Suliman Al-Fayoumi

Pharmacokinetics and Pharmacodynamics of LCZ696, a Novel Dual-Acting Angiotensin Receptor−Neprilysin Inhibitor (ARNi)

Angiotensin receptor blockade and neprilysin (NEP) inhibition together offer potential benefits for the treatment of hypertension and heart failure. LCZ696 is a novel single molecule comprising molecular moieties of valsartan and NEP inhibitor prodrug AHU377 (1:1 ratio). Oral administration of LCZ696 caused dose‐dependent increases in atrial natriuretic peptide immunoreactivity (due to NEP inhibition) in Sprague‐Dawley rats and provided sustained, dose‐dependent blood pressure reductions in hypertensive double‐transgenic rats. In healthy participants, a randomized, double‐blind, placebo‐controlled study (n = 80) of single‐dose (200–1200 mg) and multiple‐dose (50–900 mg once daily for 14 days) oral administration of LCZ696 showed that peak plasma concentrations were reached rapidly for valsartan (1.6–4.9 hours), AHU377 (0.5–1.1 hours), and its active moiety, LBQ657 (1.8–3.5 hours). LCZ696 treatment was associated with increases in plasma cGMP, renin concentration and activity, and angiotensin II, providing evidence for NEP inhibition and angiotensin receptor blockade. In a randomized, open‐label crossover study in healthy participants (n = 56), oral LCZ696 400 mg and valsartan 320 mg were shown to provide similar exposure to valsartan (geometric mean ratio [90% confidence interval]: AUC0‐∞ 0.90 [0.82–0.99]). LCZ696 was safe and well tolerated. These data support further clinical development of LCZ696, a novel, orally bioavailable, dual‐acting angiotensin receptor—NEP inhibitor (ARNi) for hypertension and heart failure.

Pharmacokinetics, safety and tolerability of single and multiple oral doses of aliskiren in healthy Chinese subjects: a randomized, single-blind, parallel-group, placebo-controlled study.

AbstractBackground: Aliskiren is the first oral direct renin inhibitor to be approved for the treatment of hypertension. The pharmacokinetic and pharmacodynamic profile of aliskiren has been extensively characterized in Caucasian individuals; however, drug disposition, treatment response and tolerability can vary among ethnic groups, and these variations are difficult to predict. Objective: To evaluate the single- and multiple-dose pharmacokinetics of aliskiren in healthy Chinese subjects. Methods: This was a randomized, single-blind, parallel-group, placebo-controlled study. On day −1, subjects were randomized to one of four cohorts (aliskiren 75, 150, 300 or 600 mg). On day 1, eight individuals in each cohort received a single dose of active treatment and two received placebo. Subjects randomized to aliskiren 300 mg received additional once-daily doses on days 5–11 to establish steady-state pharmacokinetics. Subjects receiving aliskiren 75, 150 or 600 mg (cohorts 1, 2 and 4) completed the study at the end of the 96-hour pharmacokinetic assessment period. Subjects receiving aliskiren 300 mg (cohort 3) had additional pharmacokinetic assessments on days 5–15. The study was carried out at the Peking Union Medical College Hospital, Beijing, China, and included 40 healthy Chinese subjects. The main outcome measures were the pharmacokinetic parameters for aliskiren, including area under the plasma concentration-time curve from time zero to infinity (AUC∞) and maximum plasma concentration (Cmax). Results: Aliskiren AUC∞ and Cmax increased greater than proportionally across the 8-fold dose range (75–600 mg; mean AUC∞ 291-4726 ng· h/mL, mean Cmax 62–699 ng/mL), but a dose-proportional 2-fold increase was observed within the clinically approved dose range (150–300 mg; mean AUC∞ 876–1507 ng· h/mL, mean Cmax 137–271 ng/mL). At steady state, the mean AUC during the dosage interval (AUCτ) for aliskiren 300 mg (1532 ± 592 ng · h/mL) was similar to the AUC∞ observed following a single dose. Conclusion: Aliskiren exhibits similar single-dose and steady-state pharmacokinetics in Chinese subjects compared with those observed in Caucasian individuals in previous studies.