Combination of two antihypertensive active substances to control blood pressure in patients with essential hypertension. Aliskiren belongs to the class of direct renin inhibitors and hydrochlorothiazide to the class of thiazide diuretics. The combination of these substances with complementary mechanisms of action provides an additive antihypertensive effect, reducing blood pressure to a greater degree than either component alone.
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 (angiotensin converting enzyme inhibitors (ACEI) and angiotension II receptor blockers (ARB)) 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. The clinical implications of the effects on PRA are not known at the present time.
The site of action of thiazide diuretics is primarily in the renal distal convoluted tubule. It has been shown that there is a high-affinity receptor in the renal cortex as the primary binding site for the thiazide diuretic action and inhibition of NaCl transport in the distal convoluted tubule. The mode of action of thiazides is through inhibition of the Na+Cl- symporter by competing for the Cl- site, thereby affecting electrolyte reabsorption mechanisms: directly increasing sodium and chloride excretion to an approximately equal extent, and indirectly by this diuretic action reducing plasma volume, with consequent increases in plasma renin activity, aldosterone secretion and urinary potassium loss, and a decrease in serum potassium.
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%. At steady state meals with low fat content reduce Cmax by 76% and AUC0-tau by 67% in hypertensive patients. However the efficacy of aliskiren was similar when taken with a light meal or under fasted state. 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.
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.
Following intravenous administration, the mean volume of distribution at steady state is approximately 135 litres, indicating that aliskiren distributes extensively into the extravascular space. Aliskiren plasma protein binding is moderate (47-51%) and independent of the concentration.
The mean half-life is about 40 hours (range 34-41 hours). Aliskiren is mainly eliminated as unchanged compound in the faeces (oral radioactive dose recovery = 91%). 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.
Exposure to aliskiren increased slightly 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. Mechanisms responsible for the deviation from dose proportionality have not been identified. A possible mechanism is saturation of transporters at the absorption site or at the hepatobiliary clearance route.
In a pharmacokinetic study of aliskiren treatment in 39 paediatric hypertensive patients aged 6 to 17 years given daily doses of 2 mg/kg or 6 mg/kg aliskiren administered as granules (3.125 mg/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.
In an 8-week randomised, double-blind study with aliskiren monotherapy in 267 paediatric hypertensive patients aged 6 to 17 years, mostly overweight/obese, fasting trough aliskiren concentrations at day 28 were comparable to those observed in other studies in both adults and children using similar aliskiren doses.
Results from an in vitro MDR1 human tissue study suggested an age and tissue dependent pattern of MDR1 (P-gp) transporter 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 foetuses, neonates and infants up to 23 months.
The age at which the transporter system is mature cannot be determined. There is a potential for aliskiren overexposure in children with an immature MDR1 (P-gp) system (see section “Transporters” above).
The absorption of hydrochlorothiazide, after an oral dose, is rapid (Tmax about 2 h). The increase in mean AUC is linear and dose proportional in the therapeutic range.
The effect of food on hydrochlorothiazide absorption, if any, has little clinical significance. Absolute bioavailability of hydrochlorothiazide is 70% after oral administration.
The apparent volume of distribution is 4-8 l/kg. Circulating hydrochlorothiazide is bound to serum proteins (40-70%), mainly serum albumin. Hydrochlorothiazide also accumulates in erythrocytes at approximately 3 times the level in plasma.
Hydrochlorothiazide is eliminated predominantly as unchanged compound. Hydrochlorothiazide is eliminated from plasma with a half-life averaging 6 to 15 hours in the terminal elimination phase. There is no change in the kinetics of hydrochlorothiazide on repeated dosing, and accumulation is minimal when dosed once daily. There is more than 95% of the absorbed dose being excreted as unchanged compound in the urine. The renal clearance is composed of passive filtration and active secretion into the renal tubule.
Following oral administration of aliskiren/hydrochlorothiazide tablets, the median peak plasma concentration time is within 1 hour for aliskiren and 2.5 hours for hydrochlorothiazide.
The rate and extent of absorption of aliskiren/hydrochlorothiazide fixed-dose combination are equivalent to the bioavailability of aliskiren and hydrochlorothiazide when administered as individual monotherapies. Similar food effect was observed for aliskiren/hydrochlorothiazide as for the individual monotherapies.
Aliskiren/hydrochlorothiazide combination has been shown to be effective as a once-a-day antihypertensive treatment in adult patients, regardless of gender, age, body mass index and ethnicity.
