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Mavik - Scientific Information

Manufacture: Abbott
Country: Canada
Condition: Diabetic Kidney Disease (Diabetic Nephropathy), Heart Attack (Myocardial Infarction), Heart Failure (Congestive Heart Failure), High Blood Pressure (Hypertension), Left Ventricular Dysfunction
Class: Angiotensin converting enzyme inhibitors
Form: Tablets, Capsules
Ingredients: trandolapril, erythrosine, gelatin, iron oxides and hydroxides, lactose, maize starch, povidone, sodium lauryl sulphate, sodium stearyl fumarate, titanium dioxide

Pharmaceutical Information

Proper name:Trandolapril
Chemical name:(2S, 3aR, 7aS)-1-[(S)-N-[(S)-1-(ethoxycarbonyl)-3-phenylpropyl]
alanyl] hexahydro-2-indolinecarboxylic acid
Molecular formula
and molecular
mass:
C24H34N2O5430.5
Structural formula:



Physicochemical
properties:
White crystalline powder with a melting point of approximately
125°C and a pKa=5.6. Practically insoluble in water, and freely
soluble in chloroform, dichloromethane and methanol. It is free of
odour with a bitter taste.

Clinical Trials

Study Demographics and Trial Design

Hypertension

Table 1. Summary of Patient Demographics for Clinical Trials in Patients with Mild to Moderate Essential Hypertension
Study #Trial DesignDosage, Route of
Administration
and Duration
Study Subjects
(n=number)
Mean Age
(Range)
Gender
Study IMulticentre,
randomized, doubleblind,
placebocontrolled
0.5, 1 or 2 mg daily
Oral dose
28 days
170
Placebo: 44
Trandolapril: 126
48.2 years
( 17 to 72)
Male: 66
Female: 104
Study IIMulticentre,
randomized, doubleblind,
placebocontrolled
0.25, 0.5, 1, 2 or 4
mg daily
Oral dose
6 weeks
313
Placebo: 50
Trandolapril: 263
56.0 years
(25 to 84)
Male: 203
Female: 110

Left Ventricular Dysfunction Following Acute Myocardial Infarction

Table 2. Summary of Patient Demographics for Study III (TRACE) in Patients with Left Ventricular Dysfunction Following Acute Myocardial Infarction
Study #Trial DesignDosage, Route of
Administration
and Duration
Study Subjects
(n=number)
Mean Age
(Range)
Gender
StudyIII
(TRACE*)
Multicentre,
randomized, doubleblind,
placebocontrolled
0.5, 1, 2,4 mg daily
Oral dose
24 to 50 months
1749
Placebo: 873
Trandolapril: 876
67.5 years
( 30 to 93)
Male: 1248
Female: 501

* TRACE: TRAndolapril Cardiac Evaluation study

† An oral test dose of 0.5 mg trandolapril was given to all eligible patients prior to randomization; patients were subsequentlyforce-titrated to 1-4 mg per day.

Study Results

Hypertension

Studies I and II compared the efficacy and tolerance of trandolapril to placebo. Trandolapril administered once daily at doses of 1 mg, 2 mg and 4 mg for 4-6 weeks was effective at lowering average trough supine diastolic blood pressure (DBP) in non-black patients with mild to moderate essential hypertension.

Left Ventricular Dysfunction Following Acute Myocardial Infarction

Table 3. Results of Study III (TRACE) Trial in Patients with Left Ventricular Dysfunction after Acute Myocardial Infarction
Primary EndpointsTrandolaprilPlacebop-Value
Mortality from all causes304 (34.7%)369 (42.3%)p=0.001

It can be seen in Table 3 and Figure 1 that trandolapril provides a statistically significant reduction in death from all causes (final analysis of the intent-to-treat population).



