Combination of two antihypertensive compounds with complementary mechanisms to control blood pressure in patients with essential hypertension: an angiotensin II receptor antagonist, telmisartan, and a dihydropyridinic calcium channel blocker, amlodipine.
The combination of these substances has an additive antihypertensive effect, reducing blood pressure to a greater degree than either component alone.
Telmisartan is an orally active and specific angiotensin II receptor (type AT1) antagonist. Telmisartan displaces angiotensin II with very high affinity from its binding site at the AT1 receptor subtype, which is responsible for the known actions of angiotensin II. Telmisartan does not exhibit any partial agonist activity at the AT1 receptor. Telmisartan selectively binds the AT1 receptor. The binding is long-lasting.
Telmisartan does not show affinity for other receptors, including AT2 and other less characterised AT receptors. The functional role of these receptors is not known, nor is the effect of their possible overstimulation by angiotensin II, whose levels are increased by telmisartan. Plasma aldosterone levels are decreased by telmisartan. Telmisartan does not inhibit human plasma renin or block ion channels. Telmisartan does not inhibit angiotensin converting enzyme (kininase II), the enzyme which also degrades bradykinin. Therefore it is not expected to potentiate bradykinin-mediated adverse reactions.
Amlodipine is a calcium ion influx inhibitor of the dihydropyridine group (slow channel blocker or calcium ion antagonist) and inhibits the transmembrane influx of calcium ions into cardiac and vascular smooth muscle. The mechanism of the antihypertensive action of amlodipine is due to a direct relaxant effect on vascular smooth muscle, leading to reductions in peripheral vascular resistance and in blood pressure. Experimental data indicate that amlodipine binds to both dihydropyridine and nondihydropyridine binding sites. Amlodipine is relatively vessel-selective, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells.
Telmisartan/amlodipine combination once daily produces effective and consistent reductions in blood pressure across the 24-hour therapeutic dose range.
In humans, an 80 mg dose of telmisartan almost completely inhibits the angiotensin II evoked blood pressure increase. The inhibitory effect is maintained over 24 hours and still measurable up to 48 hours.
After the first dose of telmisartan, the antihypertensive activity gradually becomes evident within 3 hours. The maximum reduction in blood pressure is generally attained 4 to 8 weeks after the start of treatment and is sustained during long-term therapy.
The antihypertensive effect persists constantly over 24 hours after dosing and includes the last 4 hours before the next dose as shown by ambulatory blood pressure measurements. This is confirmed by trough to peak ratios consistently above 80% seen after doses of 40 and 80 mg of telmisartan in placebo controlled clinical studies. There is an apparent trend to a dose relationship to a time to recovery of baseline systolic blood pressure. In this respect data concerning diastolic blood pressure are inconsistent.
In patients with hypertension telmisartan reduces both systolic and diastolic blood pressure without affecting pulse rate. The contribution of the medicinal product’s diuretic and natriuretic effect to its hypotensive activity has still to be defined. The antihypertensive efficacy of telmisartan is comparable to that of substances representative of other classes of antihypertensive medicinal products (demonstrated in clinical trials comparing telmisartan to amlodipine, atenolol, enalapril, hydrochlorothiazide, and lisinopril).
Upon abrupt cessation of treatment with telmisartan, blood pressure gradually returns to pre-treatment values over a period of several days without evidence of rebound hypertension.
The incidence of dry cough was significantly lower in patients treated with telmisartan than in those given angiotensin converting enzyme inhibitors in clinical trials directly comparing the two antihypertensive treatments.
In patients with hypertension, once daily dosing provides clinically significant reductions of blood pressure in both the supine and standing positions throughout the 24 hour interval. Due to the slow onset of action, acute hypotension is not a feature of amlodipine administration. In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow, without change in filtration fraction or proteinuria.
Amlodipine has not been associated with any adverse metabolic effects or changes in plasma lipids and is suitable for use in patients with asthma, diabetes, and gout.
The rate and extent of absorption of telmisartan/amlodipine are equivalent to the bioavailability of telmisartan and amlodipine when administered as individual tablets.
Absorption of telmisartan is rapid although the amount absorbed varies. The mean absolute bioavailability for telmisartan is about 50%. When telmisartan is taken with food, the reduction in the area under the plasma concentration-time curve (AUC0-∞) of telmisartan varies from approximately 6% (40 mg dose) to approximately 19% (160 mg dose). By 3 hours after administration, plasma concentrations are similar whether telmisartan is taken fasting or with food.
After oral administration of therapeutic doses, amlodipine is well absorbed with peak blood levels between 6-12 hours post dose. Absolute bioavailability has been estimated to be between 64 and 80%. Amlodipine bioavailability is not affected by food ingestion.
Telmisartan is largely bound to plasma protein (>99.5%), mainly albumin and alpha-1 acid glycoprotein. The mean steady state apparent volume of distribution (Vdss) is approximately 500 l.
The volume of distribution of amlodipine is approximately 21 l/kg. In vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to plasma proteins in hypertensive patients.
Telmisartan is metabolised by conjugation to the glucuronide of the parent compound. No pharmacological activity has been shown for the conjugate.
Amlodipine is extensively (approximatively 90%) metabolised by the liver to inactive metabolites.
