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Wang Z, Xiang X, Liu S, Tang Z, Sun H, Parvez M, Ghim JL, Shin JG, Cai W. A physiologically based pharmacokinetic/pharmacodynamic modeling approach for drug-drug interaction evaluation of warfarin enantiomers with sorafenib. Drug Metab Pharmacokinet 2020; 39:100362. [PMID: 34242938 DOI: 10.1016/j.dmpk.2020.10.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 09/13/2020] [Accepted: 10/01/2020] [Indexed: 10/23/2022]
Abstract
Sorafenib was suggested to cause drug-drug interaction (DDI) with the common anticoagulant, warfarin based on published studies. The inhibition on CYP2C9 enzyme was thought to be the mechanism, but further studies are warranted. Thus, a mechanistic PBPK/PD model for warfarin enantiomers was developed to predict DDI potential with sorafenib, aiming at providing reference for the rational use of both drugs. PBPK models of warfarin enantiomers were constructed by Simcyp software. A mechanistic PK/PD model was built in NONMEM software. PBPK model of sorafenib was fitted via a top-down method. The final PBPK/PD model of warfarin enantiomers was verified and validated by different dosing regimens, ethnicities and genetic polymorphisms, and used to perform DDI simulations between warfarin racemate and sorafenib among general populations and sub-populations with various CYP2C9 and VKORC1 genotypes. Results suggested low DDI risk between warfarin and sorafenib for general populations. Potentially serious consequence was seen for those carrying both CYP2C9 ∗2 and ∗3 and VKORC1 A/A genotypes. This PBPK/PD modeling approach for warfarin enantiomers enabled DDI evaluation with sorafenib. Close monitoring and warfarin dosage adjustment were recommended for patients carrying mutant genotypes. The novel model could be applied to investigate other drugs that may interact with warfarin.
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Affiliation(s)
- Ziteng Wang
- Department of Clinical Pharmacy, School of Pharmacy, Fudan University, Shanghai, 201203, China
| | - Xiaoqiang Xiang
- Department of Clinical Pharmacy, School of Pharmacy, Fudan University, Shanghai, 201203, China
| | - Shuaibing Liu
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Zhijia Tang
- Department of Clinical Pharmacy, School of Pharmacy, Fudan University, Shanghai, 201203, China
| | - Hong Sun
- Department of Clinical Pharmacy, School of Pharmacy, Fudan University, Shanghai, 201203, China
| | - Masud Parvez
- Department of Pharmacology and Pharmacogenomics Research Center, Inje University College of Medicine, Busan, 614735, Republic of Korea
| | - Jong-Lyul Ghim
- Department of Pharmacology and Pharmacogenomics Research Center, Inje University College of Medicine, Busan, 614735, Republic of Korea
| | - Jae-Gook Shin
- Department of Pharmacology and Pharmacogenomics Research Center, Inje University College of Medicine, Busan, 614735, Republic of Korea.
| | - Weimin Cai
- Department of Clinical Pharmacy, School of Pharmacy, Fudan University, Shanghai, 201203, China.
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Abstract
Each month, subscribers to The Formulary Monograph Service receive five to six well-documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to your Pharmacy and Therapeutics Committee. Subscribers also receive monthly one-page summary monographs on the agents that are useful for agendas and pharmacy/nursing in-services. A comprehensive target drug utilization evaluation (DUE) is also provided each month. With a subscription, the monographs are sent to you in print and CD-ROM forms and are available online. Monographs can be customized to meet the needs of your facility. Subscribers to the The Formulary Monograph Service also receive access to a pharmacy bulletin board, The Formulary Information Exchange (The F.I.X.). All topics pertinent to clinical and hospital pharmacy are discussed on The F.I.X. Through the cooperation of The Formulary, Hospital Pharmacy publishes selected reviews in this column. If you would like information about The Formulary Monograph Service or The F.I.X., call The Formulary at 800-322-4349. The August 2007 monograph topics are temsirolimus, formoterol fumarate inhalation solution, levocetirizine, ambrisentan, and raltegravir. The DUE is on temsirolimus.
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Affiliation(s)
- Dennis J. Cada
- College of Pharmacy, Washington State University Spokane, PO Box 1495, Spokane, WA 99210-1495
| | - Terri Levien
- Drug Information Center, Washington State University Spokane, College of Pharmacy, Washington State University Spokane, PO Box 1495, Spokane, WA 99210-1495
| | - Danial E. Baker
- Drug Information Center, College of Pharmacy, Washington State University Spokane, PO Box 1495, Spokane, WA 99210-1495
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Van Tassell BW, Munger MA. Aliskiren for Renin Inhibition: A New Class of Antihypertensives. Ann Pharmacother 2016; 41:456-64. [PMID: 17341529 DOI: 10.1345/aph.1h549] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
Objective: To review the safety, efficacy, pharmacology, pharmacokinetics, and drug interactions of aliskiren for the treatment of mild-to-moderate hypertension. Data Sources: A literature search was conducted using MEDLINE (1966'January 2007), International Pharmaceutical Abstracts (1970'January 2007), and Cochrane database (2006) for the key words aliskiren or SPP100. References of selected articles were also reviewed. Abstract data were included only in the absence of significant published data. Study Selection And Data Extraction: Available English-language data from reviews, abstracts, and clinical trials were selected. For review of efficacy, randomized controlled trials were preferred. Data Synthesis: Aliskiren is a renin inhibitor, the first in a new class of antihypertensives. As renin catalyzes the rate-limiting step of the renin–angiotensin system (RAS), renin inhibition may offer a theoretical advantage over other RAS inhibitors, such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs). In short-term clinical trials (≤8 wk) of subjects with mild-to-moderate hypertension, single daily doses of aliskiren 150–300 mg produced significant systolic and diastolic blood pressure reduction similar to that achieved with ACE inhibitors and ARBs, with placebo-like tolerability, without an elevation in heart rate or evidence of tolerance. Conclusions: Aliskiren appears to be a safe and effective treatment option in mild-to-moderate hypertension. Although long-term outcome data have not been published, aliskiren is a promising option for RAS inhibition.
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Affiliation(s)
- Benjamin W Van Tassell
- Experimental Cardiovascular Pharmacotherapy, Department of Pharmacotherapy, College of Pharmacy, University of Utah, Salt Lake City, UT 84112, USA.
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Abstract
Hypertension is one of the most common causes of death across the globe. Many trials and drugs have been used for controlling the debilitating effects of hypertension. One such new class of drug is direct renin inhibitors (DRI), e.g., aliskiren, which block the renin-angiotensin system (RAS). It blocks the very first step in the RAS system. Multiple trials have been carried out debating the outcome of monotherapy and combination therapy with other classes of hypertensive drugs. Focus on compliance, adverse effects, and the cost have also been in the news. Extensive studies are still needed to justify the clinical use of a DRI in the effective treatment of hypertension.