Figure 1. Cumulative Mortality from All Causes among Patients Receiving Trandolapril or Placebo

Detailed Pharmacology

Animal

Pharmacodynamics

Mechanism of Action

Table 4 summarizes the trandolapril mechanism of action in animal models

Table 4. Trandolapril Mechanism of Action
StudySpeciesNo. of
animals
per
group
RouteDoseResults
Inhibition of Angiotensin
I induced pressor
response after oral
trandolapril
Rat
(Male)
(Sprague
Dawley)
9-4Oral
Single
Dose
0.003
0.01
0.03
0.1
0.3
ID50: trandolapril 35 mcg/kg
trandolaprilat 500 mcg/kg
Inhibition of Angiotensin
I induced pressor
response after oral
trandolapril
Dog
Beagle
4Oral0.03
0.1
0.3
1.0
Dose dependent inhibition.
At 0.3 mg/kg: 93% inhibition after
1.5 h and 29% after 6 h.
At 1.0 mg/kg: 100% inhibition after
30 min and 59% after 6 h.
Effect of bilateral
nephrectomy
Rat
(spontaneously
hypertensive)
11-10Oral
Single
dose
3The antihypertensive effect was
abolished.
Effect of inhibition of
prostaglandin
biosynthesis (via
Indomethacin 5 mg/kg
p.o.)
Rat
(spontaneously
hypertensive)
11-10Oral
Single
dose
3The antihypertensive effect was not
modified.
In vitro inhibition of
ACE by trandolapril
Blood serum
from
Rat (Sprague
Dawley)
Dog (Beagle)
Human (healthy
male
volunteers)
-In
vitro
-Rat: IC50 = 1.67 ± 0.74 nM
Dog: IC50 = 368 ± 50 nM
Human: IC50 = 7.06 ± 2.11 nM
Regional and general
hemodynamic effects
Rat
(spontaneously
hypertensive)
10Oral5
(for 8
days)
On day 8 systolic blood pressure (SBP)
was reduced by 31% with no effect on
heart rate, cardiac index and stroke
volume. Total peripheral resistance
was reduced by 37%. Regional
vascular resistance was reduced in all
territories (34-65%) whereas regional
blood flow was increased in all regions
explored (33-88%).
Determination of
minimum effective dose
Rat (Male)
(spontaneously
hypertensive)
20Oral0.003
0.01
0.1
0.3
1.0
3.0
(for 14
days)
Dose dependent reduction in BP;
ranged from 8.5-39%. Dose
dependent reduction in cardiac
hypertrophy ranged from 5-17%.
ACE inhibition by
measurement of the
potentiation of the
hypotensive response to
bradykinin
Rat
(Sprague
Dawley) (Male)
6i.v.0.003
0.006
0.010
0.03
1
(single
dose)
ED50 = Dose yielding 50% of the
maximum increase in the hypotensive
response to bradykinin
Trandolapril = 4.9 mg/kg
Trandolaprilat = 4.1 mg/kg
ACE inhibition in the rat
aorta, atrium and
ventricle
Rat (Okamoto)
hypertensive
(Male)
10-7Oral0.0001
0.0003
0.001
0.003
0.01
1.0
ID50 = Dose inhibiting enzyme activity
by 50%
Right atrium = 0.00132
Left atrium = 0.00107
Aorta = 0.00066
Apex = 0.00798
Right ventricular wall = 0.01510
Septum = 0.00740
Effects on Blood Pressure

Table 5 summarizes the effects of trandolapril on BP in animal models.

Table 5. Effects of Trandolapril on Blood Pressure
Hypertensive
Model
SpeciesNo. of
animals
per
group
RouteDose
(mg/kg)
DurationResult
Antihypertensive
effects in
spontaneously
hypertensive rats
Rat12-22Oral0.3
3.0
30
Single
dose
Fall in mean BP 6 h after gavage:
10%, 13% and 17% at 0.3, 3.0 and
30 mg/kg, respectively. 24 h after
gavage the fall was 10%, 11% and
15% at 0.3, 3.0 and 30 mg,
respectively.
Antihypertensive
effect in the
spontaneously
hypertensive rat pretreated
with a
thiazide diuretic
Rat12-22Oral0.3
3.0
30
Single
dose
A dose-dependent fall in mean BP
of 14, 30 and 34% at doses of 0.3,
3.0 and 30 mg/kg, respectively
was found. The peak effect
occurred after 24 h.
Antihypertensive
activity after 14 days
of treatment in
spontaneously
hypertensive rats
Rat11-12Oral3.014 daysMean BP decreased by 33% after
14 days.
Antihypertensive
effect on conscious
normotensive dog
Dog
(Male
Beagle)
5-6Oral3.0
10
Single
dose
At 3 mg/kg: DBP was reduced by
14% after 3.5-4 h postadministration.
At 10 mg/kg: A
decrease of 15% was observed
1.5-4 h post-administration

