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Publisher: College of Pharmacy, University of Florida
Publication Date: March 2007
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ALISKIREN: A DIRECT RENIN
INHIBITOR


Shenjin Paul, Pharm.D. Candidate



Hypertension affects over 1 billion patients
worldwide. The World Health Organization (WHO)
estimated that poor blood pressure (BP) control is
responsible for 66% of the strokes and 50% of
ischemic heart disease.1 New data from the Fram-
ingham Heart Study suggests that individuals who
are normotensive at age 55 have a 90% lifetime risk
for developing hypertension.2 Even though general
awareness and treatment options for hypertension
have increased, control rates are still inadequate.
For several decades, renin (re' nin) and the
enzymes that catalyze the renin-angiotensin-
aldosterone system (RAAS) have been targets of in-
terest as inhibitors of the RAAS. Inhibition of this
system is a viable therapeutic strategy, not only for
treatment of hypertension, but also for the clinical
benefits that it provides beyond BP reduction, such
as in the management of heart failure ad progressive
kidney disease.3 The RAAS can be manipulated at
several steps including enzyme inhibition reninn and
angiotensin converting enzyme (ACE)] and angio-
tensin II receptor blockade (ARB) (Figure 1). Sev-
eral peptide-like renin inhibitors have been synthe-
sized in the past, but poor pharmacokinetic proper-
ties limited the clinical use of these agents.5 In April
2006, the FDA accepted the new drug application of
aliskiren (a lis' kar in) by Novartis for the treatment
for hypertension both as monotherapy and in co-


administration with other antihypertensive agents.
Aliskiren (Tekturna [tek' tfir na]) was approved by
the FDA on March 6, 2007 for the treatment of hy-
pertension either as monotherapy or in combination
with other agents. This approval marks the first new
class of antihypertensive to be available in over 10
years. This article will evaluate the clinical pharma-
cology, pharmacokinetics and review published
clinical trials on aliskiren.

Clinical pharmacology
Direct renin inhibitors target the renin system
at the point of activation. Aliskiren binds to a pocket
in the renin molecule, blocking angiotensinogen
cleavage. It is a highly specific inhibitor of renin and
has little to no effect on other human enzymes.5 Cur-
rently there are 4 classes of agents that act on the
renin system: ACE-inhibitors, ARBs, beta-blockers
and aldosterone receptor antagonists. However,
ACE-inhibitors and ARBs both activate compensa-
tory feedback mechanisms that result in renin re-
lease. Increased plasma renin activity (PRA) stimu-
lates conversion of angiotensinogen to angiotensin I
(Ang I) with subsequent conversion to angiotensin II
(Ang II) by remaining uninhibited angiotensin con-
verting enzyme (ACE) and ACE independent
rIL U


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SPharmaNote


VOLUME 22, ISSUE 6 MARCH 2007


INSIDE THIS ISSUE:

ALISKIREN: A DIRECT RENIN INHIBITOR



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Volume 22, Issue 6 March 2007


PharmaNote







(chymase) pathways. In contrast, renin inhibitors
neutralize any compensatory increase in PRA and
prevent the formation of both Ang I and Ang II.
Kleinhert et al.6 suggested that blood pressure lower-
ing activity of renin inhibitors must be due, in part, to
inhibition of plasma renin activity, but at higher
doses, renin inhibitors might also act via other
mechanisms, such as inhibition of tissue renin.
In healthy volunteers, after oral doses of 40 to
640 mg/day of aliskiren, plasma alikiren concentra-
tion increased with increasing dose, with peak con-
centrations after 3 to 6 hours. The plasma half-life
averaged 23.7 hours (range 20-45 h), allowing once
daily administration. Oral bioavailability of aliskiren
is very low (2.7%) with plasma steady-state concen-
trations reached after 5 to 8 days of treatment. When
aliskiren is taken with food, AUC is reduced by ap-
proximately 62%; whether this is a clinically signifi-


cant reduction is currently unclear. Volume of distri-
bution is < 2 L/kg and the drug is approximately
50% protein bound.7 The main elimination route is
via biliary excretion as unchanged drug. Less than
1% of the oral drug is excreted in the urine. It is not
metabolized by CYP450, does not interfere with the
action of warfarin, and shows no clinically relevant
pharmacokinetic interactions with lovastatin, at-
enolol, celecoxib, or cimetidine. Aliskiren displays
linear pharmacokinetics across a dose range of 75 to
600 mg.8

