Sujata Vaidyanathan

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

Interrupting the renin-angiotensin system (RAS) with a usual daily dose of a single-site RAS inhibitor does not achieve complete and long-lasting pharmacologic blockade. Hormonal and BP effects were compared for 48 h after administration of single oral doses of 300 mg (high dose) of the renin inhibitor aliskiren (A300) and 160 mg (standard antihypertensive dose) of the AT1 receptor antagonist valsartan (V160) and their combination each at half dose (A150+V80) in 12 mildly sodium-depleted normotensive individuals. In this double-blind, placebo-controlled, randomized, four-period crossover study, A300 decreased plasma renin activity and angiotensin I and II levels for 48 h, stimulated immunoreactive active renin release more strongly than V160, and decreased urinary aldosterone excretion for a longer duration than V160. In contrast to V160, the A150+V80 combination did not increase plasma angiotensins. The renin and aldosterone effects of the A150+V80 combination were similar to those of A300 and greater than those of V160. When plasma drug concentrations were taken into account, the A150 +V80 combination had a synergistic effect on renin release. The A150+V80 combination lowered BP at least as effectively as either higher dose monotherapy. In conclusion, in mildly sodium-depleted normotensive individuals, the long-lasting effects of aliskiren alone or in combination with valsartan on plasma immunoreactive active renin and urinary aldosterone effects demonstrate strong and prolonged blockade of angiotensin II at the kidney and the adrenal level. Moreover, a renin inhibitor and AT1R antagonist combination may provide synergistic effects on RAS hormone levels.

Clinical Pharmacokinetics and Pharmacodynamics of Aliskiren

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 concentration. Moreover, PRA inhibition and BP reductions persist for 2–4 weeks after stopping treatment, which is likely to be of benefit in patients with hypertension who occasionally miss a dose of medication.Preliminary data on the antiproteinuric effects of aliskiren in type 2 diabetes mellitus suggest that renoprotective effects beyond BP lowering may be possible. Further studies to evaluate the effects of aliskiren on cardiovascular outcomes and target organ protection are ongoing and will provide important new data on the role of direct renin inhibition in the management of hypertension and other cardiovascular disease.

Pharmacokinetics of the Oral Direct Renin Inhibitor Aliskiren in Combination With Digoxin, Atorvastatin, and Ketoconazole in Healthy Subjects: The Role of P-Glycoprotein in the Disposition of Aliskiren

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 (Km 2.1 μmol/L) and was transported by organic anion‐transporting peptide OATP2B1‐expressing HEK293 cells with moderate affinity (Km 72 μmol/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 AUCτ and Cmax,ss of digoxin, atorvastatin, o‐hydroxy‐atorvastatin, and ρ‐hydroxy‐atorvastatin, indicating no clinically significant interaction with P‐glycoprotein or CYP3A4 substrates. Aliskiren AUCτwas 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.

Lack of pharmacokinetic interactions of aliskiren, a novel direct renin inhibitor for the treatment of hypertension, with the antihypertensives amlodipine, valsartan, hydrochlorothiazide (HCTZ) and ramipril in healthy volunteers.

Aliskiren is a novel, orally active direct renin inhibitor that lowers blood pressure alone and in combination with existing antihypertensive agents. As aliskiren does not affect cytochrome P450 enzyme activities, is minimally metabolised, and is not extensively protein bound, the potential for drug interactions is predicted to be low. Four open‐label studies investigated the pharmacokinetic interactions between aliskiren 300 mg and the antihypertensive drugs amlodipine 10 mg (n = 18), valsartan 320 mg (n = 18), hydrochlorothiazide 25 mg (HCTZ, n = 22) and ramipril 10 mg (n = 17) in healthy subjects. In each study, subjects received multiple once‐daily doses of aliskiren and the test antihypertensive drug alone or in combination in two dosing periods separated by a drug‐free washout period. Plasma concentrations of drugs were determined by liquid chromatography and mass spectrometry methods. At steady state, relatively small changes in exposure to aliskiren were observed when aliskiren was co‐administered with amlodipine (AUC increased by 29%, p = 0.032), ramipril (Cmax,ss increased by 31%, p = 0.043), valsartan (AUC decreased by 26%, p = 0.002) and HCTZ (Cmax,ss decreased by 22%, p = 0.039). Co‐administration with aliskiren resulted in small changes in exposure to ramipril (AUC increased by 22%, p = 0.002), valsartan (AUC decreased by 14%, p = 0.062) and HCTZ (AUC decreased by 10% and Cmax,ss by 26%, both p < 0.001). All other changes in pharmacokinetic parameters were also small, and not statistically significant. None of the observed pharmacokinetic changes was considered clinically relevant. Aliskiren inhibited plasma renin activity (PRA) and also prevented the reactive rise in PRA induced by valsartan. The most commonly reported adverse events were headache, dizziness and gastrointestinal symptoms (all mild in severity), which were similar in frequency during antihypertensive drug treatment alone and in combination with aliskiren except for an increase in dizziness during treatment with the combination of aliskiren and HCTZ. In conclusion, aliskiren shows no clinically relevant pharmacokinetic interactions and is generally well tolerated when administered in combination with amlodipine, valsartan, HCTZ or ramipril.