The pharmacokinetics of aliskiren are not significantly affected in patients with mild to moderate liver disease. Consequently, no initial dose adjustment of aliskiren/hydrochlorothiazide is required in patients with mild to moderate hepatic impairment. No data are available on patients with severe hepatic impairment treated by aliskiren/hydrochlorothiazide. Aliskiren/hydrochlorothiazide combination is contraindicated in patients with severe hepatic impairment.
No adjustment of the initial dose is required for patients with mild to moderate renal impairment. In the presence of renal impairment, mean peak plasma levels and AUC values of hydrochlorothiazide are increased and the urinary excretion rate is reduced. In patients with mild to moderate renal impairment, a 3-fold increase in hydrochlorothiazide AUC has been observed. In patients with severe renal impairment an 8-fold increase in AUC has been observed.
The pharmacokinetics of aliskiren were evaluated in patients with end stage renal disease receiving haemodialysis. 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 haemodialysis did not significantly alter the pharmacokinetics of aliskiren in ESRD patients. Therefore, if administration of aliskiren in ESRD patients receiving haemodialysis is considered necessary, no dose adjustment is warranted in these patients. However, the use of aliskiren is not recommended in patients with severe renal impairment.
No initial dose adjustment of aliskiren/hydrochlorothiazide is required in elderly patients. Limited data suggest that the systemic clearance of hydrochlorothiazide is reduced in both healthy and hypertensive elderly subjects compared to young healthy volunteers.
No pharmacokinetic data on aliskiren/hydrochlorothiazide are available in the paediatric population.
Safety pharmacology studies with aliskiren did not reveal any adverse effects on central nervous, respiratory or cardiovascular function. Findings during repeat-dose toxicity studies in animals were consistent with the known local (gastrointestinal tract) irritation potential or the expected pharmacological effects of aliskiren.
No carcinogenic potential for aliskiren was detected in a 2-year rat study and a 6-month transgenic mouse study. One colonic adenoma and one caecal adenocarcinoma recorded in rats at the dose of 1500 mg/kg/day were not statistically significant.
Although aliskiren has known local (gastrointestinal tract) irritation potential, safety margins obtained in humans at the dose of 300 mg during a study in healthy volunteers were considered to be appropriate at 9-11-fold based on faecal concentrations or 6-fold based on mucosa concentrations in comparison with 250 mg/kg/day in the rat carcinogenicity study.
Aliskiren was devoid of any mutagenic potential in the in vitro and in vivo mutagenicity studies.
Reproductive toxicity studies with aliskiren did not reveal any evidence of embryofoetal toxicity or teratogenicity at doses up to 600 mg/kg/day in rats or 100 mg/kg/day in rabbits. Fertility, pre-natal development and post-natal development were unaffected in rats at doses up to 250 mg/kg/day. The doses in rats and rabbits provided systemic exposures of 1 to 4 and 5 times higher, respectively, than the maximum recommended human dose (300 mg).
Preclinical evaluations to support the administration of hydrochlorothiazide in humans included in vitro genotoxicity assays and reproductive toxicity and carcinogenicity studies in rodents. Extensive clinical data are available for hydrochlorothiazide and these are reflected in the relevant sections.
The findings observed in the 2-week and 13-week toxicity studies were consistent with those observed previously with aliskiren or hydrochlorothiazide monotherapies. There were no new or unexpected findings observed of relevance to human use. Increased cellular vacuolation of the adrenal gland zona glomerulosa was observed during the 13-week toxicity study in rats. The finding was observed in animals treated with hydrochlorothiazide but not in those animals receiving aliskiren alone or vehicle. There was no evidence that this finding was enhanced in the aliskiren/hydrochlorothiazide combination as it was only apparent at a minimal severity in all animals.
In a juvenile toxicity study in 8-day-old rats, aliskiren administration at 100 mg/kg/day and 300 mg/kg/day (2.3- and 6.8-fold the maximum recommended human dose) was associated with high mortality and severe morbidity. In another juvenile toxicity study in 14-day old rats, aliskiren administration at 300 mg/kg/day (8.5-fold the maximum recommended human dose) was associated with delayed mortality. The systemic exposure to aliskiren in 8-day old rats was >400-fold higher than in adult rats. Results from a mechanistic study showed that the MDR1 (P-gp) gene expression in juvenile rats was significantly lower when compared to adult rats. The increased aliskiren exposure in juvenile rats appears to be attributed mainly to lack of maturation of P-gp in the gastrointestinal tract. There is therefore a potential for aliskiren overexposure in paediatric patients with immature MDR1 efflux system.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
