binding concentrations being independent over the range of 10–500 ng/ml (Azizi et al 2006). Interactions with other drugs Aliskiren is not metabolized by cytochrome P450 and is not bound extensively to blood proteins therefore having a low potential for drug interactions. It has been shown that multiple doses of aliskiren have no detectable effects on the pharmacodynamics or pharmacokinetics of a single dose of warfarin (Dieterle et al 2004). Aliskiren shows no clinically relevant pharmacokinetic interactions with lovastatin, atenolol, celecoxib, or cimetidine in healthy male volunteers (Dieterle et al 2005). No interac- tions with digoxin were observed in a pharmacokinetic study in 22 healthy volunteers (Dieterich et al 2006). With regard to other antihypertensive medication, phar- macokinetic interactions between aliskiren 300 mg and valsartan (320 mg), hydrochlorthiazide (HCTZ; 25 mg), amlodipine (10 mg) and ramipril (10 mg) have been studied in healthy subjects and no clinically relevant effects were shown (Vaidyanathan et al 2006). Pharmacodynamic properties Aliskiren is a highly potent inhibitor of human renin in vitro (IC50 = 0.6 nmol/L), this compares favourably with the earlier renin inhibitor compounds. Thus, the IC50 for enalkiren (A-64662) is 14 nmol/L (Rongen et al 1995), IC50 for remikiren (Ro 42-5892) and zankiren (A-72517) are 0.8 nmol/L and 1.1 nmol/L, respectively (Kleinbloesem et al 1993; Menard et al 1995). Aliskiren shows high speciﬁcity for human renin, with almost no inhibitory effect against other aspartic peptidases such as cathepsin D and pepsin. Although aliskiren also exhibits high afﬁnity for primate renin, it is signiﬁcantly less active against renin from dog, rat, rabbit, pig and cat (Wood et al 2003). This high potency for human renin compensates for the relatively low oral bioavailability of the drug. Renin displays high speciﬁcity for its substrate and this species speciﬁcity complicates the preclinical experimental studies with renin inhibitors. Special transgenic model that over-expresses both renin and angiotensinogen (ie, double transgenic rats) has been developed and has provided an alternative to primate models for the evaluation of renin inhibitors (Ganten et al 1992; Fukamizu et al 1993). Pre-clinical and clinical studies have shown that aliski- ren effectively inhibits RAAS, along with dose-dependent decrease in BP. In a double-blind, randomised, crossover study in normotensive volunteers (n = 18), aliskiren was administered in two oral doses (either 40 mg and 80 mg or Vascular Health and Risk Management 2007:3(6) Aliskiren in essential hypertension 160 mg and 640 mg once daily) and compared to enalapril 20 mg/day, or placebo (Nussberger et al 2002). Aliskiren dose-proportionally decreased PRA and plasma Ang I and Ang II concentrations. Compared with placebo, the high- est dose of aliskiren reduced plasma Ang II by about 80%, although the plasma concentration of renin rose by more than ten times. Inhibition was still signiﬁcant after repeated dosing, with maximal decreases in Ang II levels by 89% and 75% on days 1 and 8, respectively. The inhibitory effects of aliskiren (160 mg) on Ang II were comparable to the effects of enalapril (20 mg). Decreases in plasma and urinary aldo- sterone levels were detected with aliskiren at daily doses of 80 mg or more but not at 40 mg (Nussberger et al 2002). The effects of aliskiren on plasma renin activity (PRA) were assessed in an open-label, 8-week dose escalation study in patients with mild-to-moderate essential hyperten- sion (n = 8). Aliskiren, 75 mg for 4-weeks, reduced PRA to 34 ± 7% of baseline levels, with 4-weeks of further treatment with 150 mg of aliskiren giving an additional reduction to 27 ± 6% of baseline activity (Wood et al 2003). Importantly, the rapid rise in plasma immunoreactive renin levels observed following aliskiren administration, caused by the removal of the normal feedback inhibition of Ang II on renin release, did not compromise the ability of aliskiren to provide sustained PRA inhibition and BP lowering (Wood et al 2003). This is in accordance with the sustained inhibition of Ang II production observed over 8-day period with once-daily oral administration of aliskiren in doses of 40–640 mg in healthy volunteers (Nussberger et al 2002). In a small pilot trial with a four-period randomised crossover design, single doses of 300 mg aliskiren, 160 mg valsartan, the combination of 150 mg aliskiren plus 80 mg valsartan, or placebo were given to 12 male volunteers with mild sodium depletion (Azizi et al 2004). Aliskiren reduced PRA and plasma levels of Ang I and II for 48 h. Compared with valsartan, aliskiren more strongly stimulated the release of active renin into the circulation (about 10 times compared with about 15 times) while inhibiting PRA, and reduced the urinary aldosterone excretion for a longer period (8 vs 48 h). The effects of the combination of the lower doses of aliski- ren and valsartan were similar to those of 300 mg aliskiren and larger than those of 160 mg valsartan. Aliskiren also blunted the valsartan-induced rise in plasma renin activity and in plasma concentration of angiotensin I and II (Azizi et al 2004). These ﬁndings suggest that, at lower doses, renin inhibitors and angiotensin-receptor blockers might have synergistic effects on the renin system. 811