Clinical Data
Mitchell et al.9 measured mean 24-hour am-
bulatory systolic and diastolic blood pressure (SBP,
DBP) in patients with mild-to-moderate hypertension
(mean sitting DBP > 95 mm Hg and < 110 mm Hg)
who had been randomized to receive once-daily al-


Figure 1. Renin-Angiotensin-Aldosterone System (RAAS)


ACE-I angiotensin converting enzyme inhibitors; ARB = angiotensin receptor blocker; AT1 = angiotensin II receptor type 1; AT2 = angiotensin II receptor type 2
(-) inhibits

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Volume 22, Issue 6 March 2007


PharmaNote







Tablel. Change from baseline in 24-hour mean ambulatory DBP (MADBP) and SBP (MASBP)9

Aliskiren (p < .0001 vs. placebo)
Blood Pressure
Bl resre Placebo 150 mg/day 300 mg/day 600 mg/day
Measurement

MADBP (mm Hg) 1.61 + 0.67 -6.55 + 0.67 -5.96 + 0,66 -7.43 0.66

MASBP (mm Hg) 1.75 + 0.95 -9.63 + 0.96 -8.77 0.94 -9.92 + 0.93


iskiren 150 mg, 300 mg, or 600 mg or placebo after a
2- to 4-week, single-blind, placebo run-in. The pa-
tients were part of a larger cohort participating in an
8-week trial. A subgroup of 216 patients underwent
24-hour ambulatory blood pressure monitoring at
baseline and at the end of the study. The authors
demonstrated a statistically significant change from
baseline in 24 hour mean ambulatory DBP and SBP
with all 3 doses of aliskiren compared to placebo(p <
0.0001 for all 3 doses of aliskiren)9(Table 1).

Aliskiren therapy in combination i/ ith HCTZ
Villamil et al.10 randomized 2776 patients >
18 years of age with mild-to-moderate hypertension


(mean sitting DBP [MSDBP] 95-109 mmHg) to re-
ceive 8 weeks of double-blind treatment with once-
daily aliskiren (75 mg, 150 mg, or 300 mg), HCTZ
(6.25 mg, 12.5 mg, or 25 mg), aliskiren plus HCTZ,
or placebo. Aliskiren monotherapy was superior to
placebo (p < 0.001) in reducing MSDBP and
MSSBP. In combination with HCTZ, aliskiren pro-
vided significant additional blood pressure reduc-
tions (Fig 2 and 3). The greatest mean reduction in
blood pressure, 21.2/14.3 mm Hg, was seen with al-
iskiren 300 mg/HCTZ 25 mg. Response rates
(patients with MSDBP < 90 mm Hg and/or > 10 mm
Hg decrease) were significantly higher with aliskiren
300 mg (64%) and all combinations (58% to 81%)


Figure 2. Mean change from baseline to week 8 in MSDBP with aliskiren and HCTZ monotherapy and combination therapy
Combination


Aliskiren HCTZ A75 A75
Placebo 75 150 300 6.25 12.5 25 H6.25 H125


A75 A150 A150 A150 A300 A300
H25 H625 H125 H25 H12.5 H25


P = 0.0002 -
(overall Dunnett's test)


*** -14.3
~~



Adapted from the original article.10 *P < 0.05; ** P < 0.001; *** P < 0.0001 versus placebo

PharmaNote 0


Volume 22, Issue 6 March 2007


0

-6

-7

-8

-9

-10

-11

-12

-13

-14

-15







Figure 3. Mean change from baseline to week 8 in MSSBP with aliskiren and HCTZ monotherapy and combination therapy
Combination


Aliskiren HCTZ A75 A75 A75 A150 A150 A150 A300 A300
Placebo 75 150 300 6.25 12.5 25 H6.25 H12.5 H25 H6.25 H12.5 H25 H12.5 H25
Sn=192 n=l n=183, n=180 1 n=194, n=188 n=173 ,n=187, n=1891 ri = 18 n, =173 n=184 n=187 0 n=1 n=173


