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CLINICAL SCIENCE |
*Clinical Investigation Center 9201, Assistance Publique des Hôpitaux de Paris/INSERM, Hôpital Européen Georges Pompidou, Paris, France; Novartis Pharmaceuticals Corporation, East Hanover, New Jersey; and Novartis Pharma AG, Basel, Switzerland
Correspondence to Dr. Michel Azizi, Centre d’Investigations Cliniques, AP-HP/INSERM, Hôpital Européen Georges Pompidou, 20-40 rue Leblanc, 75908 Paris cedex 15, France. Phone: 33-1-56-09-29-11; Fax: 33-1-56-09-29-29; E-mail: michel.azizi{at}egp.ap-hop-paris.fr
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Abstract |
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Introduction |
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Direct demonstration of the importance of renin in this counterregulatory mechanism has not previously been possible in humans because of the absence of convenient orally available renin inhibitors. Thus, we investigated whether a combination of the orally active potent alkane carboxamide renin inhibitor aliskiren (150 mg) (9,10) and the AT1R antagonist valsartan (80 mg), which inhibit the RAS at the first and last steps, respectively, results in a stronger blockade of the RAS and larger decreases in aldosterone excretion than higher doses of each RAS inhibitor given alone. Synergistic effects of a combination of a renin inhibitor and AT1R blocker on BP have been demonstrated in a preclinical study (11). We have used the same clinical and laboratory methods as those previously used to differentiate the combination of an ACE inhibitor and AT1R antagonist from each component (12,13). The present study therefore compared, in mildly sodium-depleted normotensive volunteers, the pharmacokinetic–pharmacodynamic relationship on renin release of a single oral dose of a 150-mg aliskiren–80-mg valsartan combination with those of 300 mg of aliskiren and 160 mg of valsartan.
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Materials and Methods |
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Study Protocol
Mild sodium depletion, which results in a two- to threefold increase in plasma active renin concentration, was used to amplify the renin response to RAS blockade and to provide optimal conditions to unmask the renin dependence of BP in the normotensive volunteers (12,13). Volunteers were instructed to arrive at the Clinical Investigation Center at 6 p.m. on the evening before each phase of the study (day 0). Mild sodium depletion was induced on day 0 by giving volunteers a single oral dose of 40 mg of furosemide at 9 p.m. and supplying them with a sodium-restricted diet (30 mmol/d) during each 60-h treatment period as described previously (12,13). Between treatment periods, sodium intake was unrestricted.
At 9 a.m. on the study day (day 1), volunteers received the study drugs, their combination, or matched placebos, according to the randomization schedule, after a 1-h period of rest in a semirecumbent position to allow for equilibration of BP, heart rate, and hormones. Fluid intake was unrestricted on the study days (1500 to 2000 ml/24 h). Volunteers remained in a resting, semirecumbent position for blood sampling and BP measurements. All volunteers were in a fasting state from 12 h before to 6 h after drug administration. Blood was sampled before and at various time points after drug intake for plasma active renin, plasma renin activity (PRA; measured by the trapping assay), plasma Ang I and Ang II, aldosterone, and circulating drug levels. PRA measures the enzymatic activity of active renin in plasma and investigates the inhibitory effect of aliskiren. Plasma active renin is determined using an immunoradiometric assay and measures the number of active renin molecules independent of their enzymatic activity (15). Mean arterial pressure (MAP; mean of 10 measurements performed at 2-min intervals) was determined using an automatic validated BP recorder (Press Mate BP 8800; Colin Co., Komaki-City, Japan). Urine volume and aldosterone extractable at pH1 were measured for each fractionated urine sample.
Laboratory Methods
The methods and antibodies used for sampling and determining plasma and urine hormones were as described in a previous clinical investigation of renin inhibitors (16,17). Circulating levels of aliskiren and valsartan were determined by liquid chromatography with tandem mass spectrometric detection (LC/MS/MS) (detection limits, 0.5 ng/ml and 20 ng/ml, respectively). The peak plasma concentration (Cmax), time to peak (tmax), the area under the curve up to the last measured time point (AUC0–48), and the AUC extrapolated to infinity (AUC0–
) were determined for each individual concentration-time profile (A300, A150, V160, and V80) by a noncompartmental method using WinNonlin Pro 4.0 software (Mountain View, CA).
Statistical Analyses
Data were analyzed by ANOVA for a four-by-four crossover design (18). When the F test was significant (P < 0.05), paired comparisons were made between specific treatments, using the Holm procedure (19). Regression was estimated by the least squares method. Stata Statistical Software (Release 7.0; College Station, TX) was used for statistical analysis. Data are expressed as geometric means with 95% confidence intervals (CI) for non-normal data and as means ± 1 SD for normally distributed data. P < 0.05 was considered to be significant.
