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TELAVANCIN: A LIPOGLYCO-
PEPTIDE FOR THE TREATMENT
OF COMPLICATED SKIN & SKIN
STRUCTURE INFECTIONS

Sonali Patel, Pharm.D.


currently, vancomycin is the mainstay of ther-

apy for treatment of infections caused by me-
thicillin-resistant Staphylococcus aureus
(MRSA).1 Recent epidemiologic data have highlighted
the decreasing susceptibility of MRSA to vancomycin2,3
and the development of vancomycin resistant entero-
coccus (VRE) strains, requiring the development of
newer antibiotics. Theravance Inc, on September 11th
2009, received FDA approval for Telavancin
(Vibativ), a novel lipoglycopeptide, which targets
gram-positive organisms including MRSA, heteroresis-
tant vancomycin intermediate Staphylococcus aureus
(hVISA), vancomycin-intermediate Staphylococcus
aureus (VISA), and vancomycin-resistant Staphylococ-
cus aureus (VRSA). This article will describe the phar-
macokinetics and pharmacodynamics of telavancin,
the FDA approved indication for complicated skin and
skin structure infections (cSSSI), pending approval for
pneumonia, and a safety analysis. Lastly, a cost com-
parison of vancomycin to telavancin will be provided.


PHARMACOLOGY


Mechanism ofAction
Similar to vancomycin, telavancin inhibits cell wall
synthesis by binding to peptidoglycan precursors con-
taining the D-alanine-D-alanine terminal, and thus
prevents cross linking of bacterial cell wall compo-
nents. Telavancin anchors to the binding site with


greater affinity and is approximately 10 times more
potent than vancomycin.
A secondary mechanism, not seen with vancomy-
cin, includes the ability of telavancin to change mem-
brane potential and permeability in a concentration-
dependent manner in Gram-positive bacteria.4 The
consequent disruption of the cell membrane results in
cell lysis and rapid bactericidal activity.

Pharmacokinetics & Pharmacodynamics
At standard dosing of 10mg/kg, plasma concentra-
tions increase linearly proportional to the dose of tela-
vancin.5 The observed half-life at this dose is 7 to 9
hours. Approximately 72% of the dose of telavancin is
really eliminated which warrants changes in dosing
based on renal function.7 Unlike vancomycin, clinical
cure rates decline with a creatinine clearance < 50ml/
min.8 Plasma protein binding of telavancin is high at
approximately 90% with primary binding to serum
albumin. Telavancin is metabolized hepatically to
three hydroxylated metabolites. Mean plasma concen-
trations are 21% lower in patients with hepatic im-
pairment compared to control (p<0.05) but the clinical
significance of this finding is unclear. Although the
metabolic pathway is not identified, cytochrome P450
enzymes do not appear to be involved. Consequently,
mild-to-moderate hepatic impairment (Child-Pugh B)




INSIDE THIS ISSUE:

TELAVANCIN: A LIPOGLYCOPEPTIDE FOR THE
TREATMENT OF COMPLICATED SKIN AND SKIN
STRUCTURE INFECTIONS

VALTURNA (ALISKIREN/VALSARTAN): A NEW
COMBINATION RAAS INHIBITOR


.1^^ ^ ^^ ^ ^^ ^^


mm.


PharmaNote


VOLUME 25, ISSUE 9 JUNE 2010
ih 1f


Volume 25, Issue 9 1 June 2010


PharmaNote








Table 1. In vitro activity of telavancin against key gram-positive bacteria.