V

-6-
--6-i


-8 -7.5

-10- -9.4

-12 -
-12.2
-14 -


-16 -
-i -


-18 -

-20 -

-22 -


-11.0





-15.7
+a**


- I I
-13.9 -14.3
****(*


-14.3



-15.6
##Q


-15,3
Y**


-17.3
** *


- P < 0.0001
(overall Dunnett's test)


-17.6
*41*


-19.5



-19.8
1*


-21.2



Adapted from the original article.10 *P < 0.05; ** P < 0.001; *** P < 0.0001 versus placebo


than placebo (46%; all p < .05). Combinations of al-
iskiren/HCTZ 75/25 mg, 150/25 mg, 300/12.5 mg,
and 300/25 mg produced significantly greater re-
sponse rates than each component monotherapy (all
p <.05).

Aliskiren monotherapy and combination i/ iih valsar-
tan
Pool et al11 randomized 1123 patients with
mild-to-moderate hypertension (MSDBP > 95 mm
Hg) to receive once-daily placebo, aliskiren mono-
therapy (75 mg, 150 mg, 200 mg) valsartan mono-
therapy (80 mg, 160 mg or 320 mg), aliskiren and
valsartan combination or valsartan/HCTZ (160/12.5
mg). Once-daily oral treatments with aliskiren 300
mg significantly (p < 0.001) reduced MSDBP (-12.3
mm Hg vs. -8.6 mm Hg placebo) and MSSBP (-15.0
mm Hg vs. -10 mm Hg placebo). Aliskiren 75 mg
and 150 mg failed to reach statistical significance in
comparison to placebo. In comparison to all 3 doses
of valsartan monotherapy (80 mg, 160 mg, 300 mg),
aliskiren monotherapy (75mg, 150mg, and 200mg)


was comparable in SBP and DBP reduction. How-
ever, only aliskiren 300 mg, valsartan 160 mg and
valsartan 320 mg provided statistically significant
reductions in SBP (p < 0.05, p <0.001, p <0.001 re-
spectively) and DBP (p <0.001, p <0.05, p <0.05 re-
spectively). All three aliskiren/valsartan combina-
tions significantly lowered MSDBP and MSSBP
compared to placebo (Table 2).

Aliskiren in combination i/ iih HCTZ, ACEI, or ARB
O'Brien et al.12 assessed blood pressure in
three open-label studies in patients with mild-to-
moderate hypertension. Patients were administered
aliskiren in combination with HCTZ (n=23), ramipril
(n=21) or irbesartan (n=23). In the diuretic combina-
tion study, the addition of 25 mg of hydrochlorothi-
azide to 150 mg of aliskiren daily for 3 weeks sig-
nificantly lowered daytime pressure, compared with
aliskiren monotherapy. In the ACEI combination
study, the addition of 75 or 150 mg of aliskiren to 5
mg of ramipril alone for 3 weeks further lowered
both daytime and nighttime pressures compared with


mm
PharmaNote Volume 22, Issue 6 March 2007


Volume 22, Issue 6 March 2007


PharmaNote







Table 2. Summary of major clinical trials with aliskiren
Duration of A SBP A DBP
Study N Stuy Demographics Treatment (mmHg) (mmH
Study (mmHg) (mmHg)


Mean 24-hour
216 ambulatory BP
over 8 weeks


Mild-mod
HTN
MDSBP > 95
&
MSBP <110


Mean sitting
2776 DBP and SBP
over 8 weeks


Mean sitting
1123 DBP and SBP
over 8 weeks


Mild-mod
HTN
MSDBP 95-
109


Mild-mod
HTN
MSDBP > 95


A75/150/300
H6.25/12.5/25
A75 &
H6.25/12.5/25
A150 &
H6.25/12.5/25
A300 &
H12.5/25
Placebo


A75/150/300
V80/160/320
A75/V80
A150/V160
A300/V320
Placebo


-9.4/-12.2*/-15.7'
-11.0/-13.9"/-14.3

-14.3"/-15.6'/-17.3'

