Favotan Mechanism of Action

Pharmacotherapeutic group: Angiotensin II antagonists, plain (losartan), combinations with dihydropyridine derivatives (amlodipine). ATC code: C09DB06.
Pharmacology: Pharmacodynamics: Amlodipine: The amlodipine component of FAVOTAN inhibits the transmembrane entry 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, causing reductions in peripheral vascular resistance and in blood pressure. Experimental data suggest that amlodipine binds to both dihydropyridine and non-dihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels.
Following administration of therapeutic doses to patients with hypertension, amlodipine produces vasodilatation, resulting in a reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing.
Plasma concentrations correlate with effect in both young and elderly patients.
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.
As with other calcium channel blockers, hemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with amlodipine have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume. In hemodynamic studies, amlodipine has not been associated with a negative inotropic effect when administered in the therapeutic dose range to intact animals and humans, even when co-administered with beta-blockers to humans.
Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals or humans. In clinical studies in which amlodipine was administered in combination with beta-blockers to patients with either hypertension or angina, no adverse effects on electrocardiographic parameters were observed.
Losartan: Losartan is a synthetic oral angiotensin - II receptor (type AT₁) antagonist. Angiotensin II, a potent vasoconstrictor, is the primary active hormone of the renin/angiotensin system and an important determinant of the pathophysiology of hypertension. Angiotensin II binds to the AT₁ receptor found in many tissues (e.g. vascular smooth muscle, adrenal gland, kidneys and the heart) and elicits several important biological actions, including vasoconstriction and the release of aldosterone. Angiotensin II also stimulates smooth muscle cell proliferation.
Losartan selectively blocks the AT₁ receptor. In vitro and in vivo losartan and its pharmacologically active carboxylic acid metabolite EXP-3174 block all physiologically relevant actions of angiotensin II, regardless of the source or route of its synthesis.
Losartan does not have an agonist effect nor does it block other hormone receptors or ion channels important in cardiovascular regulation. Furthermore, losartan does not inhibit ACE (kininase II), the enzyme that degrades bradykinin. Consequently, there is no potentiation of undesirable bradykinin-mediated effects.
During administration of losartan, removal of the angiotensin II negative feedback on renin secretion leads to increased plasma renin activity (PRA). Increase in the PRA leads to an increase in angiotensin II in plasma. Despite these increases, antihypertensive activity and suppression of plasma aldosterone concentration are maintained, indicating effective angiotensin II receptor blockade. After discontinuation of losartan, PRA and angiotensin II values fell within three days to the baseline values. Both losartan and its principal active metabolite have a far greater affinity for the AT₁-receptor than for the AT₂-receptor. The active metabolite is 10-40 times more active than losartan on a weight for weight basis.
Amlodipine/Losartan: Hypertension studies: The proposed indication for FAVOTAN 5/50 mg and 5/100 mg tablets is the treatment of essential hypertension in patients whose blood pressure is not adequately controlled on amlodipine or losartan monotherapy.
The clinical development programme for FAVOTAN included the following studies where the main efficacy objective was to demonstrate increased blood pressure lowering by the combination treatment over each component administered as monotherapy: HM-ALOS-201: Phase II efficacy and safety study in hypertensive patients. Four combinations of amlodipine camsylate/losartan 5/50 mg, 5/100 mg, 10/50 mg, 10/100 mg compared to amlodipine camsylate 5 mg, 10 mg and losartan 50 mg, 100 mg.
HM-ALOS-301: Phase III efficacy and safety study in patients with hypertension unresponsive to 5 mg amlodipine. Comparison of amlodipine camsylate/losartan 5/50 mg with amlodipine camsylate 10 mg monotherapy.
HM-ALOS-302: Phase III efficacy and safety study in patients with hypertension unresponsive to 100 mg losartan. Comparison of amlodipine camsylate/losartan 5/100 mg with losartan 100 mg monotherapy.