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Affiliation(s)
- Adnan Bashir Bhatti
- Department of Medicine, Capital Development Authority Hospital, Islamabad, Pakistan
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Lack of clinical pharmacodynamic and pharmacokinetic drug-drug interactions between warfarin and the antisense oligonucleotide mipomersen. J Cardiovasc Pharmacol 2015; 64:164-71. [PMID: 24691275 DOI: 10.1097/fjc.0000000000000101] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Mipomersen is a second-generation antisense oligonucleotide indicated as an adjunct therapy for homozygous familial hypercholesterolemia (HoFH). Warfarin is commonly prescribed for a variety of cardiac disorders in homozygous familial hypercholesterolemia population, and concurrent use of warfarin and mipomersen is likely. This open-label, single-sequence 2-period phase 1 study in healthy subjects evaluated the potential drug-drug interactions between mipomersen and warfarin. The subjects received a single oral 25 mg dose of warfarin alone on day 1, and after a 7-day washout period, received 200 mg mipomersen alone subcutaneously every other day on days 8-12, and received both concurrently on day 14. Coadministration of mipomersen did not change the pharmacodynamics (international normalized ratio, prothrombin time, and activated partial thromboplastin time) and pharmacokinetics (PK) of warfarin. There were no clinically significant changes in the PK of mipomersen with concurrent administration of warfarin. There were no events indicative of an increase in bleeding tendency when warfarin was coadministered with mipomersen, and the adverse event profile of mipomersen did not appear to be altered in combination with warfarin, as compared with that of the respective reference treatment. The combination of these 2 medications appeared to be safe and well tolerated. These results suggest that the dosage adjustment of warfarin or mipomersen is not expected to be necessary with coadministration.
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Estacio RO. Renin-Angiotensin-Aldosterone System Blockade in Diabetes: Role of Direct Renin Inhibitors. Postgrad Med 2015; 121:33-44. [DOI: 10.3810/pgm.2009.05.2000] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
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Zaporowska-Stachowiak I, Hoffmann K, Bryl W, Minczykowski A. Aliskiren - an alternative to angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in the therapy of arterial hypertension. Arch Med Sci 2014; 10:830-6. [PMID: 25276171 PMCID: PMC4175758 DOI: 10.5114/aoms.2013.34723] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2012] [Revised: 10/23/2012] [Accepted: 12/20/2012] [Indexed: 12/11/2022] Open
Abstract
There has been enormous progress in antihypertensive therapy over the last few decades. However, the management of arterial hypertension is still insufficient and more efforts are needed to improve both non-pharmacological and pharmacological treatment of this widely prevalent disease. Renin-angiotensin-aldosterone system (RAAS) inhibition is crucial both for blood pressure (BP) control and for prevention of organ damage or its development in patients with hypertension. Angiotensin-converting enzyme inhibitors and/or sartans block RAAS incompletely. Aliskiren is one of the novel drugs that has been introduced to antihypertensive therapy recently. Up to now no trial has confirmed that aliskiren is efficacious in reducing cardiovascular events. Double RAAS blockade with aliskiren was not always safe. This review article presents the current view on the place of aliskiren in the therapy of arterial hypertension.
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Affiliation(s)
| | - Karolina Hoffmann
- Chair and Department of Internal Medicine, Metabolic Disorders and Arterial Hypertension, Poznan University of Medical Sciences, Poland
| | - Wiesław Bryl
- Chair and Department of Internal Medicine, Metabolic Disorders and Arterial Hypertension, Poznan University of Medical Sciences, Poland
| | - Andrzej Minczykowski
- Department of Cardiology-Intensive Therapy, Poznan University of Medical Sciences, Poland
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Ferrão FM, Lara LS, Lowe J. Renin-angiotensin system in the kidney: What is new? World J Nephrol 2014; 3:64-76. [PMID: 25332897 PMCID: PMC4202493 DOI: 10.5527/wjn.v3.i3.64] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2014] [Revised: 07/07/2014] [Accepted: 07/29/2014] [Indexed: 02/06/2023] Open
Abstract
The renin-angiotensin system (RAS) has been known for more than a century as a cascade that regulates body fluid balance and blood pressure. Angiotensin II(Ang II) has many functions in different tissues; however it is on the kidney that this peptide exerts its main functions. New enzymes, alternative routes for Ang IIformation or even active Ang II-derived peptides have now been described acting on Ang II AT1 or AT2 receptors, or in receptors which have recently been cloned, such as Mas and AT4. Another interesting observation was that old members of the RAS, such as angiotensin converting enzyme (ACE), renin and prorenin, well known by its enzymatic activity, can also activate intracellular signaling pathways, acting as an outside-in signal transduction molecule or on the renin/(Pro)renin receptor. Moreover, the endocrine RAS, now is also known to have paracrine, autocrine and intracrine action on different tissues, expressing necessary components for local Ang II formation. This in situ formation, especially in the kidney, increases Ang II levels to regulate blood pressure and renal functions. These discoveries, such as the ACE2/Ang-(1-7)/Mas axis and its antangonistic effect rather than classical deleterious Ang II effects, improves the development of new drugs for treating hypertension and cardiovascular diseases.
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Chrysant SG. Aliskiren–hydrochlorothiazide combination for the treatment of hypertension. Expert Rev Cardiovasc Ther 2014; 6:305-14. [DOI: 10.1586/14779072.6.3.305] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Vaidyanathan S, Warren V, Yeh C, Bizot MN, Dieterich HA, Dole WP. Pharmacokinetics, Safety, and Tolerability of the Oral Renin Inhibitor Aliskiren in Patients With Hepatic Impairment. J Clin Pharmacol 2013; 47:192-200. [PMID: 17244770 DOI: 10.1177/0091270006294404] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
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 AUC(0-infinity) (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 AUC(0-infinity) 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.
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Affiliation(s)
- Sujata Vaidyanathan
- Novartis Institute for Biomedical Research, 400 Technology Square, Building 605-820, Cambridge, MA 02139, USA
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Angeli F, Reboldi G, Mazzotta G, Poltronieri C, Verdecchia P. Safety and efficacy of aliskiren in the treatment of hypertension: a systematic overview. Expert Opin Drug Saf 2012; 11:659-70. [PMID: 22724663 DOI: 10.1517/14740338.2012.696608] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
INTRODUCTION Aliskiren is the first orally active direct renin inhibitor approved for the treatment of hypertension. Aliskiren's inhibitory effect on angiotensin I generation, through renin blockade, is highly specific and long-lasting (24 hours). This feature differentiates aliskiren from traditional antihypertensive drugs. AREAS COVERED This paper reviews the results of various clinical trials which investigate the safety and efficacy of aliskiren on blood pressure (BP) reduction and clinical end points. EXPERT OPINION Aliskiren is suitable for once-daily administration. Its antihypertensive effect is comparable or superior to that of other antihypertensive agents at recommended doses. The tolerability profile of aliskiren is placebo-like at the licensed doses of 150 and 300 mg. In particular, the discontinuation of therapy due to clinical adverse events occurs similarly among patients treated with either aliskiren or placebo. Aliskiren is not recommended in association with ACE-inhibitors or angiotensin II receptor blockers in patients with type 2 diabetes and renal impairment. Pending disclosure of full results, the early termination of the ALTITUDE seems to confirm previous concerns about the safety of the dual pharmacological blockade of the renin-angiotensin system in these patients. Aliskiren is a well-tolerated antihypertensive drug that may help to achieve the recommended targets of BP control.
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Affiliation(s)
- Fabio Angeli
- Hospital Media Valle del Tevere - Pantalla, AUSL 2 Umbria, Department of Cardiology, Section of Cardiology, Perugia, Italy.
