and Ang II plasma
levels measured at the first and eighth administration of placebo or
TCV-116. Both PRA and Ang II showed a marked dose-related increase 6
hours after drug intake, and this increase reached clearly higher
values on day 8 than on day 1. Both variables had already increased
significantly 4 hours after administration of 2, 4, and 8 mg TCV-116 on
the first day (P<.05 versus placebo).
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A very close correlation was found between PRA and plasma Ang II (r=.91, n=348, P<.001). There was also a negative correlation between the increase in PRA and the SBP response to exogenous Ang II (r=-.456, n=348, P<.001). Neither plasma norepinephrine nor plasma epinephrine (not shown) changed during the 8-day administration of TCV-116.
Fig 6 shows plasma aldosterone concentrations. Plasma aldosterone levels decreased after administration of single doses of TCV-116, but a similar decrease was also seen after placebo, reflecting the circadian variation in aldosterone concentrations.
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Discussion |
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The present data demonstrate that TCV-116 is a potent, orally active Ang II antagonist with a relatively long duration of action. At peak effect (8 hours after drug intake), the 4-mg dose induced a 72±5% and 77±4% reduction in the systolic and diastolic blood pressure responses to Ang II, respectively. With the three higher doses used, ie, 2, 4, and 8 mg, a definite blocking effect was still present 24 hours after drug intake (day 1). With these three higher doses, the trough inhibition of Ang II pressor effect was greater on day 8 than on day 1, so that before drug intake on day 8, the pressor response to Ang II was only approximately 75% of the comparable response on day 1, suggesting that the drug exerts an effect that lasts for more than 24 hours. With repeated administration, no significant cumulative progressive enhancement of the blocking action could be observed at peak or trough. The dose dependency of the hemodynamic effect was clearly demonstrated with the four doses of TCV-116 throughout the treatment period (Fig 2).
The presence of constant trough levels from day 2 to day 8 suggests that no accumulation is occurring. These residual levels account for a negligible fraction (<6%) of the AUC values. The absence of a dose-proportional increase in the AUC values between the 4- and 8-mg doses of TCV-116 could be due to nonlinear pharmacokinetics. Saturable absorption of TCV-116 or conversion to CV-11974 at a high dose is another possibility, as suggested by the prolongation of MRT values with increasing doses, that is also compatible with a lengthened absorption process. The CV-11974 concentration–blood pressure effect curve revealed an anticlockwise hysteresis loop, probably caused by pharmacokinetic influences determining the distribution of the drug to its site of action.
PRA and Ang II levels exhibited dose-related compensatory increases as described with previously tested Ang II antagonists.6 34 The rise in renin and Ang I is similar to that observed after administration of ACE inhibitors.35 With repeat administration of TCV-116, the increase was accentuated, the PRA and Ang II levels being much higher on day 8 than on day 1. The greater increase on day 8 than on day 1 in the PRA and Ang II values probably reflects the indirect effects of prolonged Ang II inhibition on sodium balance. The long duration of the blocking effect of TCV-116 is also reflected in the PRA and Ang II levels. Thus, 24 hours after the administration of 2, 4, or 8 mg, PRA and Ang II remained increased.
As expected, Ang II plasma levels were strongly correlated with PRA, and the response of both variables was inversely correlated with the SBP response to Ang II challenges. However, when individual data are considered, a substantial variability in these reactive increases becomes evident, as observed previously with losartan.22 Therefore, the SBP response to Ang II challenges rather than the response of circulating levels of renin or Ang II should be used to predict the degree of Ang II receptor blockade in the individual subject.
Can such high Ang II plasma levels after an 8-day treatment with an Ang II antagonist finally reduce the effect of the Ang II antagonist? This is a priori unlikely to occur, because the exogenous Ang II probably induces much higher Ang II plasma levels than those occurring during the compensatory increase in renin secretion. Furthermore, the fact that for a given plasma CV-11974 level the degree of inhibition of the pressor response to Ang II tends to be greater on day 8 than on day 1 (Figs 2 and 4B) also suggests that the level of circulating Ang II has no measurable influence on the blocking effect of the AT1 antagonist.
No effect of the Ang II antagonist on plasma aldosterone could be demonstrated. Indeed, plasma aldosterone levels decreased in treated subjects in a manner similar to that in the control group on placebo. This decrease in aldosterone levels is mainly due to the circadian rhythm of aldosterone secretion.36
The most relevant question clinically is how TCV-116 will compare as a therapeutic agent with the various agents currently available for blockade of the renin-angiotensin system. Obviously, results from the present study cannot provide any conclusive answer to this question because the drug was administered only to healthy volunteers. Nevertheless, it is already evident that this Ang II antagonist exhibits features that make it appear promising as a therapeutic agent. As with losartan,18 19 it is orally active and does not seem to have any agonist effect. With the use of ACE inhibitors, the antihypertensive effect has been shown to be well correlated with the decrease in plasma Ang II concentration. Furthermore, blockade of the pressor effect of exogenous angiotensin has been shown to be strongly correlated with plasma Ang II37 concentration. Consequently, since doses of 4 to 8 mg induce a more than 75% blockade of the pressor effect of Ang II in our study, we speculate that the oral antihypertensive dose of TCV-116 will be in the range of 4 mg/d. A similar projection was made with losartan. This agent was shown to maximally inhibit the pressor response to Ang II with doses less than 40 mg but less than or equal to 80 mg18 ; the full antihypertensive effect was subsequently obtained with 50 mg/d.21 38 39 40
In conclusion, TCV-116 appears to be a well-tolerated, orally active, potent, and long-lasting antagonist of Ang II in men. TCV-116 induced neurohumoral compensatory mechanisms that did not decrease its effect as measured by inhibition of blood pressure response to exogenous Ang II.
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Acknowledgments |
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This work was supported by the Cardiovascular Research Foundation, the Swiss National Science Foundation, and Takeda Europe Research and Development Centre.
Received June 27, 1994; first decision July 27, 1994; accepted September 8, 1994.
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