-15.3"/-17.6"/-19.5'

-19.8'/-21.2'T

-7.5


-12.1/-12.1/-15*
-11.2/-15.5**/-16.5**
-14.5T
-16.6T
-18**
-10


-8.7*/-8.9*/-10.3'
-9.1/-10.7/-9.4

-10.8'/-11.1'/-11.5'

-10.4'/-11.9'/-12.7'

-13.9'/-14.3'

-6.9


-10.3/-10.3/-12.3**
-10.5/-11.0*/-11.3*
-11.3T
-11.8?
-12.1**
-12.9


HCTZ
(n= 23)
O'Brien Ramipril
et al.12 (n= 21)
Irbesartan
(n=23)


24-hour mean
daytime sys-
tolic and dia-
stolic ambula-
tory blood
pressure over 3
weeks


A150
A150/H25
Mild-mod R5 &
HTN A75/150

1150 & A75/150


A75/150/300 = aliskiren 75mg/150mg/300mg daily; H6.25/12.5/25 = HCTZ 6.25/12.5/25; V80/160/320-
irbesartan 150mg ; DBP= diastolic blood pressure ; SBP= systolic blood pressure
*p <0.05, **p <0.001, fp <0.01, 'p <0.0001


ramipril monotherapy. In the ARB combination the 600 mg
study, the addition of 75 or 150 mg of aliskiren to incidence of
150 mg of irbesartan alone, for 3 weeks, resulted in was reduced
significantly lower night-time pressures compared with aliskire
with irbesartan monotherapy. effects note
rized in Tab
Adverse Effects
Aliskiren was well tolerated as either mono- Dosing/Cosi
therapy or in combination therapy with other anti- Alth
hypertensive agents. Discontinuation occurred in 3.5 treatment of
to 5 % of the patients.13 The most common adverse dations and
events included headaches (2.7% 6.1%) and naso- clinical trial
pharyngitis (0.5 5.4%). Diarrhea occurred in a day. No sign
dose-related manner, with the highest incidence at served with


valsartan ,.... I, 1-,_ C', ,,, R5= ramipril 5mg; 1150=




(9.5% vs. placebo p < .0001 ).14,15 The
cough occurring with an ACE inhibitor
when the ACE inhibitor was combined
n (4.7 % vs. 1.8%).16 Important adverse
d during the clinical trials are summa-
le 3.17

t
tough aliskiren has been approved for the
hypertension, formal dosing recommen-
cost are not available. Doses used in the
s ranged from 37.5 mg to 600 mg once a
lificant blood pressure reduction was ob-
the 37.5 mg daily dose; thus, is not likely


Phara~oe Voume22, ssu 6 Mrch200


Mitchell
et al.9


A150


A300
A600
Placebo


-9.63'

-8.77"
-9.92"
1.75


-6.55"

-5.96"
-7.43'
1.61


Villamil
et al.10


Pool et
al.1


-10.4**
-18.4


-10.6


-10.5*/-14**

-14.8*/-13.3*


Volume 22, Issue 6 March 2007


PharmaNote







Table 3. Adverse effects observed in clinical trials with aliskiren therapy 17
Aliskiren
Placebo Aliskiren/CCB Aliskiren/ACEI CCB ACEI
N= 781 +/- other drugs N= 187 N= 277 N= 357 N+278
N = 2598
Any Adverse Event 314 (40.2) 1013 (39.0) 59 (31.6) 83 (30.0) 106 (29.7) 94 (33.8)
Headache 68 (8.7) 141(5.4) 5 (2.7) 8 (2.9) 12 (3.4) 17 (6.1)
Nasopharyngitis 45(5.8) 110 (4.2) 1(0.5) 3 (1.1) 2 (0.6) 5 (1.8)
Diarrhea 9 (12) 64 (2.5) 3 (1.6) 3 (1.1) 3 (0.8) 7 (2.5)
Dizziness 17 (2.2) 47 (1.8) 2 (1.1) 3 (1.1) 5 (1.4) 5 (1.8)
Fatigue 12(1.5) 38(1.5) 2(1.1) 3 (1.1) 4(1.1) 3 (1.1)
Back pain 11(1.4) 32 (1.2) 1(0.5) 2 (0.7) 1(0.3) 4 (1.4)
Cough 5 (0.6) 28 (1.1) 1(0.5) 5 (1.8) 1(0.3) 13 (4.7)
Peripheral edema 5(0.6) 24(0.9) 4(2.1) 1(0.4) 26(7.3) 1(0.4)
Influenza 5 (0.6) 19 (0.7) 1(0.5) 3 (1.1) 1(0.3) 1(0.4)
Data are presented as the number (%) of patients reporting adverse events.