Pharmacokinetics of the Oral Direct Renin Inhibitor Aliskiren Alone and in Combination with Irbesartan in Renal Impairment

BackgroundAliskiren is an orally active direct renin inhibitor approved for the treatment of hypertension. This study assessed the effects of renal impairment on the pharmacokinetics and safety of aliskiren alone and in combination with the angiotensin receptor antagonist irbesartan.MethodsThis open-label study enrolled 17 males with mild, moderate or severe renal impairment (creatinine clearance [CLCR] 50–80, 30–49 and <30 mL/minute, respectively) and 17 healthy males matched for age and bodyweight. Subjects received oral aliskiren 300mg once daily on days 1–7 and aliskiren coadministered with irbesartan 300mg on days 8–14. Plasma aliskiren concentrations were determined by high-performance liquid chromatography/tandem mass spectrometry at frequent intervals up to 24 hours after dosing on days 1, 7 and 14.ResultsRenal clearance of aliskiren averaged 1280 ± 500 mL/hour (mean ± SD) in healthy subjects and 559 ± 220, 312 ± 75 and 243 ± 186 mL/hour in patients with mild, moderate and severe renal impairment, respectively. At steady state (day 7), the geometric mean ratios (renal impairment: matched healthy volunteers) ranged from 1.21 to 2.05 for the area under the plasma concentration-time curve (AUC) over the dosage interval τ (24h) [AUCτ]) and from 0.83 to 2.25 for the maximum observed plasma concentration of aliskiren at steady state. Changes in exposure did not correlate with CLCR, consistent with an effect of renal impairment on non-renal drug disposition. The observed large intersubject variability in aliskiren pharmacokinetic parameters was unrelated to the degree of renal impairment. Accumulation of aliskiren at steady state (indicated by the AUC from 0 and 24 hours [AUC24] on day 7 vs day 1) was similar in healthy subjects (1.79 [95% CI 1.24, 2.60]) and those with renal impairment (range 1.39–1.99). Coadministration with irbesartan did not alter the pharmacokinetics of aliskiren. Aliskiren was well tolerated when administered alone or with irbesartan.ConclusionsExposure to aliskiren is increased by renal impairment but does not correlate with the severity of renal impairment (CLCR). 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.

Aliskiren Exhibits Similar Pharmacokinetics in Healthy Volunteers and Patients with Type 2 Diabetes Mellitus

AbstractBackground: The renin system is an attractive target for antihypertensive therapy in patients with diabetes mellitus. However, diabetes is associated with changes in gastrointestinal, renal and hepatic function that may affect the absorption and disposition of oral drugs. This study compared the pharmacokinetics and pharmacodynamics of the orally active direct renin inhibitor, aliskiren, in healthy volunteers and patients with type 2 diabetes. Methods: This was an open-label study conducted in 30 patients with type 2 diabetes and 30 healthy volunteers matched for age, bodyweight and race. Following a 10-hour fast, all participants received a single oral dose of aliskiren 300mg. Blood samples were taken at frequent intervals for 96 hours post-dose for determination of plasma concentrations of aliskiren (using a high-performance liquid chromatography-tandem mass spectroscopy method). Plasma renin activity (PRA) and renin concentration (RC) were also measured for 24 hours after dosing. Results: Aliskiren exhibited similar pharmacokinetics in patients with type 2 diabetes and healthy volunteers. Exposure to aliskiren was slightly higher in patients with type 2 diabetes compared with healthy volunteers (mean area under the plasma concentration-time curve from 0 to 24 hours 1859 vs 1642 ng · h/mL; maximum observed plasma drug concentration 394 vs 348 ng/mL), while apparent clearance corrected for bioavailability was slightly lower (205 vs 234 L/h) and elimination half-life slightly longer (44 vs 39.9 hours), but there were no statistically significant differences for any pharmacokinetic parameters. There was no significant correlation between glycaemic control (% glycosylated haemoglobin) and any of the measured pharmacokinetic parameters in patients with type 2 diabetes. Aliskiren caused sustained suppression of PRA for at least 24 hours after dosing despite increasing RC; there were no major differences in the pharmacodynamic effects of aliskiren between patients with type 2 diabetes and healthy volunteers. Aliskiren was well tolerated in both patient groups, with no clinically significant changes in laboratory values and a low risk of adverse events. Conclusion: Aliskiren showed a similar pharmacokinetic profile in healthy volunteers and patients with type 2 diabetes, and administration of a single oral 300mg 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.