ANTIBACTERIAL/ORGANISM (# of isolates) MIC90 RANGE (mg/ml) Breakpoint

S. aureus: Telavancin 0.25-0.5 methicillin susceptible (2515) Vancomycin 1 <2mg/ml
S. aureus: Telavancin 0.25-0.5 methicillin resistant (1669) Vancomycin 1-2 <2mg/ml
S. aureus: Telavancin 1 glycopeptide intermediate (50) Vancomycin 8 <2mg/ml
S. pneumoniae: Telavancin 0.03 NA
penicillin susceptible (371) Vancomycin 0.5 <2mg/ml
S. pneumoniae: Telavancin 0.015-0.03 NA
penicillin resistant (74) Vancomycin 0.5 <2mg/ml
E. faecalis: Telavancin 0.5 -1 vancomycin susceptible (928) Vancomycin 2 <4mg/ml
E. faecalis: Telavancin 8-16 NA
vancomycin nonsusceptible (60) Vancomycin >512 NA
E. faecium: Telavancin 0.25 vancomycin susceptible (427) Vancomycin 1 <4mg/ml
E. faecium: Telavancin 2-8 NA
vancomycin nonsusceptible (352) Vancomycin >512 NA
Telavancin 0.06 <0.12mg/ml
S. pyogenes
Vancomycin 0.5 STelavancin 0.06 <0.12mg/ml
S. agalactiae
Vancomycin 0.5 Adapted from Dunbar et al.5 and References 8, 13, and 26.



does not appear to affect the pharmacokinetics of tela- vancomycin MICs are approximately 2 to 4 times
vancin and therefore dosing changes for hepatic insuf- higher, linezolid are 4 to 80 times higher, and dapto-
ficiency are not necessary.9 mycin has a MIC range that is 2 times higher than that
In vivo and in vitro animal studies of telavancin of telavancin for the treatment of MSSA and MRSA in-
show concentration-dependent, bactericidal activity fections. The MIC9o and minimum bactericidal concen-
with the presence of significant post antibiotic effects. tration (MBCgo) for community-acquired MRSA iso-
In an in vitro study conducted by Pace et al., telavancin lates is 0.5 mg/ml and 1 mg/ml respectively for tela-
showed a post antibiotic effect that lasted approxi- vancin.12 For infections caused by VISA, telavancin has
mately 4 to 6 hours against strains of methicillin sensi- an MIC9o of 1 mg/ml as compared to 8 mg/ml for van-
tive S. aureus (MSSA), MRSA, and VISA.10 The best pre- comycin and 1 mg/ml and 2 mg/ml for daptomycin
dictor of efficacy of telavancin is the ratio of the area and linezolid respectively. Telavancin also exhibits
under the curve (AUC) to minimum inhibitory concen- good activity against Gram-positive anaerobes such as
tration (MIC). Clostridiumjeikeium for cSSSI and C. difficile.

IN VITRO SPECTRUM OF ACTIVITY FDA-APPROVED INDICATION FOR CSSTI

Telavancin is active against gram-positive organ- To date, the only FDA-approved indication for tela-
isms including vancomycin-resistant organisms, but is vancin is complicated skin and skin structure infec-
not effective in infections caused by gram-negative tions (cSSSI). For telavancin to be effective, it must
organisms (Table 1). Jansen et al. showed an MIC9o penetrate into the site of infection. After 3 to 4 days of
range of telavancin, for MSSA and MRSA infections, treatment with 7.5 mg/kg daily, penetration into the
between 0.06 mg/ml and 0.5 mg/ml.11 In comparison, abscess fluid compared to plasma levels was 0.79 and


rihI+ \NIVliiW 5C I n I9 201 A


I JUlIICn --I


I I ma IIC UL


oume ssue







Table 2: Clinical studies evaluating telavancin.

STUDY DESIGN N INCLUSION CRITERIA STUDY LENGTH RESULTS


. Randomized
. Double-blinded
. Active-control
. Parallel-group


. Randomized
. Double-blinded
. Active-controlled
. Multinational


. Randomized
. Double-blinded
. Active-controlled
. Multinational


. Telavancin (n=100)
. Standard Care (n=95)
Vancomycin (93%)
Antistaphylococcal
PCN (7%)


. Telavancin (n=426)
. Vancomycin (n=429)


. Telavancin (n=502)
. Vancomycin (n=510)


. Age > 18 years
. Diagnosis of cSSSI
presence of major abscess
requiring surgical drainage
Deep, extensive cellulitis
an infected wound or ulcer
an infected burn


. Age > 18 years
. Diagnosis of cSSSI
Major abscess
Infected burn
Deep/extensive cellulitis
Infected ulcer
Wound infection
. Infection requiring 7-14 days
of IV antibiotic therapy


