Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Agents acting on the renin-angiotensin system; renin inhibitor, ATC code: C09XA02.
Aliskiren is an orally active, non-peptide, potent and selective direct inhibitor of human renin.
By inhibiting the enzyme renin, aliskiren inhibits the RAAS at the point of activation, blocking the conversion of angiotensinogen to angiotensin I and decreasing levels of angiotensin I and angiotensin II. Whereas other agents that inhibit the RAAS (ACEI and ARBs) cause a compensatory rise in plasma renin activity (PRA), treatment with aliskiren decreases PRA in hypertensive patients by approximately 50 to 80%. Similar reductions were found when aliskiren was combined with other antihypertensive agents. Elevated PRA has been independently associated with increased cardiovascular risk in hypertensive and normotensive patients. The clinical implications of the differences in effect on PRA are not known at the present time.

Hypertension
In hypertensive patients, once-daily administration of Rasilez at doses of 150 mg and 300 mg provided dose-dependent reductions in both systolic and diastolic blood pressure that were maintained over the entire 24-hour dose interval (maintaining benefit in the early morning) with a mean peak to trough ratio for diastolic response of up to 98% for the 300 mg dose. 85 to 90% of the maximal blood-pressure-lowering effect was observed after 2 weeks. The blood-pressure- lowering effect was sustained during long-term treatment, and was independent of age, gender, body mass index and ethnicity. Rasilez has been studied in 1,864 patients aged 65 years or older, and in 426 patients aged 75 years or older.


RAS API JUN15 CL V10                                          REF CDS 6May14 & 18Dec14 Rasilez monotherapy studies have shown blood pressure lowering effects comparable to other classes of antihypertensive agents including ACEI and ARB. Compared to a diuretic (hydrochlorothiazide - HCTZ), Rasilez 300 mg lowered systolic/diastolic blood pressure by 17.0/12.3 mmHg, compared to 14.4/10.5 mmHg for HCTZ 25 mg after 12 weeks of treatment. In diabetic hypertensive patients, Rasilez monotherapy was safe and effective.

Combination therapy studies are available for Rasilez added to the diuretic hydrochlorothiazide, the calcium channel blocker amlodipine and the beta blocker atenolol. These combinations were well tolerated. Rasilez induced an additive blood-pressure-lowering effect when added to hydrochlorothiazide. In patients who did not adequately respond to 5 mg of the calcium channel blocker amlodipine, the addition of Rasilez 150 mg had a blood-pressure-lowering effect similar to that obtained by increasing amlodipine dose to 10 mg, but had a lower incidence of oedema (aliskiren 150 mg/amlodipine 5 mg 2.1% vs. amlodipine 10 mg 11.2%).

In obese hypertensive patients who did not adequately respond to HCTZ 25 mg, add-on treatment with Rasilez 300 mg provided additional blood pressure reduction that was comparable to add-on treatment with irbesartan 300 mg or amlodipine 10 mg. In diabetic hypertensive patients, Rasilez provided additive blood pressure reductions when added to ramipril, while the combination of Rasilez and ramipril had a lower incidence of cough (1.8%) than ramipril (4.7%).
There has been no evidence of first-dose hypotension and no effect on pulse rate in patients treated in controlled clinical studies. Excessive hypotension was uncommonly (0.1%) seen in patients with uncomplicated hypertension treated with Rasilez alone. Hypotension was also uncommon (<1%) during combination therapy with other antihypertensive agents. With cessation of treatment, blood pressure gradually returned towards baseline levels over a period of several weeks, with no evidence of a rebound effect for blood pressure or PRA.
In a 3-month study of 302 patients with mild stable heart failure, all of whom were receiving standard therapy for stable heart failure, addition of Rasilez 150 mg was well tolerated. B-type natriuretic peptide (BNP) levels were reduced by 25% in the Rasilez arm compared to placebo.
However the clinical significance of this reduction is unknown.
Beneficial effects of Rasilez on mortality and cardiovascular morbidity and target organ damage are currently unknown.
Efficacy and safety of aliskiren-based therapy were compared to ramipril-based therapy in a 9- month study in 901 elderly patients (>=65 years) with essential systolic hypertension. Aliskiren 150 mg or 300 mg per day or ramipril 5 mg or 10 mg per day were administered for 36 weeks with optional add-on therapy of hydrochlorothiazide (12.5 mg or 25 mg) at week 12, and amlodipine (5 mg or 10 mg) at week 22. Over the 12 week period, aliskiren monotherapy lowered systolic/diastolic blood pressure by 14.0/5.1 mmHg, compared to 11.6/3.6 mmHg for ramipril.
The differences in both systolic and diastolic blood pressure were statistically significant. After 12 weeks, 46.3 % of patients required add-on treatment with hydrochlorothiazide in the aliskiren- regimen compared to 55.5 % of patients receiving a ramipril-based regimen. After 22 weeks 11.5 % of patients required add-on treatment with amlodipine in the aliskiren regimen compared to 15.7 % of patients receiving a ramipril-based regimen. Tolerability was comparable in both treatment arms, however cough was more often reported with the ramipril regimen than the aliskiren regimen (14.2 % vs. 4.4 %). The most common adverse event for the aliskiren-regimen was diarrhea (6.6 % vs. 5.0 % for the ramipril-regimen).


