Aliskiren is the first orally bioavailable direct renin inhibitor approved for the treatment of hypertension. It acts at the point of activation of the renin-angiotensin-aldosterone system, or renin system, inhibiting the conversion of angiotensinogen to angiotensin I by renin and thereby reducing the formation of angiotensin II by angiotensin-converting enzyme (ACE) and ACE-independent pathways. Aliskiren is a highly potent inhibitor of human renin in vitro (concentration of aliskiren that produces 50% inhibition of renin 0.6 nmol/L). Aliskiren is rapidly absorbed following oral administration, with maximum plasma concentrations reached within 1-3 hours. The absolute bioavailability of aliskiren is 2.6%. The binding of aliskiren to plasma proteins is moderate (47-51%) and is independent of the concentration. Once absorbed, aliskiren is eliminated through the hepatobiliary route as unchanged drug and, to a lesser extent, through oxidative metabolism by cytochrome P450 (CYP) 3A4. Unchanged aliskiren accounts for approximately 80% of the drug in the plasma following oral administration, indicating low exposure to metabolites. The two major oxidized metabolites of aliskiren account for less than 5% of the drug in the plasma at the time of the maximum concentration. Aliskiren excretion is almost completely via the biliary/faecal route; 0.6% of the dose is recovered in the urine. Steady-state plasma concentrations of aliskiren are reached after 7-8 days of once-daily dosing, and the accumulation factor for aliskiren is approximately 2. After reaching the peak, the aliskiren plasma concentration declines in a multiphasic fashion. No clinically relevant effects of gender or race on the pharmacokinetics of aliskiren are observed, and no adjustment of the initial aliskiren dose is required for elderly patients or for patients with renal or hepatic impairment. Aliskiren showed no clinically significant increases in exposure during coadministration with a wide range of potential concomitant medications, although increases in exposure were observed with P-glycoprotein inhibitors. Aliskiren does not inhibit or induce CYP isoenzyme or P-glycoprotein activity, although aliskiren is a substrate for P-glycoprotein, which contributes to its relatively low bioavailability. Aliskiren is approved for the treatment of hypertension at once-daily doses of 150 mg and 300 mg. Phase II and III clinical studies involving over 12,000 patients with hypertension have demonstrated that aliskiren provides effective long-term blood pressure (BP) lowering with a good safety and tolerability profile at these doses. Aliskiren inhibits plasma renin activity (PRA) by up to 80% following both single and multiple oral-dose administration. Similar reductions in PRA are observed when aliskiren is administered in combination with agents that alone increase PRA, including diuretics (hydrochlorothiazide, furosemide [frusemide]), ACE inhibitors (ramipril) and angiotensin receptor blockers (valsartan), despite greater increases in the plasma renin concentratio...

This study investigated the potential pharmacokinetic interaction between the direct renin inhibitor aliskiren and modulators of P-glycoprotein and cytochrome P450 3A4 (CYP3A4). Aliskiren stimulated in vitro P-glycoprotein ATPase activity in recombinant baculovirus-infected Sf9 cells with high affinity (K(m) 2.1 micromol/L) and was transported by organic anion-transporting peptide OATP2B1-expressing HEK293 cells with moderate affinity (K(m) 72 micromol/L). Three open-label, multiple-dose studies in healthy subjects investigated the pharmacokinetic interactions between aliskiren 300 mg and digoxin 0.25 mg (n = 22), atorvastatin 80 mg (n = 21), or ketoconazole 200 mg bid (n = 21). Coadministration with aliskiren resulted in changes of <30% in AUC(tau) and C(max,ss) of digoxin, atorvastatin, o-hydroxy-atorvastatin, and rho-hydroxy-atorvastatin, indicating no clinically significant interaction with P-glycoprotein or CYP3A4 substrates. Aliskiren AUC(tau) was significantly increased by coadministration with atorvastatin (by 47%, P < .001) or ketoconazole (by 76%, P < .001) through mechanisms most likely involving transporters such as P-glycoprotein and organic anion-transporting peptide and possibly through metabolic pathways such as CYP3A4 in the gut wall. These results indicate that aliskiren is a substrate for but not an inhibitor of P-glycoprotein. On the basis of the small changes in exposure to digoxin and atorvastatin and the <2-fold increase in exposure to aliskiren during coadministration with atorvastatin and ketoconazole, the authors conclude that the potential for clinically relevant drug interactions between aliskiren and these substrates and/or inhibitors of P-glycoprotein/CPY3A4/OATP is low.