. Age > 18 years
. Diagnosis of cSSSI
Major abscess
Infected burn
Deep/extensive cellulitis
Infected ulcer
Wound infection
. Infection requiring 7 days of
IV antibiotic therapy


FAST 1118


Pts treated for and evalu-
ated at 7 14 days post
administration of abx


Pts treated for and evalu-
ated at 7 14 days post
administration of abx












Pts treated for and evalu-
ated at 7 14 days post
administration of abx


a = end of therapy visit
b= test-of-cure visit


Telavancin vs. standard therapy
showed:
Cure rates were similar (82% vs. 85%;
p=0.37
Eradication of pathogens were simi-
lar:
At EOTa: 89% vs. 77%; p=0.09
At TOCb: 94% vs. 83%; p=0.06
For MRSA 92% vs. 68%; p=0.04




No difference between telavancin and
vancomycin in clinical cure rates and
microbiological eradication, including
MRSA

Cure rates 87.9% vs. 86.5% (95% Cl -
3.6 6.3)
Microbiological eradication (89.5% vs.
85.9% (95% Cl
-2.2-0.4)
Discontinuation due to ADR 7% tela-
vancin vs. 5% vancomycin



No difference between telavancin and
vancomycin in clinical cure rates and
microbiological eradication, including
MRSA

Cure rates 77.1% vs. 73.7% (95% Cl -
1.9-8.7)
Microbiological eradication (76.9% vs.
74.8% (95% Cl
-4.0 8.2)


ATLAS 119


ATLAS 1120







0.82 respectively. The steady state AUC in the blister
fluid was -40% of that found in plasma and was suffi-
cient to eradicate pathogens causing the infection.14
In a phase III randomized, parallel, double-
blinded, active control trial, Strykewski et al compared
the use of standard telavancin dosing (10 mg/kg every
24 hours) to vancomycin (1 g every 12 hours or indi-
vidualized dosing based on standard practice at the
site) for the treatment of cSSSI (Table 2).15 Infections
were defined by the presence of either cellulitis, major
abscess requiring surgical drainage, infected wound or
ulcer, or infected burn. Patients were required to have
an active infection defined as 3 or more of the follow-
ing signs or symptoms: erythema, heat and/or local-
ized warmth, fluctuance, swelling and/or induration,
pain and/or tenderness to palpitation, fever
(temperature > 38oc), WBC count > 10,000 cells/mm3,
or > 15% bands. The most common organisms cul-
tured included S. aureus, MRSA, E. faecalis, other En-
terococcus species, S. pyogenes, S. agalactiae, and some
gram-negative organisms. The authors defined cure as
resolution of clinically significant signs and symptoms
or improvement in the extent of infection such that
the patient no longer required antimicrobial treat-
ment The primary endpoint was clinical response at
test-of-cure evaluation, 7-14 days after administration
of the last dose.
The study demonstrated that telavancin is at least
as effective to twice-daily vancomycin for the treat-
ment of cSSSI. Telavancin demonstrated significant
microbial eradication rates and overall therapeutic
responses that support clinical response. When com-
pared to vancomycin, response rates were similar
across the most common types of infections and the
most common gram-positive pathogens. The authors
concluded that the use of telavancin is an alternative
to vancomycin for the treatment of cSSSI caused by a
variety of gram-positive microorganisms, including
MRSA (Table 2).15