Blood pressure reductions and responder rates at Week 8 are summarised for studies HM-ALOS-201, HM-ALOS-301, and HM-ALOS-302. The same primary efficacy variable (reduction from baseline in sitDBP) and secondary efficacy variables (reductions in sitDBP at 4 weeks, sitSBP and responder rates at 4 and 8 weeks) were used in all studies.
The Phase II efficacy study (HM-ALOS-201) evaluated 4 combinations of amlodipine camsylate/losartan (5/50 mg, 5/100 mg, 10/50 mg and 10/100 mg in comparison with each monotherapy (amlodipine 5 mg or 10 mg, losartan 50 mg or 100 mg) in a double blind factorial design trial. After 8 weeks of treatment, clinically and statistically superior hypotensive effects on sitDBP were achieved with the combinations 5/50 mg, 5/100 mg and 10/50 mg and on sitSBP with the combinations 5/50 mg and 5/100 mg compared to the respective monotherapies. The reductions in sitDBP at 8 weeks were also significantly greater in the 10/100 mg combination group compared to losartan 100 mg monotherapy but not to amlodipine 10 mg monotherapy.
The two Phase III studies for assessment of efficacy of the combination products were of similar design. In the first study (HM-ALOS-301), the combination amlodipine camsylate/losartan 5/50 mg was compared to amlodipine camsylate 10 mg monotherapy and in the second study (HM-ALOS-302) amlodipine camsylate/losartan 5/100 mg was compared to losartan 100 mg monotherapy.
In study HM-ALOS-301 the combination of amlodipine camsylate/losartan 5/50 mg was statistically non-inferior to amlodipine camsylate 10 mg in reducing sitDBP after 8 weeks of treatment in patients unresponsive to 5 mg amlodipine. Clinically relevant reductions of 8.85 mmHg and 9.37 mmHg respectively were obtained. Although, there were no statistically significant differences between treatments for the secondary endpoints, at the end of the study clinically meaningful reductions in sitSBP of 12.22 mmHg and 13.38 mmHg and response rates of 89.13% and 87.91% were achieved in the 5/50 mg combination group and amlodipine 10 mg monotherapy groups respectively.
In study HM-ALOS-302 the combination of amlodipine camsylate/losartan 5/100 mg was statistically superior to losartan 100 mg in reducing sitDBP after 8 weeks of treatment in patients unresponsive to 100 mg losartan. A mean reduction in sitDBP of 11.69 mmHg was achieved with the combination compared to a mean reduction of 3.17 mmHg achieved with losartan 100 mg monotherapy. There were also significant differences in favour of the combination for the secondary efficacy parameters. At the end of the study reductions in sitSBP of 13.37 mmHg and 3.39 mmHg and response rates of 90% and 66.67% were achieved in the 5/100 mg combination group and losartan 100 mg monotherapy groups respectively.
The clinical development program for the FAVOTAN combination products fulfilled the efficacy objective with regard to mean reductions in sitting blood pressure. Over a range of doses used clinically for each monotherapy, the combination of amlodipine camsylate with losartan produced clinically relevant reductions in blood pressure which, at the doses of 5/50 mg, 5/100 mg and 10/50 mg, were significantly greater than those achieved with either monotherapy. In patients whose blood pressure was not optimally controlled with amlodipine 10 mg monotherapy, equivalent blood pressure lowering was obtained with the combination amlodipine 5 mg and losartan 50 mg. In patients whose blood pressure was inadequately controlled on losartan 100 mg monotherapy, an additional blood pressure lowering effect was achieved by combination.
Pharmacokinetics: Amlodipine: Absorption: After intake of therapeutic doses, amlodipine is well absorbed and the maximum plasma concentration is obtained after 6-12 hours. Absolute bioavailability has been estimated to be between 64 and 80%. The volume of distribution is approximately 21 l/kg. Food does not affect the absorption of amlodipine.