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Results |
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Effects of A300, V160, and the A150+V80 Combination on PRA
A300 and V160 had opposing effects on PRA. A300 completely inhibited PRA within 1 h of intake, and this inhibition persisted for 48 h. By contrast, PRA increased considerably within 4 h of V160 intake and was still higher than placebo at 24 and 48 h after dosing (Table 1, Figure 1).
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Effects of A300, V160, and the A150+V80 Combination on Plasma Active Renin Concentration
Baseline plasma active renin concentrations were high and significantly correlated with baseline PRA (r = 0.70, P < 0.001, not shown). Placebo intake was associated with an increase in plasma active renin concentration from 42 (95% CI; 33 to 54) to 73 (95% CI; 54 to 98) pg/ml at 48 h; this was due to the effects of sodium restriction. All active drugs given alone or in combination massively increased plasma active renin levels from baseline within 4 h of drug intake, and all had a similar 48-h plasma active renin profile (Table 1, Figure 2). The peak plasma active renin concentration with the A150+V80 combination was of similar magnitude to that observed with A300 alone and significantly higher than after V160 alone. The duration of the increase in plasma active renin concentration was significantly longer for A300 or A150+V80 than for V160, as indicated by the significantly higher 24- and 48-h post-dose plasma active renin concentrations and AUC values (Table 1). The AUC values of plasma active renin concentration for A300 and the A150+V80 combination were similar, but plasma active renin concentration 48 h after A300 intake was significantly higher than that after intake of the A150+V80 combination (Table 1).
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Effects of A300, V160, and the A150+V80 Combination on Plasma Ang I and Ang II Concentrations
Baseline plasma Ang I and Ang II concentrations were strongly correlated with plasma active renin concentrations (r = 0.91 and r = 0.93, P < 0.001, respectively, not shown). After treatment with A300, V160, or the A150+V80 combination, plasma Ang I and Ang II profiles followed the same pattern as the PRA profiles (Table 3, Figure 2). The concentrations of Ang I and Ang II increased in parallel in response to V160 for up to 48 h after drug intake. In contrast, A300 significantly decreased plasma Ang I and Ang II concentrations to very low levels, which remained significantly lower than those measured after placebo for >24 h. In volunteers who were given the A150+V80 combination, plasma levels of both Ang I and Ang II remained similar to the values measured after placebo administration, in contrast to the increase in both peptides that was observed with V160 (Table 3, Figure 2).
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Discussion |
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Comparison of the Hormonal Effects of the Renin Inhibitor and the AT1R Antagonist and Analysis of the RPI
Our results showed that in mildly sodium-depleted normotensive individuals, (1) aliskiren decreases PRA and plasma Ang I and Ang II concentrations in a dose-dependent manner for up to 48 h after intake, confirming that it is a potent, orally active, long-lasting renin inhibitor; and (2) a single oral dose of A300 stimulated greater immunoreactive active renin release from the juxtaglomerular cells of the kidney than the standard daily dose of V160.
The potency of aliskiren by comparison with valsartan was assessed according to the plasma levels achieved by each drug, by the calculation of the RPI. The RPI is a pharmacokinetic/pharmacodynamic index that takes into account actual drug exposure rather than the oral dose of the drug administered and has been used previously to characterize two different AT1R antagonists, valsartan and candesartan (20). This correction is especially important in studies in which drug pharmacokinetics are nonlinear, as was the case in the present study. The RPI for A300 was 7.87 pg/ml per ng/ml (95% CI, 6.21 to 9.97), and that for V160 was 0.34 pg/ml per ng/ml (95% CI, 0.21 to 0.55). Thus, according to the RPI, exposure to 
20 times more valsartan than aliskiren is required to trigger the release of one renin molecule in plasma.
Finally, the duration of the decrease in urinary aldosterone was longer after A300 treatment than after V160 treatment. However, the decrease in BP was similar for both drugs in these mildly sodium-depleted normotensive individuals.
Combined Blockade of the RAS by Aliskiren and Valsartan
We have compared the effects on hormone and BP levels of a high dose of a renin inhibitor or a standard dose of an AT1R antagonist given alone with those of each of these components administered in combination (at half dose). Under conditions in which the pharmacokinetic parameters of neither drug were modified when the drugs were combined, combination of aliskiren with valsartan prevented the increase in PRA and plasma Ang I and Ang II concentrations that was observed with valsartan alone. The AUC0–24 of plasma active renin concentration for the A150+V80 combination was significantly higher than that achieved with 160 mg of valsartan and similar to that achieved by A300 alone. A300 and the A150+V80 combination decreased urinary aldosterone excretion for a similar duration, whereas V160 had a shorter effect. A300 and the A150+V80 combination thus seemed to be equipotent with regard to these two parameters. However, to interpret these results correctly, we must take into account that plasma aliskiren concentration does not increase proportionally to the dose given. The plasma concentrations of aliskiren increased by a factor of 4.4 (95% CI, 3.1 to 6.2), rather than by two, when the dose was doubled from 150 to 300 mg. This observation accounts for the larger-than-expected increase in the amount of renin released in response to A300, because the amount of renin release is directly related to the aliskiren concentration achieved at the level of the juxtaglomerular cells. After taking this nonproportionality into account, we can conclude that there is a synergistic effect on immunoreactive active renin release and on the decrease in urinary aldosterone excretion when these doses of a renin inhibitor (A150) and an AT1R antagonist (V80) are combined. In mildly sodium-depleted normotensive individuals, lower dose combination therapy lowered BP to a similar extent as either high-dose aliskiren monotherapy or standard-dose valsartan monotherapy. This may be due to the limited range of BP variation that can be detected in mildly sodium-depleted normotensive individuals, the large within-subject BP variability, and the low statistical power of the study for this parameter. The BP effects of a combination treatment associating various doses of aliskiren and valsartan need to be investigated in hypertensive patients.