Pharmacokinetics

Table 6 summarizes the pharmacokinetic parameters following oral administration of trandolapril to animals and man.

Table 6. Pharmacokinetic Parameters Following Oral Administration of Trandolapril to Animals and Man
Dose (mg/kg)RatDogMan
110.033
Cmax (mcg/mL)trandolaprilND0.050.002
trandolaprilat1.020.280.003
Tmax (hr)trandolaprilND0.770.5
trandolaprilat0.140.726
AUC (mcg·hr/mL)trandolaprilND0.0550.002
trandolaprilat0.470.460.046
T1/2 (hr)trandolaprilND0.60.7
trandolaprilat61.63.5
% BioavailabilitytrandolaprilND197.5
trandolaprilat374340-60
% Eliminationbile3639ND
urine181633
feces364066

Toxicology

Acute Toxicity

Table 7 summarizes the species-specific LD50 values for both oral and intraperitoneal administrations of trandolapril.

Table 7. Species-Specific LD50 Values for Both Oral and Intraperitoneal Administrations of Trandolapril
RoutesSpeciesSexLD50 (mg/kg)
OralMouseMale4 875
Female3 990
RatMale> 5 000
Female> 5 000
IntraperitonealMouseMale1 285
Female1 330
RatMale1 420
Female1 435

The symptoms observed in mice were: slight hypotonicity, pilo-erection, hunched back, motor incoordination, lethargy, locomotion difficulties and tremors. Deaths occurred within 48 hours after intraperitoneal administration and 3 hours after oral administration. Residual signs of toxicity persisted for a maximum of 3 days. On autopsy macroscopic examination revealed lesions of the liver, lungs and gastrointestinal tract. In rats, pilo-erection and epistaxis were the main clinical signs of toxicity after oral administration. After intraperitoneal administration clinical signs were similar to those found in mice. Autopsy findings included: lung congestion, hemorrhagic appearance of pancreas and internal wall of abdominal cavity, deformation of lobes of liver and hypertrophy of spleen and kidneys. A dose of 200 mg/kg in the dog caused the death of 2/4 animals, 24 hours after administration. Hypotonicity, hypomobility, dehydration and respiratory difficulties were observed in the surviving animals. Autopsy revealed hemorrhagic thymus lesions of the liver, lungs and gastrointestinal tract.

Chronic Toxicity

Table 8 summarizes the chronic toxic1ity results for oral administrations of trandolapril in animals.