Biotransformation/elimination: Plasma half-life is about 30-40 hours and a stable concentration is achieved in 7-8 days. Distribution volume is up to 21 l/kg. Plasma protein binding is high (98%). Plasma elimination is 7 ml/min/kg. Amlodipine is extensively metabolised by the liver to inactive metabolites with 10% of the parent compound and 60% of metabolites excreted in the urine. Amlodipine half-life will be extended for patients with impaired hepatic function.
A comparison of the pharmacokinetics of amlodipine camsylate with the reference product Norvasc (amlodipine besylate Pfizer Korea) administered as a single oral dose of 5 mg (amlodipine base) showed similar absorption profiles. Mean peak plasma levels of 3.6 and 3.7 ng/ml were attained at means of 6.9 and 7.3 hours after Norvasc and amlodipine camsylate respectively and mean elimination half-lives were 42.2 and 39.3 hours respectively. These values are consistent with prescribing information for Norvasc. Bioequivalence of Hanmi's amlodipine camsylate 5 mg formulation to Norvasc 5 mg was demonstrated.
Losartan: Absorption: Following oral administration, losartan is well absorbed and undergoes first-pass metabolism, forming an active carboxylic acid metabolite and other inactive metabolites. The systemic bioavailability of losartan tablets is approximately 33%. Mean peak concentrations of losartan and its active metabolite are reached in 1 hour and in 3-4 hours, respectively.
Distribution: Both losartan and its active metabolite are ≥99% bound to plasma proteins, primarily albumin. The volume of distribution of losartan is 34 litres.
Biotransformation: About 14% of an intravenously- or orally-administered dose of losartan is converted to its active metabolite. Following oral and intravenous administration of 14C-labelled losartan potassium, circulating plasma radioactivity primarily is attributed to losartan and its active metabolite. Minimal conversion of losartan to its active metabolite was seen in about 1% of individuals studied.
In addition to the active metabolite, inactive metabolites are formed.
Elimination: Plasma clearance of losartan and its active metabolite is about 600 ml/min and 50 ml/min, respectively. Renal clearance of losartan and its active metabolite is about 74 ml/min and 26 ml/min, respectively. When losartan is administered orally, about 4% of the dose is excreted unchanged in the urine, and about 6% of the dose is excreted in the urine as active metabolite. The pharmacokinetics of losartan and its active metabolite are linear with oral losartan potassium doses up to 200 mg.
Following oral administration, plasma concentrations of losartan and its active metabolite decline poly-exponentially, with a terminal half-life of about 2 hours and 6-9 hours, respectively. During once-daily dosing with 100 mg, neither losartan nor its active metabolite accumulates significantly in plasma.
Both biliary and urinary excretions contribute to the elimination of losartan and its metabolites. Following an oral dose/intravenous administration of 14C-labelled losartan in man, about 35%/43% of radioactivity is recovered in the urine and 58%/50% in the faeces.
Characteristics in patients: In elderly hypertensive patients, the plasma concentrations of losartan and its active metabolite do not differ essentially from those found in young hypertensive patients.
In female hypertensive patients, the plasma levels of losartan were up to twice as high as in male hypertensive patients, while the plasma levels of the active metabolite did not differ between men and women.
In patients with mild to moderate alcohol-induced hepatic cirrhosis, the plasma levels of losartan and its active metabolite after oral administration were respectively 5 and 1.7 times higher than in young male volunteers.
Plasma concentrations of losartan are not altered in patients with a creatinine clearance above 10 ml/minute. Compared to patients with normal renal function, the AUC for losartan is about 2-times higher in haemodialysis patients.
The plasma concentrations of the active metabolite are not altered in patients with renal impairment or in haemodialysis patients.
Neither losartan nor the active metabolite can be removed by haemodialysis.
Combination: In the studies comparing co-administration and combined administration of amlodipine camsylate and losartan, pharmacokinetic parameters were similar for amlodipine, losartan and the active metabolite EXP-3174 following co- or combined administration of 5/50 mg and 5/100 mg doses. As the therapeutic activity of losartan is largely attributable to the active metabolite, it is considered that the fixed dose combination will be therapeutically equivalent to co-administered amlodipine 5 mg together with losartan 50 mg or 100 mg.