RAS API JUN15 CL V10                                         REF CDS 6May14 & 18Dec14 In a double-blind, randomized, active-controlled study in which efficacy was assessed in 1,181 patients, once-daily administration of aliskiren 300 mg with amlodipine 10 mg and HCTZ 25 mg produced statistically significant mean blood pressure reductions (systolic/diastolic) of 37.9/20.6 mmHg compared to 31.4/18.0 mmHg with aliskiren/amlodipine combination (300/10 mg), 28.0/14.3 mmHg with aliskiren/hydrochlorothazide (300/25 mg) and 30.8/17.0 mmHg with amlodipine/hydrochlorothiazide(10/25 mg) in patients with moderate to severe hypertension. In patients with severe hypertension (SBP ≥180 mmHg), the reduction in blood pressure for the triple combination of aliskiren, HCTZ and amlodipine was 49.5/22.5 mmHg compared to 38.1/17.6 mmHg with aliskiren/amlodipine combination (300/10 mg), 33.2/14.3 mmHg with alskiren/hydrochlorothiazide (300/25 mg) and 39.9/17.8 mmHg with amlodipine/hydrochlorothiazide (10/25 mg). The combination of aliskiren/amlodipine/HCTZ was generally well-tolerated and the most commonly reported adverse event was peripheral oedema.
Long-term gastrointestinal (GI) safety and tolerability of aliskiren was evaluated in a 54 week, randomized, double-blind, active controlled (ramipril) study in patients with essential hypertension at least 50 years of age. There were no statistically significant differences in the relative risk of the composite endpoint or any of its components (hyperplastic polyps, inflammatory polyps, adenomatous polyps, and carcinoma), as assessed by colonoscopy, following one year of treatment with aliskiren 300 mg daily compared to ramipril 10 mg daily with an overall relative risk of 1.03. A doubling of the relative risk of the compository endpoint (primary study outcome) was excluded with p <0.0001. Mucosal hyperplasia scores, dysplasia score, and severity of inflammation were low at baseline and no increases were observed in either of the two treatment groups. No pathologic effect of aliskiren on the colorectum was detected.


Cardiac electrophysiology
No effect on QT interval was reported in a randomised, double-blind, placebo, and active- controlled study using standard and Holter electrocardiography.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties
Absorption
Following oral absorption, peak plasma concentrations of aliskiren are reached after 1-3 hours.
The absolute bioavailability of aliskiren is approximately 2-3%. Meals with a high fat content reduce Cmax by 85% and AUC by 70%. Steady-state-plasma concentrations are reached within 5-7 days following once-daily administration and steady-state levels are approximately 2-fold greater than with the initial dose.
Transporters
MDR1/Mdr1a/1b (P-gp) was found to be the major efflux system involved in intestinal absorption and biliary excretion of aliskiren in pre-clinical studies.