PENDING FDA APPROVAL FOR PNEUMONIA

One clinically significant issue with vancomycin is


reduced penetration into lung tissue. Telavancin does
not have similar difficulties in penetrating the lungs.
Gotfried et al. conducted an in vitro study to assess
the effects of pulmonary surfactant on telavancin and
to identify the steady state concentrations achieved in
epithelial lining fluid (ELF) and alveolar macrophages
(AM). Patients received 3 consecutive days of 10mg/
kg/dose with plasma levels obtained at 4- and 8-
hours to reflect maximum intrapulmonary concentra-
tion, at 12 hours to represent the midpoint of the dos-
ing interval, and at 24 hours to signify the end of the
dosing interval. Telavancin concentrations in ELF and
AM, at any interval, were greater than the MIC9o of 0.5
mg/ml, which is considered clinically significant for
MRSA infections.16
Pulmonary surfactant does not appear to affect the
in vitro activity of telavancin against MRSA and S.
pneumonia. However, the investigation failed to pre-
dict the effectiveness of telavancin for eradication of
susceptible pathogens in pneumonia. Surfactant did
not appear to alter the effects of vancomycin or ceftri-
axone. The effects of surfactant on daptomycin was
related to the concentration of surfactant (as the con-
centration of surfactant increased, the antibacterial
activity of daptomycin decreased).16
Further in vivo studies need to be carried out to
assess the complete efficacy of telavancin for use in
pneumonia. ATTAIN I and II, phase III, randomized,
double-blind trials assessing the efficacy of telavancin
in HAP have been completed, however, results have
not been published.17

DOSING

For the treatment of cSSSI caused by susceptible
strains of S. aureus (including MSSA and MRSA), S. pyo-
genes, S. agalactiae, S. anginosus group, or vancomycin
susceptible E. faecalis, the usual dose is 10mg/kg once
daily given over 1 hour for 7 to 14 days.8 Because 72%
of the telavancin dose is cleared really, dosage ad-
justments are necessary for renal insufficiency (Table
3).


Table 3. Renal adjustments.8

CREATININE CLEARANCE DOSE FREQUENCY


>50ml/min


10mg/kg

7.5mg/kg


30 50 ml/min


Every 24 hours

Every 24 hours


10 29 ml/min 10mg/kg Every 48 hours


Volume 25, Issue 9 I June 2010


PharmaNote







SAFETY & TOLERABILITY


In the phase III ATLAS study, the most common
treatment-emergent adverse events associated with
telavancin were taste alterations, nausea, headache
and vomiting, and foamy urine. ATLAS study showed
that a QTc interval prolongation of 160 msec from
baseline was infrequent and the number of patients
with QTc interval prolongation was similar between
both groups. Caution should be used when using tela-
vancin in combination with other agents that cause
QTc prolongation.8

COST EFFECTIVENESS

The cost effectiveness of telavancin was deter-
mined during the ATLAS phase III clinical trial where
infection related length of stay (LOSIR), length of stay
(LOS), and hospitalization costs (COSTIR) were com-
pared between vancomycin and telavancin. No signifi-
cant differences were noted in total LOS, treatment
duration, LOSIR, cost of additional antibiotics received,
or COSTIR between groups.22 The main difference ob-
served was the cost of vancomycin monitoring
(median ~$51.25) as compared to telavancin ($0). The
results may not be reproducible due to differences in
healthcare systems, cost of acquisition, and medical
practice.22
The cost of a 250 mg vial of telavancin is approxi-
mately $50.00 and the 750 mg vial is $150.00. There-
fore, for a 70 kg patient the total daily cost of tela-
vancin for a patient with normal renal function is $140
compared to approximately $20 per day for vancomy-
cin administered 1 gm every 12 hours. Pharma-
coeconomic analyses from ATLAS data suggest that


telavancin may be more cost effective than vancomy-
cin if telavancin can be acquired at similar prices as
that of vancomycin, particularly in those with MRSA
infections. However, such pricing of telavancin is likely
years away.22


SUMMARY


The increase in incidence of MRSA and VRE infec-
tions has led to the development of newer antimicro-
bial agents. Telavancin, a lipoglycopeptide that targets
gram-positive microorganisms including MRSA and
VRE, is an effective alternative to vancomycin for the
treatment of cSSSI.15 Although the efficacy of tela-
vancin for pneumonia is not determined, in vitro stud-
ies suggest a possible beneficial effect but further
studies are needed.16 The major side effects include
taste disturbance, foamy urine, and nephrotoxicity.
Lastly, despite the increased acquisition cost, the lack
of therapeutic monitoring may make telavancin more
cost-effective versus vancomycin in MRSA infections.