Pharmacokinetics, safety, and tolerability of the oral renin inhibitor aliskiren in patients with hepatic impairment

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 AUC0‐∞ (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 AUC0‐∞ 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.

Pharmacokinetics, safety, and tolerability of the novel oral direct renin inhibitor aliskiren in elderly healthy subjects

This open‐label, multicenter study compared the pharmacokinetics and safety of the oral direct renin inhibitor aliskiren in 29 elderly (≤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, AUC0‐∞ was 57% higher (ratio of geometric means 1.57, 90% confidence interval: 1.19, 2.06; P = .008) and Cmax was 28% higher (1.28, 90% confidence interval: 0.91, 1.79; P = .233). Other parameters, including tmax 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 ≤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.

Effects of Aliskiren, a Direct Renin Inhibitor, on Cardiac Repolarization and Conduction in Healthy Subjects

This multicenter, double‐blind study evaluated the effects of aliskiren, a direct renin inhibitor approved for hypertension, on cardiac repolarization and conduction. Healthy volunteers (n = 298) were randomized to aliskiren 300 mg, aliskiren 1200 mg, moxifloxacin 400 mg (positive control), or placebo once daily for 7 days. Digitized electrocardiograms were obtained at baseline and day 7 of treatment over 23 hours postdose. Placebo‐adjusted mean changes from baseline in QTcF (Fridericia corrected), QTcI (individualized correction), PR, and QRS intervals were compared at each time point (time‐matched analysis) and for values averaged across the dosing period (baseline‐averaged analysis). In time‐matched analysis, mean changes in QTcF with aliskiren were below predefined limits for QTc prolongation (mean increase <5 milliseconds; upper 90% confidence interval [CI] <1 0 milliseconds) except aliskiren 1200 mg at 23 hours (5.2 milliseconds; 90% CI 2.2, 8.1). With moxifloxacin, significant QTcF prolongation occurred at most time points, confirming the sensitivity of the assay. Baseline‐averaged analysis was consistent with time‐matched analysis. Instances of QTcF interval >450 milliseconds or a >30‐millisecond increase from baseline with aliskiren (≤1%) were similar or lower than placebo (≤4%). Results were similar for QTcI. Aliskiren had no effect on PR or QRS duration. In conclusion, aliskiren at the highest approved dose (300 mg) and a 4‐fold higher dose had no effect on cardiac repolarization or conduction in healthy volunteers.

A study of the pharmacokinetic interactions of the direct renin inhibitor aliskiren with metformin, pioglitazone and fenofibrate in healthy subjects

ABSTRACT Objective: Hypertension and type 2 diabetes are common comorbidities, thus many patients receiving antihypertensive medication require concomitant therapy with hypoglycemic or lipid-lowering drugs. The aim of these three studies was to investigate the pharmacokinetics, safety and tolerability of aliskiren, a direct renin inhibitor for the treatment of hypertension, co-administered with the glucose-lowering agents metformin or pioglitazone or the lipid-lowering agent fenofibrate in healthy volunteers. Methods: In three open-label, multiple-dose studies, healthy volunteers (ages 18 to 45 years) received once-daily treatment with either metformin 1000 mg (n = 22), pioglitazone 45 mg (n = 30) or fenofibrate 200 mg (n = 21) and aliskiren 300 mg, administered alone or co-administered in a two-period study design. Blood samples were taken frequently on the last day of each treatment period to determine plasma drug concentrations. Results: Co-administration of aliskiren with metformin decreased aliskiren area under the plasma concentration–time curve during the dose interval (AUCτ) by 27% (geometric mean ratio [GMR] 0.73; 90% confidence interval [CI] 0.64, 0.84) and maximum observed plasma concentration (Cmax) by 29% (GMR 0.71; 90% CI 0.56, 0.89) but these changes were not considered clinically relevant. Co-administration of aliskiren with fenofibrate had no effect on aliskiren AUCτ (GMR 1.05; 90% CI 0.96, 1.16) or Cmax (GMR 1.05; 90% CI 0.80, 1.38); similarly, co-administration of aliskiren with pioglitazone had no effect on aliskiren AUCτ (GMR 1.05; 90% CI 0.98, 1.13) or Cmax (GMR 1.01; 90% CI 0.84, 1.20). All other AUCτ and Cmax GMRs for aliskiren, metformin, pioglitazone, ketopioglitazone, hydroxypioglitazone and fenofibrate were close to unity and the 90% CI were contained within the bioequivalence range of 0.80 to 1.25. Conclusion: 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.