Three Phase 1 clinical trials have been conducted with the amlodipine camsylate/losartan combination drugs to date: HM-ALOS-101, HM-ALOS-103 and HM-ALOS-104.
The HM-ALOS-101 study, conducted to evaluate the possible pharmacokinetic interactions between amlodipine camsylate and losartan potassium after repeated administration alone or in combination, concluded that there was no interaction between amlodipine and losartan when administered in combination compared with being administered alone.
The HM-ALOS-103 and HM-ALOS-104 studies were conducted to evaluate the pharmacokinetic equivalence between single administration of two combination therapies (amlodipine camsylate 5mg/losartan 50mg and amlodipine camsylate 5mg/losartan 100mg, respectively) and co-administration of each single agent. All parameters, area under the plasma concentration/time curve at time t (AUC_t), area under the plasma concentration/time curve at infinity (AUC_∞), and the maximum plasma concentration (C_max) except C_max of losartan 50mg were equivalent between the combination and co-administration groups.
Toxicology: No toxicology study has been conducted with this drug. Non-clinical data with amlodipine and losartan is as follows: Amlodipine: Carcinogenesis: Rats and mice treated with amlodipine in diet for up to two years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25, and 2.5 amlodipine mg/kg/day showed no evidence of a carcinogenic effect of the drug. For the mouse, the highest dose was on a mg/m² basis, similar to the maximum recommended human dose of 10 mg amlodipine/day. For rats, the highest dose was, on a mg/m² basis, about twice the maximum recommended human dose (*,based on 50 kg body weight of patient).
Mutagenesis: Mutagenicity studies conducted with amlodipine maleate revealed no drug related effects at either the gene or on chromosome level.
Impairment of Fertility: There was no effect on the fertility of rats treated with amlodipine (64 days for male and 14 days for female prior to mating) at doses up to 10 mg amlodipine/kg/day (8 times* the maximum recommended human dose of 10 mg/day on a mg/m² basis).
*In an assumption that patients weight is 50 kg.
Losartan: Carcinogenesis: Losartan potassium was not carcinogenic when administered at maximally tolerated dosages to rats and mice for 105 and 92 weeks, respectively. Female rats given the highest dose (270 mg/kg/day) had a slightly higher incidence of pancreatic acinar adenoma. The maximally tolerated dosages (270 mg/kg/day in rats, 200 mg/kg/day in mice) provided systemic exposures for losartan and its pharmacologically active metabolite that were approximately 160- and 90-times (rats) and 30- and 15-times (mice) the exposure of a 50 kg human given 100 mg per day.
Mutagenesis: Losartan potassium was negative in the microbial mutagenesis and V-79 mammalian cell mutagenesis assays and in the in vitro alkaline elution and in vitro and in vivo chromosomal aberration assays. In addition, the active metabolite showed no evidence of genotoxicity in the microbial mutagenesis, in vitro alkaline elution, and in vitro chromosomal aberration assays.
Impairment of Fertility: Fertility and reproductive performance were not affected in studies with male rats given oral doses of losartan potassium approximately 150 mg/kg/day. The administration of toxic dosage levels in females (300/200 mg/kg/day) was associated with a significant (p<0.05) decrease in the number of corpora lutea, implantation, and live fetuses at C-section. At 100 mg/kg/day has only shown a decrease in the number of corpora lutea. The relationship of these findings to the drug is uncertain because there was no effect at these dosage levels on implantation, post-implantation loss rate, or live animals at parturition. In nonpregnant rats dosed at 135 mg/kg/day for 7 days, systemic exposure (AUCs) for losartan and its active metabolite were approximately 66 and 26 times the exposure achieved in human at the maximum recommended human daily dosage (100 mg).