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Population pharmacokinetic modelling of S-warfarin to evaluate the design of drug–drug interaction studies for CYP2C9. J Pharmacokinet Pharmacodyn 2012; 39:147-60. [DOI: 10.1007/s10928-011-9235-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2011] [Accepted: 12/15/2011] [Indexed: 11/27/2022]
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Rashikh A, Ahmad SJ, Pillai KK, Najmi AK. Aliskiren as a novel therapeutic agent for hypertension and cardio-renal diseases. J Pharm Pharmacol 2011; 64:470-81. [DOI: 10.1111/j.2042-7158.2011.01414.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Abstract
Objectives
High blood pressure (BP) is a major risk factor for cardiovascular and renal complications. A majority of treated hypertensive patients still complain of high BP. The renin-angiotensin aldosterone system (RAAS) has been a centre-stage target for all the cardiovascular and cardio-renal complications. Aliskiren, is the first direct renin inhibitor (DRI) to be approved by the US FDA. Renin controls the rate-limiting step in the RAAS cascade and hence is the most favorable target for RAAS suppression.
Key findings
This review article strives to summarize the pharmacokinetic, preclinical and clinical studies done so far pertaining to the efficacy of aliskiren. Further, the pharmacology of aliskiren has been comprehensively dealt with to enhance understanding so as to further research in this unfathomed area in the multitude of cardiovascular disorders and renal diseases.
Summary
Aliskiren has been shown to have comparable BP-lowering effects to other RAAS inhibitors. Recent clinical trials have indicated that it might contribute significantly in combination with other agents for the protection of end-organ diseases.
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Affiliation(s)
- Azhar Rashikh
- Department of Pharmacology, Faculty of Pharmacy, Jamia Hamdard (Hamdard University), New Delhi, India
| | - Shibli Jameel Ahmad
- Department of Pharmacology, Faculty of Pharmacy, Jamia Hamdard (Hamdard University), New Delhi, India
| | - Krishna Kolappa Pillai
- Department of Pharmacology, Faculty of Pharmacy, Jamia Hamdard (Hamdard University), New Delhi, India
| | - Abul Kalam Najmi
- Department of Pharmacology, Faculty of Pharmacy, Jamia Hamdard (Hamdard University), New Delhi, India
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Reboldi G, Gentile G, Angeli F, Verdecchia P. Pharmacokinetic, pharmacodynamic and clinical evaluation of aliskiren for hypertension treatment. Expert Opin Drug Metab Toxicol 2010; 7:115-28. [DOI: 10.1517/17425255.2011.538681] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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Affiliation(s)
- Sean T Duggan
- Adis, a Wolters Kluwer Business, Mairangi Bay, North Shore, Auckland, New Zealand.
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Abstract
Hypertension, a serious disease affecting almost a billion people (25% of adults) worldwide, is a major modifiable risk factor for cardiovascular (CV) and renal disease. Despite numerous advances in the pharmacologic treatment of high blood pressure (BP) and availability of several antihypertensive drugs to treat hypertension, a significant proportion of treated hypertensive patients still have uncontrolled high BP, and thus, face serious morbidity and mortality. Furthermore, it is not sufficient to aim for optimum BP control, but to treat all CV risk factors, protect end-organ damage, prevent progression of disease, and prevent long-range adverse effects of the drugs. Therefore, new therapeutic modalities have to be developed to achieve the above objectives. Some years ago, investigators identified renin inhibition as the preferred pharmacologic approach to blockade of the renin-angiotensin system. Renin is a monospecific enzyme that catalyzes the rate-limiting step in the synthesis of angiotensin II. Amplified enzymatic activity and additional physiologic effects occur when renin and prorenin bind to the (pro)renin receptor. Until very recently, development of clinically effective renin inhibitors remained elusive but molecular modeling was used to develop aliskiren and other renin inhibitors that produce sustained suppression of plasma renin activity after oral administration with a dose-dependent BP. Additional studies will ultimately determine the place of renin inhibition in the treatment of hypertension and related CV disorders.
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Abstract
BACKGROUND The renin-angiotensin-aldosterone system (RAAS) has long been recognized to play a significant role in hypertension pathophysiology. Certain agents that modify the RAAS can control blood pressure and improve cardiovascular outcomes. Aliskiren is the first of a new class of antihypertensive agents known as renin inhibitors. OBJECTIVE The goal of this article was to discuss the clinical pharmacology of aliskiren and its use in the management of hypertension, as well as potential uses in other cardiovascular disorders. METHODS Peer-reviewed articles and abstracts were identified from the MEDLINE and Current Contents databases (both 1966-October 1, 2007) using the search terms aliskiren, drug interaction, pharmacokinetics, and pharmacology. Citations from available articles were reviewed for additional references. Abstracts presented at recent professional meetings were also examined. RESULTS Nine published clinical studies have evaluated the effect of aliskiren in lowering blood pressure in hypertensive patients, either alone or in combination with other antihypertensive agents. This review summarizes those studies. Patients treated with aliskiren had significantly lower blood pressure compared with patients with mild to moderate hypertension (systolic blood pressure [SBP] 140-180 mm Hg and diastolic blood pressure [DBP] 95-110 mm Hg) who received placebo. Aliskiren in doses of 75 to 300 mg daily produced reductions of SBP (-5.3 to -15.8 mm Hg) and DBP (-5.8 to -12.3 mm Hg); placebo produced reductions of SBP that ranged from -2.85 to -10.0 mm Hg and DBP reductions from -3.26 to -8.6 mm Hg (P < 0.05 in all studies between aliskiren and placebo). Aliskiren's blood pressure-lowering effect at doses of 75 to 300 mg daily was comparable to irbesartan 150 mg daily and valsartan 80 to 360 mg daily alone. When aliskiren was added to ramipril, hydrochlorothiazide, amlodipine, irbesartan, or valsartan, significant additive blood pressure-lowering effects were reported (P < 0.05 in all clinical trials). The total incidence of adverse events was similar to placebo and other comparative agents, including irbesartan, valsartan, losartan, ramipril, and hydrochlorothiazide. The overall adverse-event rates were 22%, 35% to 52%, 25% to 52%, 34% to 55%, and 33% to 52% for aliskiren 37.5, 75, 150, 300, and 600 mg, respectively. The most commonly reported adverse events included headache, dizziness, and fatigue. Studies with cardiovascular outcomes as end points have not been performed with aliskiren. CONCLUSIONS Aliskiren is an effective alternative agent for blood pressure management. Before aliskiren can be recommended as a routine first-line agent, however, clinical studies must explore if the blood pressure-lowering effect will translate into improvement in cardiovascular outcomes.
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Vets E, Rossignol JF, Jackson AS. Effects of nitazoxanide on pharmacokinetics and pharmacodynamics of a single dose of warfarin. Am J Health Syst Pharm 2009; 66:838-42. [PMID: 19386947 DOI: 10.2146/ajhp080332] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
PURPOSE The effects of nitazoxanide on warfarin pharmacokinetics and pharmacodynamics are examined. METHODS This was a Phase I, single-center, open-label, randomized, two-way, crossover study. Secondary endpoints included an evaluation of the effect of nitazoxanide on coagulation parameters observed after a single dose of warfarin and an assessment of the overall tolerability of study treatments. Fourteen healthy men were selected for the study. The study consisted of two treatment periods (Treatment A and Treatment B), each lasting 6 days, with a washout period of at least 21 days between both warfarin intakes. All subjects were scheduled to receive both Treatment A and Treatment B, according to the randomization list. Treatment A consisted of a single oral dose of 25 mg warfarin sodium (five 5-mg tablets). Treatment B consisted of a single oral intake of 25 mg warfarin sodium (five 5-mg tablets) and one 500-mg tablet of nitazoxanide (with nitazoxanide 500 mg continued twice daily for up to 6 days). RESULTS All 14 subjects received Treatment B, and 13 of the 14 subjects received Treatment A. Pharmacokinetic results were similar in both treatments, and pharmacodynamic parameters were similar in both treatments. Fourteen adverse events occurred in eight subjects after administration of at least one dose of the study drug. Eleven adverse events occurred in six subjects after treatment with warfarin and nitazoxanide, and three adverse events occurred in two subjects after treatment with warfarin alone. At discharge, a high hemoglobin level and a low total bilirubin level were reported in both groups. CONCLUSION Coadministration of nitazoxanide twice daily for six days did not affect the pharmacokinetic or pharmacodynamic properties of a single 25-mg dose of warfarin sodium. Administration of a single dose of warfarin or combined administration of a single dose of warfarin and multiple doses of nitazoxanide appeared safe and well tolerated.
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Affiliation(s)
- Eva Vets
- SGS Biopharma Research Unit, Stuivenbert, Antwerp, Belgium
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Verdecchia P, Calvo C, Möckel V, Keeling L, Satlin A. Safety and efficacy of the oral direct renin inhibitor aliskiren in elderly patients with hypertension. Blood Press 2009; 16:381-91. [PMID: 18058456 DOI: 10.1080/08037050701717014] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Affiliation(s)
- Paolo Verdecchia
- Department of Cardiology, Hospital S. Maria della Misericordia, Perugia, Italy
| | - Carlos Calvo
- Unidad de Hipertensión, Hospital Clínico Universitario, Santiago de Compostela, La Coruna, Spain
| | | | | | - Andrew Satlin
- Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA
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Riccioni G, Vitulano N, D'Orazio N, Bellocci F. Aliskiren, the first approved renin inhibitor: Clinical application and safety in the treatment of hypertension. Adv Ther 2009; 26:700-10. [PMID: 19649581 DOI: 10.1007/s12325-009-0050-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2009] [Indexed: 02/07/2023]
Abstract
Hypertension is one of the most important risk factors for, and causes of, cardiovascular disease. The difficulty in achieving a normal blood pressure range in some patients makes the rate of cardiovascular disease high. For some years renin-angiotensin system inhibitors such as angiotensin-converting enzyme (ACE) and angiotensin receptor blockade have been objects of interest for treatment of cardiovascular disease. Aliskiren, the first approved renin inhibitor to reach the market, is a low molecular weight, orally active, hydrophilic nonpeptide molecule, which blocks angiotensin I generation. However it might also become a reasonable therapeutic choice in a broad number of clinical conditions, as stable coronary artery disease, cerebrovascular and cardiorenal disease, diabetes, and peripheral arterial disease. The aim of this review is to describe the effectiveness and safety of aliskerin in the treatment of hypertension.
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Affiliation(s)
- Graziano Riccioni
- Cardiology Unit San Camillo de Lellis Hospital, Manfredonia, Foggia, Italy.
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Pimenta E, Oparil S. Role of aliskiren in cardio-renal protection and use in hypertensives with multiple risk factors. Vasc Health Risk Manag 2009; 5:453-63. [PMID: 19475781 PMCID: PMC2686262 DOI: 10.2147/vhrm.s4291] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
The renin-angiotensin-aldosterone system (RAAS) is an important mediator of blood pressure (BP) and volume regulation in both normotensive and hypertensive persons and is a major contributor to hypertension-related target organ damage. The concept of renin inhibition for managing hypertension by blocking the RAAS pathway at its point of activation is very attractive since the renin-angiotensinogen reaction is the first and rate-limiting step in the generation of angiotensin II (Ang II). Aliskiren, the first in a new class of orally effective direct renin inhibitors (DRIs), is approved for the treatment of hypertension. It is effective in reducing BP in the general population of hypertensive patients and in special patient groups such as obese persons, and has a tolerability and safety profile similar to placebo. Aliskiren has renoprotective, cardioprotective and anti-atherosclerotic effects in animal models that appear to be independent of BP lowering. It reduces proteinuria in diabetic patients and has favorable neurohumoral effects in patients with symptomatic heart failure. Additional outcome trials are needed to establish the role of this novel class of antihypertensive medication in the therapeutic armamentarium.
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Affiliation(s)
- Eduardo Pimenta
- Endocrine Hypertension Research Center and Clinical Center of Research Excellence in Cardiovascular Disease and Metabolic Disorders, University of Queensland School of Medicine, Princess Alexandra Hospital, Brisbane, QLD, Australia.
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Duprez DA. Aliskiren: the next innovation in renin–angiotensin–aldosterone system blockade. ACTA ACUST UNITED AC 2009. [DOI: 10.2217/ahe.09.21] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Blockade of the renin–angiotensin–aldosterone system (RAAS) with angiotensin-converting enzyme inhibitors or Ang II-receptor blockers has been demonstrated to lower blood pressure and to be effective in heart failure and postmyocardial infarction. It is also beneficial in renal disease. These RAAS blockers further activate the RAAS, leading to an increase of plasma renin activity and plasma renin concentration. Aliskiren, the first orally active direct renin inhibitor, is an effective and well-tolerated antihypertensive agent when used as monotherapy or in combination with other antihypertensive agents in patients with mild-to-moderate hypertension. In contrast with angiotensin-converting enzyme inhibitors and Ang II-receptor blockers, aliskiren reduces plasma renin activity. A number of clinical trials with aliskiren are ongoing or completed and provide us with objective evidence regarding the clinical importance of direct renin inhibition in the treatment of cardiovascular disease.
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Affiliation(s)
- Daniel A Duprez
- Cardiovascular Division, Medical School, University of Minnesota, VCRC – Room 270, 420 Delaware St SE, MMC 508, Minneapolis, MN 55455, USA
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Abassi Z, Winaver J, Feuerstein GZ. The biochemical pharmacology of renin inhibitors: implications for translational medicine in hypertension, diabetic nephropathy and heart failure: expectations and reality. Biochem Pharmacol 2009; 78:933-40. [PMID: 19477166 DOI: 10.1016/j.bcp.2009.05.018] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2009] [Revised: 05/18/2009] [Accepted: 05/18/2009] [Indexed: 12/13/2022]
Abstract
The renin-angiotensin-aldosterone system (RAAS) plays a dominant role in the pathophysiology of hypertension, Diabetes mellitus (DM), chronic kidney disease (CKD) and chronic heart failure (CHF). Therefore, drugs that block key components of the RAAS such as ACE inhibitors (ACEi) and angiotensin receptor blockers (ARBs) have gained wide clinical use for these indications. Despite progress, the morbidity and mortality of patients treated with ACEi or ARBs remain high. Small molecules that directly inhibit renin (DRI) and are orally active have also been developed and one such drug, aliskiren, was introduced into clinical use for treatment of hypertension in 2007. Further clinical trials aimed to expand the therapeutic use of aliskiren are in progress for CKD-DM and CHF. In this review we analyze and review the translational medicine prospects of aliskiren in respect to the biochemical pharmacology of the RAAS, the marketed RAAS modulators and the new emerging science regarding the role of prorenin, renin and renin receptors in cardiovascular biology and disease. The information already gained with aliskiren, raises questions regarding the advantages of DRIs as monotherapy compared to marketed ACEis and ARBs, their potential added value in combination with other RAAS modulators and other unproven benefits in relation to prorenin and renin receptor biology. This review will also indicate basic and clinical research needs that are critical to determine whether DRIs can provide meaningful added medical benefits over contemporary medicines that regulate the RAAS, and the need to identify patients that are more likely to benefit from DRIs and any possible long term adverse effects.
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Affiliation(s)
- Zaid Abassi
- Department of Physiology and Biophysics, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Israel.
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Sanoski CA. Aliskiren: an oral direct renin inhibitor for the treatment of hypertension. Pharmacotherapy 2009; 29:193-212. [PMID: 19170589 DOI: 10.1592/phco.29.2.193] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Aliskiren is the first member of the new class of orally active direct renin inhibitors to receive approval from the United States Food and Drug Administration for the treatment of hypertension. In patients with hypertension, aliskiren can be used either as monotherapy or in combination with other antihypertensive agents. By inhibiting renin, aliskiren blocks the conversion of angiotensinogen to angiotensin I, which subsequently results in a reduction in angiotensin II concentrations. Unlike the angiotensin-converting enzyme inhibitors and the angiotensin II receptor blockers (ARBs), which reactively stimulate an increase in plasma renin activity, aliskiren suppresses the effects of renin and leads to a reduction in plasma renin activity. In clinical trials involving patients with mild-to-moderate hypertension, aliskiren provided antihypertensive efficacy that was comparable to that of an ARB. Combination therapy with aliskiren and an ARB may provide additional blood pressure-lowering effects compared with the respective monotherapies with each of the agents. The results from surrogate outcome studies have also alluded to the potential for aliskiren to prevent target organ damage. Because aliskiren does not significantly affect the cytochrome P450 system, it has been associated with few drug interactions. In clinical studies, aliskiren was well tolerated, and its adverse-effect profile was similar to that of placebo. Fatigue, headache, dizziness, diarrhea, nasopharyngitis, and back pain were the most commonly reported adverse events. Overall, aliskiren appears to be a reasonable treatment option for patients with mild-to-moderate hypertension who are intolerant of first-line antihypertensive therapies. Aliskiren may also be a promising renoprotective strategy in patients with concomitant hypertension and diabetes mellitus. Its potential as a first-line antihypertensive agent will have to be further examined once studies evaluating its effects on long-term clinical outcomes are completed.
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Affiliation(s)
- Cynthia A Sanoski
- Department of Pharmacy Practice, Jefferson School of Pharmacy, Jefferson College of Health Professions, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
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Pasha Y, Gusbeth-Tatomir P, Covic A, Goldsmith D. Direct renin inhibitors: ONTARGET for success? Int Urol Nephrol 2009; 41:341-55. [PMID: 19296235 DOI: 10.1007/s11255-009-9556-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2009] [Accepted: 02/27/2009] [Indexed: 11/26/2022]
Abstract
Direct renin inhibitors are the first new class of antihypertensive to emerge since angiotensin II receptor blockers. We discuss their reno- and cardioprotective potential, based on extrapolation from animal models and phase three trials that are currently ongoing. This paper reviews the potential benefits of direct renin inhibitors (DRIs), the only new anti-hypertensive class developed in the last decade, as compared to pre-existing classes of drug inhibiting more downstream, such as Angiotensin Converting Enzyme inhibitors (ACEI), Angiotensin 2 Receptor Blockers (ARBS).
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Affiliation(s)
- Yasmin Pasha
- Chelsea and Westminster Hospital, Fulham Road, London, UK
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Pimenta E, Oparil S. Renin inhibitors: novel agents for renoprotection or a better angiotensin receptor blocker for blood pressure lowering? Cardiol Clin 2009; 26:527-35. [PMID: 18929229 DOI: 10.1016/j.ccl.2008.06.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Aliskiren, the first in a new class of orally effective direct renin inhibitors (DRIs) was recently approved for the treatment of hypertension. In this review, we discuss the history of the development of DRIs and available data regarding the effects of DRIs in the treatment of hypertension and related target organ damage.
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Affiliation(s)
- Eduardo Pimenta
- Department of Hypertension and Nephrology, Dante Pazzanese Institute of Cardiology, Av. Dr. Dante Pazzanese, 500, Sao Paulo, SP, Brazil.
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Huang HLA, Vaidyanathan S, Yeh CM, Bizot MN, Dieterich HA, Dole WP, Howard D. Effect of aliskiren, an oral direct renin inhibitor, on the pharmacokinetics and pharmacodynamics of a single dose of acenocoumarol in healthy volunteers. Curr Med Res Opin 2008; 24:2449-56. [PMID: 18662494 DOI: 10.1185/03007990802285763] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
OBJECTIVE Aliskiren is a direct renin inhibitor approved for the treatment of hypertension. This study investigated the effects of aliskiren on the pharmacokinetics and pharmacodynamics of a single dose of acenocoumarol in healthy volunteers. METHODS This two-sequence, two-period, randomized, double-blind crossover study recruited 18 healthy subjects (ages 18-45) to receive either aliskiren 300 mg or placebo once daily on days 1-10 of each treatment period and a single dose of acenocoumarol 10 mg on day 8. Treatment periods were separated by a 10-day washout. Blood samples were taken frequently for determination of steady-state plasma concentrations of aliskiren (LC-MS/MS) and of R(+)- and S(-)-acenocoumarol (HPLC-UV), prothrombin time (PT) and international normalized ratio (INR). RESULTS Co-administration with aliskiren had no effect on exposure to R(+)-acenocoumarol. Geometric mean ratios (GMR; aliskiren:placebo co-administration) for R(+)-acenocoumarol AUC(0-t) and C(max) were 1.08 and 1.04, respectively, with 90% CI within the range 0.80-1.25. Co-administration of aliskiren resulted in a 19% increase in S(-)-acenocoumarol AUC(0-t) (GMR 1.19; 90% CI 0.92, 1.54) and a 9% increase in C(max) (GMR 1.09; 90% CI 0.88, 1.34). The anticoagulant effect of acenocoumarol was not affected by co-administration of aliskiren. Geometric mean ratios were 1.01 for all pharmacodynamic parameters (AUC(PT), PT(max), AUC(INR) and INR(max)), with 90% CI within the range 0.97-1.05. CONCLUSION Aliskiren has no clinically relevant effect on the pharmacokinetics or pharmacodynamic effects of a single dose of acenocoumarol in healthy volunteers, hence no dosage adjustment of acenocoumarol is likely to be required during co-administration with aliskiren.
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Affiliation(s)
- H-L A Huang
- Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA
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Abstract
BACKGROUND Aliskiren, an antihypertensive drug approved in the United States and Europe, is the first in a new class known as direct renin inhibitors. Aliskiren has been evaluated for safety and tolerability in more than 6400 patients. It has demonstrated a favorable safety and tolerability profile alone or in combination with other drugs. OBJECTIVE This article reviews the currently available safety and tolerability data for aliskiren. METHODOLOGY Using the search term aliskiren, MEDLINE (no timeframe set) and major cardiovascular congresses (2005-2008) were searched. Articles and abstracts with safety and drug interaction data were included. FINDINGS Aliskiren may share common adverse effects observed with angiotensin-converting enzyme (ACE)-inhibitor and angiotensin receptor blocker (ARB) therapy. In placebo-controlled trials, those commonly reported for aliskiren at the approved dosage were headache, diarrhea, for personal and fatigue, with incidences similar to those of placebo. Aliskiren has been well tolerated in black, geriatric, diabetic, or obese patients and patients with renal or hepatic impairment. Aliskiren neither inhibits nor induces the cytochrome P450 system; it does not inhibit P-glycoprotein, but is a substrate for this drug transporter. Adding a direct renin inhibitor to another renin-angiotensin-aldosterone system (RAAS) inhibitor may further improve cardiovascular outcomes, renal outcomes, or both, without increasing the incidence of adverse effects. CONCLUSIONS Aliskiren is well tolerated, has an adverse effect profile comparable to that of placebo, and has a low potential for drug interactions. Data from ongoing trials evaluating the effects of aliskiren on surrogate markers, morbidity, and mortality will further define the role of direct renin inhibition in the antihypertensive armamentarium.
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Affiliation(s)
- Haroonur Rashid
- Baylor College of Medicine, Texas Heart Institute, St Luke's Episcopal Hospital, Houston, TX 77030, USA.
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Vaidyanathan S, Maboudian M, Warren V, Yeh CM, Dieterich HA, Howard D, Dole WP. A study of the pharmacokinetic interactions of the direct renin inhibitor aliskiren with metformin, pioglitazone and fenofibrate in healthy subjects. Curr Med Res Opin 2008; 24:2313-26. [PMID: 18786303 DOI: 10.1185/03007990802259354] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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 (AUC(tau)) by 27% (geometric mean ratio [GMR] 0.73; 90% confidence interval [CI] 0.64, 0.84) and maximum observed plasma concentration (C(max)) 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 AUC (GMR 1.05; 90% CI 0.96, 1.16) or C(max) (GMR 1.05; 90% CI 0.80, 1.38); similarly, co-administration of aliskiren with pioglitazone had no effect on aliskiren AUC(tau) (GMR 1.05; 90% CI 0.98, 1.13) or C(max) (GMR 1.01; 90% CI 0.84, 1.20). All other AUC and C(max) GMRs for aliskiren, metformin, pioglitazone, ketopioglitazone, hydroxypioglita-zone 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.
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Hamet P. Direct renin inhibition: Mechanistic advantages and disadvantages compared with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers. Can J Cardiol 2008. [DOI: 10.1016/s0828-282x(08)71038-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
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Abstract
PURPOSE The pharmacology, bioavailability and pharmacokinetics, clinical efficacy, adverse effects and toxicity, drug interactions, and dosage and administration of aliskiren as well as safety and economic issues related to its use are reviewed. SUMMARY Aliskiren is the first of a new class of antihypertensive agents, direct renin inhibitors, that act by blocking the rate- limiting step of the renin-angiotensin- aldosterone system (RAAS). It was approved by the Food and Drug Administration in 2007 for use as monotherapy or in combination with other antihypertensives. Clinical studies comparing aliskiren monotherapy with placebo indicated a dose-dependent reduction in both systolic and diastolic blood pressure (BP). Greater reductions in BP have been achieved when aliskiren was used in combination with hydrochlorothiazide or an angiotensin-receptor blocker. The most common adverse effects reported in clinical trials were headache, fatigue, dizziness, diarrhea, and nasopharyngitis. Aliskiren has not been studied in patients with moderate renal dysfunction; as a RAAS-acting drug, it should be prescribed for such patients only with caution. CONCLUSION Aliskiren at a dosage of 150 or 300 mg daily may be a good option for control of mild-to-moderate hypertension in patients with or without diabetes in whom first-line antihypertensives have failed to adequately control BP; comparative studies with other antihypertensives are needed to determine which patients can most benefit from aliskiren therapy.
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Affiliation(s)
- Kimberly K Daugherty
- Department of Clinical and Administrative Sciences, Sullivan University College of Pharmacy, Louisville, KY, USA
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Abstract
1. Initial attempts to inhibit renin in humans have faced numerous difficulties. Molecular modelling and X-ray crystallography of the active site of renin have led to the development of new orally active renin inhibitors, such as aliskiren. 2. Aliskiren has a low bioavailability (between 2.6 and 5.0%) compensated by its high potency to inhibit renin (IC50: 0.6 nmol/L) and a long plasma half-life (23-36 h), which makes it suitable for once-daily dosing. 3. The once-daily administration of aliskiren to hypertensive patients lowers BP as strongly as standard doses of established angiotensin II type 1 (AT1) receptor blockers (losartan, valsartan, irbesartan), hydrochlorothiazide, angiotensin converting enzyme inhibitors (ramipril and lisinopril) or long acting calcium channel blockers (amlodipine). In combination therapy, aliskiren further decreases blood pressure when combined with either hydrochlorothiazide, amlodipine, irbesartan or ramipril. 4. The biochemical consequences of renin inhibition differ from those of angiotensin I-converting enzyme (ACE) inhibition and Ang II antagonism, particularly in terms of angiotensin profiles and interactions with the bradykinin-nitric oxide-cyclic guanosine monophosphate pathway and possibly the (pro)renin receptor. 5. Blockade of the renin angiotensin system (RAS) with ACE inhibitors, AT1 receptor blockers or a combination of these drugs has become one of the most successful therapeutic approaches in medicine. However, it remains unclear how to optimize RAS blockade to maximize cardiovascular and renal benefits. In this context, renin inhibition to render the RAS fully quiescent is a new possibility requiring further study.
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Lu H, Rateri DL, Feldman DL, Charnigo RJ, Fukamizu A, Ishida J, Oesterling EG, Cassis LA, Daugherty A. Renin inhibition reduces hypercholesterolemia-induced atherosclerosis in mice. J Clin Invest 2008; 118:984-93. [PMID: 18274671 DOI: 10.1172/jci32970] [Citation(s) in RCA: 83] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2007] [Accepted: 01/02/2008] [Indexed: 11/17/2022] Open
Abstract
The role of the renin angiotensin system (RAS) in atherosclerosis is complex because of the involvement of multiple peptides and receptors. Renin is the rate-limiting enzyme in the production of all angiotensin peptides. To determine the effects of renin inhibition on atherosclerosis, we administered the novel renin inhibitor aliskiren over a broad dose range to fat-fed LDL receptor-deficient (Ldlr(-/-)) mice. Renin inhibition resulted in striking reductions of atherosclerotic lesion size in both the aortic arch and the root. Subsequent studies demonstrated that cultured macrophages expressed all components of the RAS. To determine the role of macrophage-derived angiotensin in the development of atherosclerosis, we transplanted renin-deficient bone marrow to irradiated Ldlr(-/-) mice and observed a profound decrease in the size of atherosclerotic lesions. In similar experiments, transplantation of bone marrow deficient for angiotensin II type 1a receptors failed to influence lesion development. We conclude that renin-dependent angiotensin production in macrophages does not act in an autocrine/paracrine manner. Furthermore, in vitro studies demonstrated that coculture with renin-expressing macrophages augmented monocyte adhesion to endothelial cells. Therefore, although previous work suggests that angiotensin peptides have conflicting effects on atherogenesis, we found that renin inhibition profoundly decreased lesion development in mice.
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Affiliation(s)
- Hong Lu
- Cardiovascular Research Center, University of Kentucky, Lexington, Kentucky, USA
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35
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Direct renin inhibition: clinical pharmacology. J Mol Med (Berl) 2008; 86:647-54. [DOI: 10.1007/s00109-008-0329-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2008] [Accepted: 01/28/2008] [Indexed: 10/22/2022]
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Affiliation(s)
- Alan H Gradman
- Division of Cardiovascular Diseases, The Western Pennsylvania Hospital, Pittsburgh, Pennsylvania 15224, USA.
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Frishman WH, Aronow WS, Cheng-Lai A. Cardiovascular Drug Therapy in the Elderly. FUNDAMENTAL AND CLINICAL CARDIOLOGY SERIES 2008. [DOI: 10.3109/9781420061710.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
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Verdecchia P, Angeli F, Mazzotta G, Gentile G, Reboldi G. The renin angiotensin system in the development of cardiovascular disease: role of aliskiren in risk reduction. Vasc Health Risk Manag 2008; 4:971-81. [PMID: 19183745 PMCID: PMC2605336 DOI: 10.2147/vhrm.s3215] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
An association has been shown between plasma renin activity (PRA) and the risk of cardiovascular disease. There is also evidence that angiotensin II exerts detrimental effects on progression and instabilization of atherosclerotic plaque. The renin-angiotensin system (RAS) can be inhibited through inhibition of angiotensin I (Ang I) generation from angiotensinogen by direct renin inhibitors, inhibition of angiotensin II (Ang II) generation from angiotensin I by angiotensin-converting enzyme inhibitors and finally by direct inhibition of the action of Ang II receptor level. Aliskiren, the first direct renin inhibitor to reach the market, is a low-molecular-weight, orally active, hydrophilic nonpeptide. Aliskiren blocks Ang I generation, while plasma renin concentration increases because the drugs blocks the negative feed-back exerted by Ang II on renin synthesis. Because of its long pharmacological half-life, aliskiren is suitable for once-daily administration. Its through-to-peak ratio approximates 98% for the 300 mg/day dose. Because of its mechanism of action, aliskiren might offer the additional opportunity to inhibit progression of atherosclerosis at tissue level. Hypertension is an approved indication for this drug, which is also promising for the treatment of heart failure. The efficacy of this drug in reducing major clinical events is being tested in large ongoing clinical trials.
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Affiliation(s)
- Paolo Verdecchia
- Department of Cardiology, Clinical Research Unit Preventive Cardiology, Hospital Santa Maria della Misericordia, and Fondazione Umbra Cuore e Ipertensione - AUCI Onlus, Perugia, Italy.
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Sureshkumar KK. Renin inhibition with aliskiren in hypertension: focus on aliskiren/hydrochlorothiazide combination therapy. Vasc Health Risk Manag 2008; 4:1205-1220. [PMID: 19337534 PMCID: PMC2663460 DOI: 10.2147/vhrm.s3364] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Hypertension is a major risk factor for the development of cardiovascular and renal disease. The incidence of hypertension is increasing globally and the rate of blood pressure control remains inadequate. Renin-angiotensin-aldosterone system (RAAS) plays a crucial role in volume regulation and maintenance of blood pressure. Pathological activation of RAAS results in chronic hypertension and consequent end organ damage. Most patients with hypertension require combination therapy using agents with complimentary mechanisms of action. Hydrochlorothiazide (HCTZ) together with an agent blocking the RAAS such as an angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) are widely used effective anti-hypertensive therapy. Aliskiren is an orally effective direct renin inhibitor that blocks the generation of angiotensin I from angiotensinogen, the rate limiting step of RAAS activation. Studies have shown equivalent antihypertensive efficacy of aliskiren when compared to existing medications such as HCTZ, ACE inhibitors and ARBs. Aliskiren has also been tested in combination therapies. The current review aims to look at the efficacy of aliskiren therapy in hypertension and the evidence for using aliskiren in combination with HCTZ.
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Affiliation(s)
- Kalathil K Sureshkumar
- Division of Nephrology and Hypertension, Allegheny General Hospital, Pittsburgh, PA 15212, USA.
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Vaidyanathan S, Jarugula V, Dieterich HA, Howard D, Dole WP. Clinical Pharmacokinetics and Pharmacodynamics of Aliskiren. Clin Pharmacokinet 2008; 47:515-31. [DOI: 10.2165/00003088-200847080-00002] [Citation(s) in RCA: 126] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
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Oh BH. Aliskiren, the first in a new class of direct renin inhibitors for hypertension: present and future perspectives. Expert Opin Pharmacother 2007; 8:2839-49. [PMID: 17956203 DOI: 10.1517/14656566.8.16.2839] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Aliskiren, the direct renin inhibitor, is the first new class of drug available in 13 years for the treatment of hypertension. Renin has long been recognized as a preferred site for blockade of the renin-angiotensin-aldosterone system because it prevents conversion of angiotensinogen to angiotensin I. Aliskiren binds to the active site of the renin molecule, blocking angiotensinogen cleavage, thus, preventing the formation of angiotensin I. Clinical studies have demonstrated at least equivalent or superior blood pressure lowering efficacy compared with existing drugs with a favorable side effect profile. Aliskiren possesses possible synergistic potential when combined with a thiazide diuretic, ACE inhibitor, angiotensin receptor blocker and calcium channel blocker both in terms of efficacy and tolerability. This review aims to define the role of aliskiren in the therapeutic management of hypertension.
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Affiliation(s)
- Byung-Hee Oh
- Seoul National University College of Medicine, Department of Internal Medicine, 28 Yongon-dong, Jongno-gu, Seoul, 110-744, Korea.
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Abstract
The important role of renin-angiotensin-aldosterone system blockade in the treatment of systemic hypertension, heart failure, diabetic kidney disease, and atherogenesis has been clearly established. The theoretical therapeutic advantages for inhibiting the detrimental effects of the renin-angiotensin system at its most upstream point have served as the impetus for the development of renin inhibitors. The advent of aliskiren, the first in a novel class of orally active, nonpeptide, highly specific, human renin inhibitors, provides a new modality in the armamentarium of renin-angiotensin system antagonists. Studies in marmosets and rats demonstrated that aliskiren reduced blood pressure in a dose-dependent manner and is highly efficacious in blocking plasma renin activity with parallel reductions in the levels of the other downstream constituents of the renin-angiotensin system. Clinical trials in hypertensive patients have confirmed these benefits with aliskiren whose blood pressure-lowering efficacy is similar to or better than those of standard therapeutic doses of enalapril, losartan, irbesartan, and hydrochlorothiazide. Aliskiren is well tolerated, with few reported adverse effects even at the highest doses tested. Given the established beneficial effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in the treatment of cardiovascular and renovascular diseases, future studies may further elucidate a similar protective role for aliskiren both as a monotherapy and as part of a combination therapy.
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Affiliation(s)
- Reza Sepehrdad
- Department of Internal Medicine, UC Davis Medical Center, Sacramento, California, USA
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Waldmeier F, Glaenzel U, Wirz B, Oberer L, Schmid D, Seiberling M, Valencia J, Riviere GJ, End P, Vaidyanathan S. Absorption, distribution, metabolism, and elimination of the direct renin inhibitor aliskiren in healthy volunteers. Drug Metab Dispos 2007; 35:1418-28. [PMID: 17510248 DOI: 10.1124/dmd.106.013797] [Citation(s) in RCA: 102] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Aliskiren (2(S),4(S),5(S),7(S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)phenyl]-octanamid hemifumarate) is the first in a new class of orally active, nonpeptide direct renin inhibitors developed for the treatment of hypertension. The absorption, distribution, metabolism, and excretion of [(14)C]aliskiren were investigated in four healthy male subjects after administration of a single 300-mg oral dose in an aqueous solution. Plasma radioactivity and aliskiren concentration measurements and complete urine and feces collections were made for 168 h postdose. Peak plasma levels of aliskiren (C(max)) were achieved between 2 and 5 h postdose. Unchanged aliskiren represented the principal circulating species in plasma, accounting for 81% of total plasma radioactivity (AUC(0-infinity)), and indicating very low exposure to metabolites. Terminal half-lives for radioactivity and aliskiren in plasma were 49 h and 44 h, respectively. Dose recovery over 168 h was nearly complete (91.5% of dose); excretion occurred almost completely via the fecal route (90.9%), with only 0.6% recovered in the urine. Unabsorbed drug accounted for a large dose proportion recovered in feces in unchanged form. Based on results from this and from previous studies, the absorbed fraction of aliskiren can be estimated to approximately 5% of dose. The absorbed dose was partly eliminated unchanged via the hepatobiliary route. Oxidized metabolites in excreta accounted for at least 1.3% of the radioactive dose. The major metabolic pathways for aliskiren were O-demethylation at the phenyl-propoxy side chain or 3-methoxy-propoxy group, with further oxidation to the carboxylic acid derivative.
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Abstract
The first renin inhibitor, aliskiren, will soon enter the clinical arena. This review summarizes the potential differences between renin inhibitors and the currently existing blockers of the renin-angiotensin system (RAS) [ie, the ACE inhibitors and the angiotensin II type 1 (AT(1)) receptor antagonists], taking also into consideration the recently discovered (pro)renin receptor. This receptor not only activates the inactive precursor of renin, prorenin, but it also exerts direct renin/prorenin-induced effects, independently of angiotensin. The review ends with a brief overview of the available (pre)clinical aliskiren data and a description of its safety profile.
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Affiliation(s)
- A H Jan Danser
- Department of Pharmacology, Erasmus MC, Rotterdam, The Netherlands.
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Abstract
Renin is the first and rate-limiting step cleaving angiotensinogen to angiotensin I, thus influencing angiotensin II (Ang II) formation. Inhibition of the renin-angiotensin system (RAS) with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) is effective in management of several cardiovascular diseases; however, control continues to be difficult and requires multiple drug therapy. Use of RAS inhibitors does not totally prevent Ang II formation, which could continue to contribute to development of end-organ damage. Over the past two decades, renin inhibition seemed to be an attractive approach for complete blockade of the RAS. Recently, aliskiren, a renin inhibitor, was approved as the first of a new class of antihypertension drugs. Clinical trials demonstrated significant blood pressure reduction in hypertensive patients with aliskiren used alone or combined with hydrochlorothiazide, ACE inhibitors, or ARBs. Studies are in progress to evaluate the potential role for renin inhibition in management of kidney and cardiac diseases.
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Affiliation(s)
- Helmy M Siragy
- Division of Endocrinology and Metabolism, Department of Medicine, PO Box 801409, University of Virginia Health System, Charlottesville, VA 22908-1409, USA.
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Athyros VG, Mikhailidis DP, Kakafika AI, Tziomalos K, Karagiannis A. Angiotensin II reactivation and aldosterone escape phenomena in renin-angiotensin-aldosterone system blockade: is oral renin inhibition the solution? Expert Opin Pharmacother 2007; 8:529-535. [PMID: 17376010 DOI: 10.1517/14656566.8.5.529] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
This editorial considers the use of the first selective oral renin inhibitor, aliskiren, in reducing angiotensin (Ang) II reactivation or aldosterone (ALDO) escape during renin-angiotensin-aldosterone system (RAAS) inhibition. RAAS blockade with angiotensin converting enzyme inhibitors (ACEIs) and/or angiotensin receptor AT(1) blockers (ARBs) is very useful for the treatment of arterial hypertension, chronic heart failure (CHF), atherosclerosis and diabetes. 'Ang II reactivation' and 'ALDO escape' or 'breakthrough' have been observed during either ACEI or ARB treatment, and may attenuate the clinical benefit of RAAS blockade. Renin and Ang I accumulate during ACE inhibition, and might overcome the ability of an ACEI to effectively suppress ACE activity. There is also data suggesting that 30 - 40% of Ang II formation in the healthy human during RAAS activation is formed via renin-dependent, but ACE-independent, pathways. Moreover, ACE gene polymorphisms contribute to the modulation and adequacy of the neurohormonal response to long-term ACE inhibition, at least in patients with CHF (up to 45% of CHF patients have elevated Ang II levels despite the long-term use of an ACEI) or diabetes. The reactivated Ang II promotes ALDO secretion and sodium reabsorption. ALDO breakthrough also occurs during long-term ARB therapy, mainly by an AT(2)-dependent mechanism. This was related to target-organ damage in animal models. Oral renin inhibition with aliskiren has showed excellent efficacy and safety in the treatment of hypertension. Aliskiren can be co-administered with ACEIs, ARBs or hydrochlorothiazide. Furthermore, there is evidence suggesting that aliskiren reduces Ang II reactivation in ACE inhibition and ALDO escape during treatment with an ACEI or an ARB, at least to the degree that this is associated with the RAAS. For RAAS-independent ALDO production, the combination of aliskiren with eplerenone might prove useful.
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Allikmets K. Aliskiren--an orally active renin inhibitor. Review of pharmacology, pharmacodynamics, kinetics, and clinical potential in the treatment of hypertension. Vasc Health Risk Manag 2007; 3:809-15. [PMID: 18200801 PMCID: PMC2350136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022] Open
Abstract
The importance of renin-angiotensin-aldosterone system (RAAS) in diseases such as hypertension, congestive heart failure and chronic renal failure has long ago been recognized. It has also been established that inhibition of RAAS, using inhibitors of the angiotensin-converting enzyme (ACE) or angiotensin II receptor blockers (ARB), is an effective way to intervene with the pathogenesis of these disorders. Renin inhibitors block the RAAS at the highest level, at its origin, and might thus offer a new exciting approach for pharmacotherapy of arterial hypertension. Aliskiren is the first in a new class of orally active, non-peptide, low molecular weight renin inhibitors, and so far the only renin inhibitor that has progressed to phase III clinical trials. This review summarizes the available data on the pharmacokinetic and pharmacodynamic properties of aliskiren and its clinical development for treatment of arterial hypertension.
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Affiliation(s)
- Kristina Allikmets
- Department of Drug Development and Medical Affairs, Nycomed Group, Roskilde, Denmark.
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Abstract
Aliskiren (Tekturna) is an orally active, nonpeptidic inhibitor of renin, the enzyme involved in the initial and rate-limiting step of the renin-angiotensin system (RAS). In the US, aliskiren is approved for the treatment of hypertension and may be used alone or in combination with other antihypertensive agents. Monotherapy with aliskiren 150-300mg once daily was effective in lowering blood pressure (BP) and providing 24-hour BP control; it was generally well tolerated when administered for up to 1 year to patients with mild to moderate hypertension. In the short term (1-3 months), the BP-lowering effect of aliskiren 150-300mg once daily was significantly greater than that of hydrochlorothiazide (HCTZ) 12.5-25mg once daily and noninferior to, or significantly greater than, that of ramipril 5-10mg once daily. It was similar to that of valsartan 160-320mg once daily and losartan 100mg once daily, and similar to, or significantly greater than, that of irbesartan 150mg once daily. Aliskiren provided significant additional BP-lowering effects when combined with HCTZ 12.5-25 mg/day, ramipril 5-10 mg/day, amlodipine 5mg once daily or valsartan 160-320 mg/day; combination therapy was well tolerated. Long-term administration of aliskiren-based therapy was superior to HCTZ- and ramipril-based therapies in lowering BP after 6 months, and was similarly well tolerated. The ultimate role of aliskiren will be determined by the results of target organ protection studies, which are ongoing, and a cardiovascular outcome trial, which is planned. Nonetheless, by offering a new approach to the blockade of the RAS, aliskiren provides a useful addition to the therapeutic options available to treat patients with mild to moderate hypertension.
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Affiliation(s)
- James E Frampton
- Wolters Kluwer Health | Adis, Auckland, New Zealand, an editorial office of Wolters Kluwer Health, Conshohocken, Pennsylvania, USA.
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