to be used clinically. Also, an aliskiren dose of 600 Summary
mg daily is not associated with additional blood pres- Renin-angiotensin-aldosterone system inhibi-
sure reduction or higher response rates than those tion is a good therapeutic strategy not only for treat-
seen with the 300 mg dose. The FDA approved the ment of hypertension, but also for the clinical bene-
manufacture of 150 mg and 300 mg tablets. fits that it provides beyond BP reduction such as
management of heart failure and progressive kidney
Future studies disease.4 Aliskiren targets renin, the enzyme catalyz-
There are several ongoing studies that are in- ing cleavage of angiotensinogen to angiotensin I
vestigating aliskiren for the prevention of end organ (Ang I), the first and rate-limiting step of the renin-
damage, primary prevention of cardiovascular dis- angiotensin system (RAS). Studies have shown
ease, and prevention of microvascular complications promising data on BP regulation when aliskiren is
in diabetes mellitus. Results from these studies used as monotherapy and in combination with the
might shed more insight into the long-term effects of currently available anti-hypertensives. Further stud-
aliskiren. Some of the ongoing clinical trials are ies will be needed to determine the effects of al-
summarized in Table 4. iskiren on long-term blood pressure regulation and
its ability to protect against end-organ damage.

Table 4. Ongoing clinical trials on aliskiren
Key outcomes studies that will define the role of direct
New studies to test effect of aliskiren on surrogate markers of target or- ey outcomes studies that i d e te re o
renin inhibition in primary and secondary prevention
gan damage (results to be released in 2007) (anticipated data in 2011)
(anticipated data in 2011)
ALLAY ALOFT AVOID AVIATOR ALTITUDE
ALiskiren in Left ven- ALiskiren Obser- Aliskiren in the eValua- Aliskiren in VIsceral ALiskiren Trial In Type 2
triculAr HypertrophY vation of heart tion Of protienuria in obesity AT risk patients Diabetic nEphropathy
Failure Treat- Diabetes Outcomes Research
ment

Aliskiren vs. losartan Aliskiren vs. pla- Aliskiren vs. placebo Does aliskiren delay the Does aliskiren delay time to
vs. combination cebo added to added to losartan time to first major CV diabetic complications in
optimal heart event in high risk pa- patients with Type 2 DM
failure treatment tients and nephropathy

Primary endpoint: LV Primary end- Primary endpoint: % re-
mass and geometry as point: fall in BNP duction urinary albumin/
measured by MRI creatnine ratio


PharmaNote Volume 22, Issue 6 March 2007







References

1. American Heart Association. 2002 Heart and
Stroke Statistical Update. Dallas, TX.
2. The Seventh Report of the Joint National Com-
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treatment of high blood pressure, U.S. Depart-
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NHLBI Publication No.03-5233 December 2003
3. Krum H, Gilbert R. Novel therapies blocking the
renin-angiotensin-aldosterone system in the man-
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4. Staessen J, Li Y, et al. Oral renin inhibitors; Lan-
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5. Wood JM, Maibaum J, Rahuel J, et al. Structure-
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8. Limoges D, Vaidyanathan S, Yeh CM, Dieterich
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9. Mitchell J, Oh B, Herron J, et al. Once-daily al-
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www.medscape.com/viewarticle/533716



The PharmaNote is Published by:
The Department of Pharmacy
Services, UF Family Practice Medical
Group, Departments of Community
Health and Family Medicine and
Pharmacy Practice
University of Florida




John G. Gums Editor
Pharm.D.

R. Whit Curry, M.D. Associate Editor

Shawn Anderson Assistant Editor
Pharm.D.


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