Distribution
Following intravenous administration, the mean volume of distribution at steady state is approximately135 liters , indicating that aliskiren distributes extensively into the extravascular space. Aliskiren plasma protein binding is moderate (47-51%) and independent of the concentration.


RAS API JUN15 CL V10                                           REF CDS 6May14 & 18Dec14 Metabolism and elimination
The mean half-life is about 40 hours (range 34-41 hours). Aliskiren is mainly eliminated as unchanged compound in the faeces (78%). Approximately 1.4% of the total oral dose is metabolised. The enzyme responsible for this metabolism is CYP3A4. Approximately 0.6% of the dose is recovered in urine following oral administration. Following intravenous administration, the mean plasma clearance is approximately 9 l/h.
Linearity/non-linearity
Exposure to aliskiren increased more than in proportion to the increase in dose. After single dose administration in the dose range of 75 to 600 mg, a 2-fold increase in dose results in a ~2.3 and 2.6-fold increase in AUC and Cmax, respectively. At steady state the non-linearity may be more pronounced. Mechanisms responsible for deviation from linearity have not been identified. A possible mechanism is saturation of transporters at the absorption site or at the hepatobiliary clearance route.
Characteristics in patients
Aliskiren is an effective once-a-day antihypertensive treatment in adult patients, regardless of gender, age, body mass index and ethnicity.
The AUC is 50% higher in elderly (>65 years) than in young subjects. Gender, weight and ethnicity have no clinically relevant influence on aliskiren pharmacokinetics.
The pharmacokinetics of aliskiren were evaluated in patients with varying degrees of renal insufficiency. Relative AUC and Cmax of aliskiren in subjects with renal impairment ranged between 0.8 to 2 times the levels in healthy subjects following single dose administration and at steady state. These observed changes, however, did not correlate with the severity of renal impairment. No adjustment of the initial dosage of
Rasilez is required in patients with mild to moderate renal impairment. Rasilez should be avoided in patients with severe renal impairment (GFR) < 30 ml/min/1.73 m2).
The pharmacokinetics of aliskiren were evaluated in patients with End Stage Renal Disease receiving henodialysis. Administration of a single oral dose of 300 mg aliskiren was associated with very minor changes in the pharmacokinetics of aliskiren (change in Cmax of less than 1.2- fold; increase in AUC of up to 1.6 fold) compared to matched healthy subjects. Timing of hemodialysis did not significantly alter the pharmacokinetics of aliskiren in ESRD patients.
Therefore, no dose adjustment in warranted in ESRD patients receiving hemosialysis. Rasilez should be avoided in patients with severe renal impairment (GFR) < 30 ml/min/1.73 m2) (see section 4.4).
The pharmacokinetics of aliskiren were not significantly affected in patients with mild to severe liver disease. Consequently, no adjustment of the initial dose of aliskiren is required in patients with mild to severe hepatic impairment.
In a pharmacokinetic study of aliskiren treatment in 39 pediatric hypertensive patients aged 6 to less than 18 years, given daily doses of 2 mg/kg or 6 mg/kg aliskiren, administered as mini-tablets (3.125 mg/mini-tablet), pharmacokinetic parameters were similar to those in adults. The results of this study did not suggest that age, body weight or gender have any significant effect on aliskiren systemic exposure (see section 4.2) .
Results from in vitro MDR1 (P-gp) human tissue study suggested an age and tissue dependent pattern of MDR1 maturation. A high inter-individual variability of mRNA expression levels was observed (up to 600-fold). Hepatic MDR1 mRNA expression was statistically significantly lower in samples from fetuses, neonates, and infants up to 23 months.

RAS API JUN15 CL V10                                          REF CDS 6May14 & 18Dec14 The age at which MDR1 (P-gp) is mature cannot be determined. There is a potential for aliskiren overexposure in children with an immature MDR1 (see “Transporters” above and sections 4.2, 4.3 and 5.3).