Aliskiren showed a similar pharmacokinetic profile in healthy volunteers and patients with type 2 diabetes, and administration of a single oral 300 mg dose of aliskiren was well tolerated by both patients and healthy volunteers. The pharmacodynamic effects of aliskiren were also similar in healthy volunteers and diabetic patients, with sustained inhibition of renin system activity observed for at least 24 hours after dosing.

Aliskiren is the first in a new class of orally active, direct renin inhibitors for the treatment of hypertension. This open-label, nonrandomized, single-center, parallel-group study compared the pharmacokinetics and safety of a single 300-mg oral dose of aliskiren in patients with mild, moderate, or severe hepatic impairment to that in healthy subjects. When pooled across subgroups, there were no significant differences between patients with hepatic impairment and healthy subjects in aliskiren AUC(0-infinity) (ratio of geometric means, 1.12; 90% confidence interval, 0.85, 1.48) or Cmax (mean ratio, 1.19; 90% confidence interval, 0.84, 1.68), and there was no correlation between severity of hepatic impairment and either AUC(0-infinity) or Cmax. Aliskiren was well tolerated by healthy subjects and patients with hepatic impairment. In conclusion, hepatic impairment has no significant effect on the pharmacokinetics of aliskiren following single-dose administration, and dosage adjustment is unlikely to be needed in patients with liver disease.

Exposure to aliskiren is increased by renal impairment but does not correlate with the severity of renal impairment (CL(CR)). This is consistent with previous data indicating that renal clearance of aliskiren represents only a small fraction of total clearance. Initial dose adjustment of aliskiren is unlikely to be required in patients with renal impairment.

This open-label, multicenter study compared the pharmacokinetics and safety of the oral direct renin inhibitor aliskiren in 29 elderly (>or=65 years) and 28 young (18-45 years) healthy subjects. Plasma drug concentrations were determined for up to 168 hours following a single 300-mg oral dose of aliskiren. In elderly compared with young subjects, AUC(0-infinity) was 57% higher (ratio of geometric means 1.57, 90% confidence interval: 1.19, 2.06; P = .008) and C(max) was 28% higher (1.28, 90% confidence interval: 0.91, 1.79; P=.233). Other parameters, including t(max) and Vd/F, were similar between age groups. No differences in aliskiren exposure were observed between subjects ages 65 to 74 years (n=16) and >or=75 years (n=13). Aliskiren was well tolerated by all age groups, including the very elderly. In conclusion, aliskiren exposure is modestly increased in elderly subjects. Based on its wide therapeutic index and shallow dose response for blood pressure lowering, no initial dose adjustment should be needed for elderly patients.

Co-administration of aliskiren with metformin, pioglitazone or fenofibrate had no significant effect on the pharmacokinetics of these drugs in healthy volunteers. These findings indicate that aliskiren can be co-administered with metformin, pioglitazone or fenofibrate without the need for dose adjustment.

BACKGROUND Aliskiren is the first in a new class of orally effective renin inhibitors for the treatment of hypertension. This study assessed the pharmacokinetic dose proportionality, safety and tolerability of aliskiren in healthy volunteers. METHODS Randomized, open‐label, four‐treatment, four‐period, crossover study in 32 healthy subjects (aged 18–45 years). Subjects were randomized into one of four dosing sequence groups; each received 75, 150, 300 and 600 mg of aliskiren once during the study. Blood samples were taken over a 96h period after dosing for measurement of aliskiren concentrations. RESULTS Following a single oral dose of 75, 150, 300 or 600 mg of aliskiren, AUC(0–96h) values (mean±SD) were 266±235, 530±360, 1480±806 and 3240±1950 ng·h/mL, respectively; Cmax(median tmax) was 26±31 (1.0 h), 72±62 (2.5 h), 202±119 (3.0 h) and 402±325 (2.0 h) ng/mL, respectively. AUC(0–96h) and Cmaxwere linear across the dose range 75–600 mg, and were dose‐proportional across a two‐fold dose range; a doubling of the dose increased AUC(0–96h) and Cmax by 2.3‐ and 2.6‐fold, respectively. t½ was comparable for all doses; the pooled t½ for aliskiren was 40.7±10.7 h. All doses of aliskiren were well tolerated. CONCLUSIONS This study shows that aliskiren displays linear pharmacokinetics. Plasma concentrations increased with doses of 75 to 600 mg and a linear relationship exists between drug dose and pharmacokinetic parameters. Aliskiren, at all doses, was well tolerated in this study. Clinical Pharmacology & Therapeutics (2005) 79, P64–P64; doi: