Aliskiren

Structural formula
General
Non-proprietary name	Aliskiren
other names	(2 S , 4 S , 5 S , 7 S ) -5- Amino- N - (2-carbamoyl-2-methylpropyl) -4-hydroxy-2-isopropyl-7- [4-methoxy-3- (3- methoxypropoxy) benzyl] -8-methylnonanamide ( IUPAC )
Molecular formula	C 30 H 53 N 3 O 6
External identifiers / databases
CAS number 173334-57-1 EC number 605-672-4 ECHA InfoCard 100.127.451 PubChem 5493444 ChemSpider 4591452 DrugBank DB09026 Wikidata Q414904
Drug information
ATC code	C09 XA02 C09 XA52
Drug class	Antihypertensive drugs
Mechanism of action	Renin inhibitor
properties
Molar mass	551.76 g · mol -1
Physical state	Solid
pK s value	15.9 (calculated) 9.49 (conjugate acid)
solubility	Water:> 350 g l −1 (pH 7.4)
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed GHS labeling of hazardous substances Caution H and P phrases H: 317-410 P: ?
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Aliskiren is a drug for the treatment of high blood pressure and the first member of the group of direct renin inhibitors . It intervenes in the body's own renin-angiotensin-aldosterone system , which is involved in regulating arterial blood pressure, among other things, and is orally effective.

Aliskiren was approved in the US in March 2007 , in Switzerland in June 2007 and in the EU in August 2007 .

Clinical information

Application areas (indications)

Aliskiren is indicated for the treatment of essential hypertension . It is used either alone or in combination with diuretics . Use in paediatrics and adolescents under 18 years of age has not been studied and no scientific data are available.

An additional reduction in blood pressure is achieved through the fixed combination with the diuretic drug hydrochlorothiazide and / or the calcium channel blocker amlodipine .

Type and duration of application

A single dose per day is sufficient. The desired antihypertensive effect is achieved in most patients (85–90%) after 2 weeks of treatment. The absorption of aliskiren is greatly reduced by ingesting high-fat foods.

Contraindications (contraindications)

Aliskiren is contraindicated in case of hypersensitivity to the active ingredient and during pregnancy or breastfeeding (see below).

• Aliskiren-containing medicinal products are contraindicated in combination with ACE inhibitors or angiotensin receptor blockers (ARB) in patients with:
  • Diabetes mellitus (type I or II)
  • Renal dysfunction (GFR <60 ml / min / 1.73 m²),
• for all other patients the use of aliskiren-containing medicinal products in combination with ACE inhibitors or ARB is not recommended.

Use during pregnancy and breastfeeding

• Pregnancy : Like all drugs that act directly on the renin-angiotensin-aldosterone system , aliskiren can have serious effects on the fruit in the womb during fetogenesis . Use during pregnancy is therefore absolutely contraindicated .
• Breast-feeding : It is not known whether aliskiren or its metabolites are excreted in breast milk . However, aliskiren was found in the milk of rats during lactation . Because the consequences and side effects in the infant are unknown, the nursing mother must consider either taking the drug or otherwise.

Adverse effects (side effects)

Aliskiren has a low side effect profile at therapeutic doses . The most common adverse effects were diarrhea and other gastrointestinal complaints. Occasionally, headache, nausea , tiredness, upper respiratory tract infections , back pain, cough and rashes have been observed.

The prematurely terminated ( ALTITUDE study ) showed that with the additional administration of 300 mg aliskiren to standard therapy with ACE inhibitors or angiotensin II receptor antagonists, an increased number of patients with type 2 diabetes “did not cause adverse events - suffered fatal strokes, renal complications, hyperkalemia and hypotension "without the active ingredient having achieved any discernible benefit. In 2014, the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) issued a recommendation that ACE inhibitors, sartans and renin inhibitors should not be combined. In the case of diabetes or kidney dysfunction, a combination is therefore strictly contraindicated.

A meta-analysis from 2012 put the increase in the risk of hyperkalaemia under therapy with aliskiren in combination therapy with ARB or ACE inhibitors at 58%. A significant risk of acute kidney failure could not be determined. The problems that arose here were probably due to the fact that one had not observed the hard endpoints (e.g. kidney failure), but rather soft surrogate parameters (here the reduction in creatinine values), which obviously only allow limited conclusions. An article for a study that also examined the joint use of these substances and assessed them with soft parameters had to be withdrawn.

There are limited data available on aliskiren overdose in humans. The most likely effect is hypotension (low blood pressure). There is no antidote available. The therapy consists in the close monitoring of the vital functions .

Pharmacological properties

Mechanism of action (pharmacodynamics)

Aliskiren is an antihypertensive drug with a novel mechanism of action. It attacks the renin-angiotensin-aldosterone system (RAAS) right at the beginning of angiotensin II biosynthesis. Aliskiren binds directly to the protease renin and thus prevents the conversion of angiotensinogen into angiotensin I. There is no inhibition of the renin-angiotensin-aldosterone system, as is only incompletely effected by the ACE inhibitors . At the same time, the angiotensin II levels also decrease.

Absorption and distribution in the body (pharmacokinetics)

After oral ingestion, aliskiren is poorly absorbed; the oral bioavailability is only about 2.6%. Aliskiren has a plasma half-life of 40 hours. The maximum concentration in the blood plasma is reached in one to four hours after oral ingestion. The volume of distribution is 4.2 l / kg. The steady-state is achieved in continuous use for about 7-8 days. These properties of aliskiren are not changed even in elderly patients, diabetics , patients with renal and hepatic dysfunction. ${\displaystyle C_{\mathrm {max} }}$

Other Information

Chemical and pharmaceutical information

Aliskiren hemifumarate, the salt of aliskiren with fumaric acid , is used in all galenic forms . It is a white to light yellow crystalline powder that is very hygroscopic . It is very easily soluble in water, well soluble in octanol and phosphate buffer . The systematic name of the compound is (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] -octanamide hemifumarate, the empirical formula is C ₃₂ H ₅₅ N ₃ O ₈ and the molar mass is 609.80 g · mol ⁻¹ .

Development history

Research at the RAAS , renin and the renin inhibitors has a history of more than thirty years. The first drugs were peptides which - administered orally - were destroyed in the digestive tract before they were absorbed and had a maximum bioavailability of 0.5%. The first preparation ready for the market, pepstatin , was presented as early as 1971. It should have been administered parenterally , which no patient with hypertension would have accepted given oral alternatives. In addition, the first peptide renin inhibitors were only effective for a very short time, which also did not promise a competitive drug because of the multiple daily application. Other preparations failed because of an insufficient effect or problems with tolerability.

With the development of aliskiren, a non-peptide , orally active, direct renin inhibitor for the treatment of arterial hypertension (high blood pressure) is available. Ciba-Geigy, now Novartis , developed Aliskiren and patented it in 1996 under US Patent No. 5,559,111. The company Speedel , one in Basel and Bridgewater ( USA located somewhere), biopharmaceutical company in-licensed SPP100 (code name for aliskiren during development) in 1999 by Novartis and conducted in phases I and II successfully completed 18 clinical Studies on around 500 patients and healthy volunteers. Based on the results generated during this program, Novartis exercised a license back in 2002 and then started clinical trials with SPP100 in phase III as a monotherapy for high blood pressure and in phase IIb as a combination therapy.

In March 2007, Aliskiren was approved by the US Food and Drug Administration ( FDA ) as Tekturna for the oral treatment of hypertension (high blood pressure). Novartis submitted the application for approval to the European Medicines Agency in autumn 2006. Based on data from over 7,800 patients in 44 clinical studies, the Committee for Medicinal Products for Human Use (CHMP) assessed the application for approval of the renin inhibitor for the treatment of essential hypertension as positive in June 2007, whereupon the EU Commission approved the approval for the entire EU issued. In Switzerland aliskiren was established in June 2007 by Swissmedic for the treatment of essential hypertension in the distribution category B admitted.

Benefit assessment / significance

A positive effect of aliskiren on mortality and cardiovascular events beyond lowering blood pressure has not yet been shown. There are no data on the safety of long-term treatment. The therapeutic value is therefore questionable. The European Medicines Agency advises patients with diabetes mellitus not to prescribe aliskiren in combination with ACE inhibitors or AT1 antagonists .

Early benefit assessment (Section 35a SGB V)

A resolution regarding the "additional benefit" of aliskiren in combination with amlodipine - based on Section 35a of the Social Code Book V ( AMNOG ) ( early benefit assessment ) - by the Federal Joint Committee (G-BA) took place in 2012. The Federal Joint Committee followed the negative assessment by the institute for quality and economy in health care (IQWiG) .

Trade names

Monopreparations : Rasilez (D, A, CH), Riprazo (A), Sprimeo (A), Tekturna (A, USA)

Combination preparations :

• with hydrochlorothiazide : Rasilez HCT (D, A, CH), Tekturna HCT (USA)
• with amlodipine : Rasiamlo (EU)
• with hydrochlorothiazide and amlodipine: Rasitrio (EU)

Web links

• Information from the US FDA : Tekturna (aliskiren) and Tekturna HCT (aliskiren / hydrochlorothiazide) tablets (English)
• Information from the European Medicines Agency on finished medicinal products containing aliskiren: European public assessment reports (English, partly German)
• Pharmaceutical newspaper online: Aliskiren, Raslilez (Novartis)
• Chemdrug.com: Synthesis of Aliskiren Hemifumarate (English)
• www.prous.com: Molecule of the Month: Aliskirenfumarate (English)

literature

General

• Hermann J. Roth: Medicinal Chemistry: Targets and Drugs. German Apotheker-Verlag, Stuttgart 2005, ISBN 3-7692-3483-9 .
• Heinz Lüllmann, Klaus Mohr, Lutz Hein: Pharmacology and Toxicology . 16th edition. Thieme, Stuttgart 2006, ISBN 3-13-368516-3 .
• Gerhard Thews : Human anatomy, physiology, pathophysiology . Knowledge Verlag-Ges., Stuttgart 2007, ISBN 978-3-8047-2342-9 .

Studies

• Juerg Nussberger, Grégoire Wuerzner, Chris Jensen, Hans R. Brunner: Angiotensin II Suppression in Humans by the Orally Active Renin Inhibitor Aliskiren (SPP100) Comparison With Enalapril . In: Hypertension . tape 39 , no. 1 , January 2002, p. e1 – e8 , doi : 10.1161 / hy0102.102293 .
• Alberto Villamil, Steven G. Chrysant, David Calhoun, Bonnie Schober, Huang Hsu, Linda Matrisciano-Dimichino, Jack Zhang: Renin inhibition with aliskiren provides additive antihypertensive efficacy when used in combination with hydrochlorothiazide . In: Journal of Hypertension . tape 25 , no. 1 , January 2007, p. 217-226 , doi : 10.1097 / HJH.0b013e3280103a6b , PMID 17143194 .
• Alice Stanton, Chris Jensen, Juerg Nussberger, Eoin O'Brien: Blood Pressure Lowering in Essential Hypertension With an Oral Renin Inhibitor, Aliskiren . In: Hypertension . tape 42 , no. 6 , December 2003, p. 1137–1143 , doi : 10.1161 / 01.HYP.0000101688.17370.87 .
• Nancy J. Brown, Sandeep Kumar, Corrie A. Painter, Douglas E. Vaughan: ACE Inhibition Versus Angiotensin Type 1 Receptor Antagonism Differential Effects on PAI-1 Over Time . In: Hypertension . tape 40 , no. 6 , December 2002, p. 859-865 , doi : 10.1161 / 01.HYP.0000040264.15961.48 .
• Michel Azizi, Joël Ménard, Alvine Bissery, Than-Tam Guyenne, Alessandra Bura-Rivière, Sujata Vaidyanathan, Riccardo P. Camisasca: Pharmacologic Demonstration of the Synergistic Effects of a Combination of the Renin Inhibitor Aliskiren and the AT1 Receptor Antagonist Valsartan II – Renin Feedback Interruption . In: Journal of the American Society of Nephrology . tape 15 , no. December 12 , 2004, pp. 3126-3133 , doi : 10.1097 / 01.ASN.0000146686.35541.29 .
• Eoin O'Brien, John Barton, Juerg Nussberger, David Mulcahy, Chris Jensen, Patrick Dicker, Alice Stanton: Aliskiren reduces blood pressure and suppresses plasma renin activity in combination with a thiazide diuretic, an angiotensin-converting enzyme inhibitor, or an angiotensin receptor blocker . In: Hypertension (Dallas, Tex .: 1979) . tape 49 , no. 2 , February 2007, p. 276-284 , doi : 10.1161 / 01.HYP.0000253780.36691.4f , PMID 17159081 .
• Victor J. Dzau: Tissue Angiotensin and Pathobiology of Vascular Disease A Unifying Hypothesis . In: Hypertension . tape 37 , no. 4 , April 2001, p. 1047-1052 , doi : 10.1161 / 01.HYP.37.4.1047 .
• Felix Waldmeier, Ulrike Glaenzel, Bernard Wirz, Lukas Oberer, Dietmar Schmid, Michael Seiberling, Jessica Valencia, Gilles-Jacques Riviere, Peter End, Sujata Vaidyanathan: Absorption, Distribution, Metabolism, and Elimination of the Direct Renin Inhibitor Aliskiren in Healthy Volunteers . In: Drug Metabolism and Disposition . tape 35 , no. 8 , August 2007, p. 1418-1428 , doi : 10.1124 / dmd.106.013797 .

Individual evidence

1. ^ Entry on Aliskiren in the DrugBank of the University of Alberta .
2. ^ ^{A b} The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals. 14th edition. Merck & Co., Whitehouse Station, NJ 2006, ISBN 0-911910-00-X .
3. ↑ There is not yet a harmonized classification for this substance . A labeling of (2S, 4S, 5S, 7S) -5-amino-N- (2-carbamoyl-2-methylpropyl) -4-hydroxy-2-isopropyl-7- [4- methoxy-3- (3-methoxypropoxy) benzyl] -8-methylnonanamide in the Classification and Labeling Inventory of the European Chemicals Agency (ECHA), accessed on December 11, 2018.
4. ↑ Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints Including 12 Month Safety Follow-up Off-treatment - Full Text View - ClinicalTrials.gov. Retrieved February 15, 2013 . 
5. ↑ Hans-Henrik Parving, Barry M. Brenner, John JV McMurray, Dick de Zeeuw, Steven M. Haffner, Scott D. Solomon, Nish Chaturvedi, Frederik Persson, Akshay S. Desai, Maria Nicolaides, Alexia Richard, Zhihua Xiang, Patrick Brunel, Marc A. Pfeffer: Cardiorenal End Points in a Trial of Aliskiren for Type 2 Diabetes . In: New England Journal of Medicine . tape 367 , no. 23 , 2012, p. 2204–2213 , doi : 10.1056 / NEJMoa1208799 (free full text).
6. ↑ Rote-Hand-Brief on potential risks of cardiovascular or renal adverse events (PDF; 61 kB) retrieved from the website of the Drug Commission of the German Medical Association (AkdÄ).
7. ↑ Rote-Hand-Brief on new contraindications and warnings (PDF; 58 kB) retrieved from the website of the Drugs Commission of the German Medical Association (AkdÄ).
8. ↑ Double RAS blockage does more harm than good. ( Memento from April 15, 2014 in the Internet Archive ) In: Pharmazeutische Zeitung. April 11, 2014.
9. ↑ Z. Harel, C. Gilbert, R. Wald, C. Bell, J. Perl: The effect of combination treatment with aliskiren and blockers of the renin-angiotensin system on hyperkalaemia and acute kidney injury: systematic review and meta-analysis. In: BMJ. 344, Jan 9, 2012, p. E42. doi: 10.1136 / bmj.e42 , PMID 22232539 .
10. ↑ Hans-Henrik Parving, Frederik Persson, Julia B. Lewis, Edmund J. Lewis, Norman K. Hollenberg: Aliskiren Combined with Losartan in Type 2 Diabetes and Nephropathy . In: New England Journal of Medicine . tape 358 , no. 23 , 2008, p. 2433–2446 , doi : 10.1056 / NEJMoa0708379 (free full text).
11. ↑ Franz H. Messerli, Sripal Bangalore: ALTITUDE trial and dual RAS blockade: The Alluring but Soft Science of the Surrogate End Point . In: The American Journal of Medicine . tape 126 , no. 3 , March 2013, p. e1-e3 , doi : 10.1016 / j.amjmed.2012.07.006 .
12. ↑ Naoyuki Nakao, Ashio Yoshimura, Hiroyuki Morita, Masyuki Takada, Tsuguo Kayano, Terukuni Ideura: RETRACTED: Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic controlled renal disease (COOPERATE): a randomized trial . In: The Lancet . tape 361 , no. 9352 , January 2003, p. 117-124 , doi : 10.1016 / S0140-6736 (03) 12229-5 .
13. ↑ Alan H. Gradman, Roland E. Schmieder, Robert L. Lins, Juerg Nussberger, Yanntong Chiang, Martin P. Bedigian: Aliskiren, a Novel Orally Effective Renin Inhibitor, Provides Dose-Dependent Antihypertensive Efficacy and Placebo-Like Tolerability in Hypertensive Patients . In: Circulation . tape 111 , no. 8 , March 2005, p. 1012-1018 , doi : 10.1161 / 01.CIR.0000156466.02908.ED .
14. ↑ Novartis - Tekturna ^® Prescribing Information ( Memento from July 20, 2011 in the Internet Archive ) (PDF; 376 kB)
15. ↑ External identifiers or database links for aliskiren hemifumarate : CAS number: 173334-58-2, EC number: 630-415-8, ECHA InfoCard: 100.158.717 , PubChem : 6918427 , ChemSpider : 5293624 , DrugBank : DB01258 , Wikidata : Q27124205 .
16. ↑ W. Forth, D. Henschler, W. Rummel: General and special pharmacology and toxicology. 9th edition. Urban & Fischer, Munich 2005, ISBN 3-437-42521-8 , p. 458.
17. ↑ Patent US5559111 : delta-amino-gamma-hydroxy-omega-aryl-alkanoic acid amides. Published on September 24, 1996 , inventors: Richard Goeschke, Jürgen Klaus Maibaum, Walter Schilling, Stefan Stutz, Pascal Rigollier, Yasuchika Yamaguchi, Clause Nissim Cohen, Peter Herold. ‌
18. ↑ FDA Approves New Drug Treatment for High Blood Pressure .
19. ↑ European Public Assessment Report for Rasilez ^® ( Memento of May 30, 2010 in the Internet Archive )
20. ↑ Authorization of aliskiren by Swissmedic: Rasilez 150mg / 300mg film-coated tablets (aliskiren) ( Memento of December 21, 2015 in the Internet Archive ).
21. ↑ Michael Zieschang: New developments in the therapy of high blood pressure: Renin inhibitors. (PDF; 536 kB) In: Drug Ordinance in Practice. Volume 34, Issue 1, January 2007, p. 27.
22. ↑ Aliskiren (Rasilez). In: KBV. Active ingredient currently. 01/2008 (PDF; 70 kB).
23. ↑ Questions and answers on ongoing review of aliskiren-containing medicines. (PDF) ema.europa.eu, December 22, 2011, accessed April 7, 2012 . 
24. ↑ Information archive | Early benefit assessment (§ 35a SGB V) , website of the Federal Joint Committee (G-BA).
25. ↑ https://www.iqwig.de/zusatznutzen-von-aliskiren-und-amlodipin-als.1421.html (link not available)
26. ↑ ROTE LISTE 2017, Verlag Rote Liste Service GmbH, Frankfurt am Main, ISBN 978-3-946057-10-9 , p. 159.
27. ↑ Red List, as of August 2009.
28. ↑ AM comp. d. Switzerland, as of August 2009.
29. ↑ AGES-PharmMed, as of August 2009.

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