Integrating Drug Pharmacokinetics for Phenotyping Individual Renin Response to Angiotensin II Blockade in Humans

Abstract

Abstract-Renin release into plasma has been used to investigate the drug dose-dependence of renin-angiotensin system inhibition because it is proportional to the interruption of the permanent negative feedback loop of angiotensin II on renin secretion. We investigated the 24-hour between-subject differences in renin profiles by analyzing the time-dependence of individual renin responses in 16 mildly sodium-depleted normotensive subjects exposed in a 4-period crossover study to single oral doses of 8-and 16-mg (C8 and C16) candesartan cilexetil and 80-and 160-mg (V80 and V160) valsartan. C8 had a similar effect to V160 in terms of the increase in active renin concentration and decrease in blood pressure. C16 had the strongest effect and V80 the weakest effect on renin release. Within-and between-subject variability was more marked for valsartan pharmacokinetics than for candesartan pharmacokinetics and influenced variability in renin response. To eliminate some of the variability caused by the pharmacokinetics of each drug, we corrected the area under time curve of plasma renin levels by that of plasma drug levels to obtain an individual normalized index of renin release or "renin/pharmacokinetic index". In these experimental conditions, this index was found to be a reproducible individual characteristic affecting renin response, in addition to the pharmacokinetics and pharmacological properties of angiotensin II type-1 receptor antagonists. The pharmacokinetic-pharmacodynamic model of renin release described here could be of value for the identification and investigation of renin release abnormalities in patients with hypertension and for the comparison of renin-angiotensin system blockers. Key Words: blood pressure Ⅲ renin Ⅲ angiotensin antagonist R enin release into plasma has been used to investigate the drug dose-dependence of renin-angiotensin system (RAS) inhibition 1-3 because the decrease in angiotensin II (Ang II) production at the level of juxtaglomerular cells induced by angiotensin I-converting enzyme (ACE) or renin inhibitors or the displacement of Ang II from Ang II type-1 (AT 1 ) receptors by antagonists interrupts the permanent feedback inhibition of renin release mediated by Ang II. 4 The use of renin release as a sensitive plasma biomarker of an acute RAS blockade has several advantages: (1) it can be used for all class of inhibitors, including the ACE inhibitor-AT 1 receptor antagonist combination 5 and renin inhibitors, 3 provided that renin concentration is measured by immunoradiometric assay; (2) the range of variation for this factor is large, at Ϸ2 orders of magnitude; and (3) it is a more precise measurement than blood pressure (BP), another marker used to quantify the intensity of RAS blockade, especially in sodium-depleted subjects. 5,6 In contrast to the increase in renin concentration observed after RAS blockade, the magnitude of the decrease in BP may be influenced by a placebo effect and offers a limited range of variation (5 to 15 mm Hg).We investigated in detail between-subject d...

Pharmacologic Demonstration of the Synergistic Effects of a Combination of the Renin Inhibitor Aliskiren and the AT1 Receptor Antagonist Valsartan on the Angiotensin II–Renin Feedback Interruption

“…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.…”

“…This analysis defines for each individual a normalized index of active renin release or "renin/pharmacokinetic index" (RPI), expressed in pg active renin/ml per ng drug/ml (20). The RPI calculated for A300 was 7.87 pg/ml per ng/ml (95% CI, 6.21 to 9.97), and the RPI calculated for V160 was 0.34 pg/ml per ng/ml (95% CI, 0.21 to 0.55).…”

Aliskiren Accumulates in Renin Secretory Granules and Binds Plasma Prorenin

“…1,2 Whether they also increase kidney renin is still being debated. [1][2][3] The rise in blood plasma has been suggested to be larger than during other types of RAS blockade, 4 either because the degree of RAS blockade is superior during renin inhibition 5 and/or because renin inhibitors increase the half-life of renin. 6 It may also be an artifact, because renin inhibitors "activate" the precursor of renin, prorenin ( Figure 1).…”

Effect of Contrasted Sodium Diets on the Pharmacokinetics and Pharmacodynamic Effects of Renin–Angiotensin System Blockers

“…The availability of oral valsartan, a readily active carboxylic acid derivative, 22 was not significantly affected by dietary sodium intake, even though the 2 diets could not be considered bioequivalent because of the high within-subject variability of valsartan pharmacokinetics, consistent with previous findings. 10 Ramipril was the only drug for which bioequivalence was strictly achieved between the 2 diets. It is a monoester carboxylic prodrug with a bioavailability of 50% to 60% extensively and rapidly metabolized to its active diacid derivative, ramiprilat, mainly in the liver.…”

“…9 Thus, any change in urinary excretion of atenolol with the sodium content of the diet should directly reflect a change in the net intestinal absorption of the drug in healthy subjects with normal renal function. The pharmacodynamic consequences of dietary sodium-induced changes in the pharmacokinetics of these drugs were assessed by determining the druginduced increase in plasma renin concentration (PRC) for the angiotensin-converting enzyme inhibitor and the angiotensin II receptor blockers resulting from interruption of the angiotensin II negative feedback loop on renin release 10 ; and the drug-induced changes in PR interval duration and heart rate (HR) on ECG recordings for atenolol. 6 We found that sodium status modulated the pharmacokinetics of candesartan and atenolol, with measurable but mild effects on the selected pharmacodynamic end points.…”