Telmisartan is characterised by biexponential decay pharmacokinetics with a terminal elimination halflife of >20 hours. The maximum plasma concentration (Cmax) and, to a smaller extent, the area under the plasma concentration-time curve (AUC), increase disproportionately with dose. There is no evidence of clinically relevant accumulation of telmisartan taken at the recommended dose. Plasma concentrations were higher in females than in males, without relevant influence on efficacy.
After oral (and intravenous) administration, telmisartan is nearly exclusively excreted with the faeces, mainly as unchanged compound. Cumulative urinary excretion is <1% of dose. Total plasma clearance (Cltot) is high (approximately 1,000 ml/min) compared with hepatic blood flow (about 1,500 ml/min).
Amlodipine elimination from plasma is biphasic, with a terminal elimination half-life of approximately 30 to 50 hours consistent with once daily dosing. Steady-state plasma levels are reached after continuous administration for 7-8 days. Ten per cent of original amlodipine and 60% of amlodipine metabolites are excreted in urine.
The small reduction in AUC for telmisartan is not expected to cause a reduction in the therapeutic efficacy. There is no linear relationship between doses and plasma levels. Cmax and to a lesser extent AUC increase disproportionately at doses above 40 mg.
Amlodipine exhibits linear pharmacokinetics.
No pharmacokinetic data are available in the paediatric population.
Differences in plasma concentrations of telmisartan were observed, with Cmax and AUC being approximately 3- and 2-fold higher, respectively, in females compared to males.
The pharmacokinetics of telmisartan do not differ in young and elderly patients. The time to reach peak plasma concentrations of amlodipine is similar in elderly and younger subjects. In elderly patients, amlodipine clearance tends to decline with resulting increases in AUC and elimination half-life.
In patients with mild to moderate and severe renal impairment, doubling of plasma concentrations of telmisartan was observed. However, lower plasma concentrations were observed in patients with renal insufficiency undergoing dialysis. Telmisartan is highly bound to plasma protein in renal-insufficient subjects and cannot be removed by dialysis. The elimination half-life is not changed in patients with renal impairment. The pharmacokinetics of amlodipine are not significantly influenced by renal impairment.
Pharmacokinetic studies in patients with hepatic impairment showed an increase in absolute bioavailability of telmisartan up to nearly 100%. The elimination half-life of telmisartan is not changed in patients with hepatic impairment. Patients with hepatic insufficiency have decreased clearance of amlodipine with resulting increase of approximately 40-60% in AUC.
Since the non-clinical toxicity profiles of telmisartan and amlodipine are not overlapping, no exacerbation of toxicity was expected for the combination. This has been confirmed in a subchronic (13-week) toxicology study in rats, in which dose levels of 3.2/0.8, 10/2.5 and 40/10 mg/kg of telmisartan and amlodipine were tested.
Preclinical data available for the components of this fixed dose combination are reported below.
In preclinical safety studies, doses producing exposure comparable to that in the clinical therapeutic range caused reduced red cell parameters (erythrocytes, haemoglobin, haematocrit), changes in renal haemodynamics (increased blood urea nitrogen and creatinine), as well as increased serum potassium in normotensive animals. In dogs, renal tubular dilation and atrophy were observed. Gastric mucosal injury (erosion, ulcers or inflammation) also was noted in rats and dogs. These pharmacologically-mediated undesirable effects, known from preclinical studies with both angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists, were prevented by oral saline supplementation. In both species, increased plasma renin activity and hypertrophy/hyperplasia of the renal juxtaglomerular cells were observed. These changes, also a class effect of angiotensin converting enzyme inhibitors and other angiotensin II receptor antagonists, do not appear to have clinical significance.
No clear evidence of a teratogenic effect was observed, however at toxic dose levels of telmisartan an effect on the postnatal development of the offspring such as lower body weight and delayed eye opening was observed.
There was no evidence of mutagenicity and relevant clastogenic activity in in vitro studies and no evidence of carcinogenicity in rats and mice.
Reproductive studies in rats and mice have shown delayed date of delivery, prolonged duration of labour and decreased pup survival at doses approximately 50 times greater than the maximum recommended dose for humans based on mg/kg.
There was no effect on the fertility of rats treated orally with amlodipine maleate (males for 64 days and females for 14 days prior to mating) at doses of up to 10 mg amlodipine/kg/day (about 8 times* the maximum recommended human dose of 10 mg/day on an mg/m² basis). In another rat study in which male rats were treated with amlodipine besilate for 30 days at a dose comparable with the human dose based on mg/kg, decreased plasma follicle-stimulating hormone and testosterone were found as well as decreases in sperm density and in the number of mature spermatids and Sertoli cells.
Rats and mice treated with amlodipine in the diet for two years, at concentrations calculated to provide daily dose levels of 0.5, 1.25, and 2.5 mg/kg/day showed no evidence of carcinogenicity. The highest dose (for mice, similar to, and for rats twice* the maximum recommended clinical dose of 10 mg on a mg/m² basis) was close to the maximum tolerated dose for mice but not for rats. Mutagenicity studies revealed no drug related effects at either the gene or chromosome levels.
* Based on patient weight of 50 kg.
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