Combined RAS inhibition makes it possible to use lower doses of each component to achieve a more effective and long-lasting RAS blockade (1). We show that, when nonlinearity of drug pharmacokinetics is taken into account, a combination of aliskiren (150 mg) and valsartan (80 mg) provided more effective RAS inhibition than double the dose of the AT1 receptor antagonist (160 mg) or renin inhibitor (300 mg) alone. The question of the influence of dose selection and dosing interval remains critical for all RAS inhibitors and their effects on BP and end-organ protection (21–23). The additive or synergistic effects of such combinations are more evident at low doses (which are the usual dose) than at high doses (22). An additional advantage of synergy or additivity between two antihypertensive drugs, therefore, is that the doses of individual drugs may be reduced to achieve the same therapeutic response. In summary, as with the dual RAS blockade generated by combining an AT1R antagonist and an ACE inhibitor (1), the combination of two pharmacologic agents inhibiting the initial and final steps of the RAS (renin and the AT1 receptor, respectively) minimizes or even overcomes the "escape" that occurs with single-site RAS blockade in an acute setting.
Potential Impact of the Results
The long duration of action of aliskiren, alone or in combination with valsartan, on the increase in plasma immunoreactive active renin and the decrease in urinary aldosterone is an interesting finding. It suggests that in both the kidneys and the adrenal glands, Ang II can be efficiently blocked through renin inhibition with aliskiren. These favorable effects of aliskiren may be due to a combination of the long plasma half-life of this drug and its high affinity for human renin in the low nanomolar range (24), which compensates for its low (2.6%) oral bioavailability. As observed with another renin inhibitor, remikiren (25), uptake by the kidney might also provide a drug reservoir that may prolong its intrarenal pharmacologic activity. Such characteristics may have useful clinical consequences. Hollenberg et al. (26) showed that renin inhibitors induce a greater renal vasodilator response than ACE inhibitors in sodium-restricted healthy subjects, an observation also made with remikiren in guinea pigs (27). Under circumstances in which intrarenal activation of Ang II production occurs via ACE- or non–ACE-dependent pathways, such as in diabetic nephropathy or in black hypertensive individuals on a high-salt diet (28), specific renal benefits thus are expected from renin inhibition in renal tissue (29) by the administration of an orally active renin inhibitor. This would be especially true if the mechanisms of intrarenal renin suppression are deficient in these forms of hypertension in humans (30). Finally, the prolonged inhibition of aldosterone excretion by aliskiren alone or in combination with valsartan, which may also be due to direct inhibition of the adrenal RAS (31), may be per se potentially beneficial to patients with chronic nephropathies (32).
These investigations of single-dose administration in mildly sodium-depleted normotensive individuals were performed to test the plausibility of a pharmacologic synergy or additivity of two RAS inhibitors acting at different steps of the pathway, renin and AT1 receptors. They have shown that the interruption of the RAS at the level of the Ang II–renin feedback with a low-dose combination of aliskiren and valsartan is similar to a high dose of aliskiren but more marked than with the standard dose of valsartan 160 mg. These results support further clinical studies at different doses of these compounds to investigate the long-term effects of renin inhibitor–AT1R antagonist combinations in various clinical contexts, including hypertension, chronic proteinuric nephropathies, and chronic heart failure. Indeed, results obtained in recent clinical trials suggest enhanced nephroprotective (3) and cardioprotective (2) effects of the dual RAS blockade with ACE inhibitors and AT1 receptor antagonists.
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Acknowledgments |
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We thank the nursing staff at the Clinical Investigation Center for carrying out our protocol. The technical contribution of Christiane Dollin in performing the assays is also much appreciated. We thank Sabine Vuillier, PhD, and Patrick Trunet, MD, at Novartis for helpful discussions.
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, A300; 
, V160; 
, A150+V80; 
, placebo. Data are geometric means.
, A300; 
, V160; 
, A150+V80; 
, placebo. Data are geometric means.