Table 8. Summary of Chronic Toxicity Results of Oral Administrations of Trandolapril in Animals
SpeciesDurationNo. of
animals
per
group
RouteDose
(mg/kg/day)
Effects
Rat
Sprague
Dawley
30 days10 M,
10 F
Oral0, 4, 20, 100At all doses: Retardation of body weight
gain, decrease in heart weight and gastric
ulceration. At 20 and 100 mg/kg/day:
Increase in magnesium and blood urea.
Rat
Sprague
Dawley
6 months60 M,
60 F
Oral0, 0.25, 2.5,
25
At all doses: Growth retardation, polyuria
and polydipsia. At 2.5 and 25 mg/kg/day:
Indications of glomerulonephritis were seen
histologically particularly in males, which
correlated with observed changes in serum
magnesium urea and creatinine.
Rat
Sprague
Dawley
18 months50 M,
50 F
Oral0, 0.25, 1.5, 9At 9 mg/kg: Water consumption,
magnesium and urea increased.
At 1.5 and 9 mg/kg: A decrease in sodium
was noted.
At 0.25 and 1.5 mg/kg in the males and at
9 mg/kg in females: Decrease in
erythrocytes.
Dog
Beagle
30 days3 M, 3 FOral0, 10, 50, 250At all doses: Increase in urinary volume for
females and microscopic renal lesions in all
animals.
At 250 mg/kg: Increase in serum alkaline
phosphatase for males; increase in urea for
all doses in females and at 50 and
250 mg/kg for males.
Dog
Beagle
6 months9 M, 9 FOral0, 2.5, 25,
125, 250
At all doses: Decreased excretion of sodium,
potassium, chloride, calcium, magnesium
and urea.
At 250 and 125 mg/kg: digestive signs of
toxicity accompanied by hypotonicity and
dehydration resulted in death and premature
sacrifice. Ulcerative inflammatory lesions of
the gastric and duodenal mucosa, and renal
lesions. Esophageal inflammatory lesions
were also seen.
At 25 mg/kg: Anemia, increase in frequency
of renal lesions in the female.
Dog
Beagle
12 months6 M, 6 FOral0, 0.25, 2.5,
25
At 0.25 mg/kg: Weight decrease in 3
animals between weeks 24-49. Decreases in
spleen, kidney and testes weights in males.
At 25 mg/kg: Increase in α2 globulin in
males. Decreases in absolute brain weights
in males.

Mutagenicity and Carcinogenicity

Trandolapril was not mutagenic in the Ames microbial mutagen test, the gene conversion test with S. cerevisiae, and in V79 cells. Detection of chromosomal aberrations in human lymphocytes and in Chinese hamster CHO cells as well as the micronucleus test in mice were all negative

There was no evidence of a carcinogenic effect when trandolapril was administered by gavage for 18 months to male and female CDI mice at doses ≤25 mg/kg/day or to male and female Sprague Dawley rats at doses ≤8 mg/kg/day.

Reproduction and Teratology

Table 9 summarizes the reproduction and teratology results following administrations of trandolapril in animals.

Table 9. Reproduction and Teratology Results Following Administrations of Trandolapril in Animals
SpeciesNo. of
animals per
group
Dose
(mg/kg/day)
Duration of
dosing
Results
Rat (Sprague
Dawley)
30 M, 30 F30 M, 30 FM: 60 days
before
mating
F: 14 days
before
mating to
day 30 of
gestation
At 10 and 100 mg/kg/day:
Fetuses showed dilated ureters and increased renal
pelvic cavitation
Rat (Sprague
Dawley)
24 F0, 100, 300,
1000
Days 6-15 of
gestation
Dilatation of renal pelvis and ureters at 1000
mg/kg/day.
Rabbit (New
Zealand
White)
21 F0, 0.2, 0.4, 0.8Days 6-18 of
gestation
At 0.8 mg/kg: Associated with maternal toxicity
and severe effects on physical conditions of
survivors, pre and post implantation losses were
increased. Some fetuses had multiple
malformations of the skull, oral cavity, heart
vessels, etc.
At 0.4 mg/kg: Deterioration in maternal condition,
no consistent treatment-related effects on fetal
development.
Rabbit
(HYLA)
15 F0, 0.1, 0.2,
0.4, 0.8
Days 6-18 of
gestation
At 0.4 and 0.8 mg/kg: Weight loss, tremors,
diarrhea and death, dilation of renal pelvis.
At 0.1 and 0.2 mg/kg: Increased rate of fetal
losses, dilation of renal pelvis.
Monkey
(Cynomolgus)
6 F0, 50, 250Days 20-50
of gestation
At all doses: No sign of teratogenesis.
Monkey
(Cynomolgus)
10 F0, 5, 25, 125Days 20-50
of gestation
At all doses: Slight decrease in body weight. No
treatment related malformations.
At 5 and 25 mg/kg: 4 abortions
At 125 mg/kg: 7 abortions