REFERENCES

1. Atwood et al. Telavancin: A novel lipoglycopeptide
antimicrobial agent. Am ] Health-Syst Pharm
2007;64:2335-48.
2. Liu C, Chambers HF. Staphylococcus aureus with het-
erogeneous resistance to vancomycin: epidemiology,
clinical significance, and critical assessment of diag-
nostic methods. Antimicrob Agents Chemother
2003;47:3040-5.
3. Centers for Disease Control and Prevention. Vanco-


Table 4. Incidence of treatment-emergent adverse drug reactions.
ADVERSE REACTION TELAVANCIN VANCOMYCIN
Nephrotoxicity 15% 7%
Taste disturbance (metallic or soapy) 33% 7%
Nausea 27% 15%
Vomiting 14% 7%
Foamy urine 13% 3%
Pruritis
Skin & appendages 6% 13%
Generalized 3% 6%
Increase in serum creatinine conc. 0.5% 2.5%
Rash 4% 5%
Adapted from Corey et al. 21 and Atwood et al.4

DPhl l I A 9 X 201
ri---------i-------------------------------------


I JUIeC --I.


r m i UUi I t LC


oume ssue







mycin-resistant Staphylococcus aureus-
Pennsylvania, 2002. MMWR Morb Mortal Wkly Rep
2002;51:902 (erratum: MMWR Morb Mortal Wkly
Rep 2002; 51:931).
4. Higgins DL, Chang R, et al. Telavancin, a multifunc-
tional lipoglycopeptide, disrupts both cell wall syn-
thesis and cell membrane integrity in methicillin-
resistant Staphylococcus aureus. Antimicrob Agents
Chemother 2005; 49:1127-34.
5. Dunbar et al. A review of telavancin in the treatment
of complicated skin and skin structure infections
(cSSSI). Therapeutics and Clinical Risk Management.
2008:4(1) 235-44.
6. Ducchin et al. Single dose pharmacokinetics (PK) of
telavancin (TLV) in health elderly subjects. 14th Euro-
pean Congress of Clinical Microbiology and Infec-
tious Disease; Prague, Chezch Republic. 2004.
7. Wong SL et al. Multiple-dose pharmacokinetics of
intravenous telavancin in healthy male and female
subjects. Journal of Antimicrobial Chemotherapy
2008;62:780-83.
8. Theravance, Inc. Vibativ (telavancin) package in-
sert South San Francisco; 2009.
9. Goldeberg et al. Lack of effect of moderate hepatic
impairment on the pharmacokinetics of telavancin.
Pharmacotherapy 2010;30:30-42.
10. Pace et al. Semi-synthetic glycopeptides antibacteri-
als. Bioorg Med Chem Lett 2003;13:4165-8.
11. Jansen WT, Verel A, et al. In vitro activity of tela-
vancin against gram-positive clinical isolates recently
obtained in Europe. Antimicrob Agents Chemother
2007;51:3420-4.
12. Saravolatz et al. Comparative activity of telavancin
against isolates of community-acquired methicillin-
resistant Staphylococcus aureus. Journal ofAntimicro-
bial Chemotherapy 2007;60:406-409.
13. Pham. Pharm D, Paul. "Telavancin." John Hopkins
ABX guide. antibiotics/antibacterial/glycopeptide/
telavancin.html?contentInstanceld=506492>.
14. Sun et al. Tissue penetration of telavancin after intra-
venous administration in healthy subjects. Antim-
icrobial agents Chemotherapy 2006;50:788-90.
15. Stryjewski ME, Graham DR, Wilson SE, et al. Tela-
vancin versus vancomycin for the treatment of com-
plicated skin and skin-structure infections caused by
Gram-positive organisms. Clin Infect Dis
2008;46:1683-93.
16. Gotfried et al. Intrapulmonary distribution of intra-
venous telavancin in healthy subjects and effect of
pulmonary surfactant on in vitro activities of tela-
vancin and other antibiotics. Antimicrob Agents
Chemother 2008;52(1):92-7.
17. Rubinstein E, Corey GR, Stryjewski ME. Abstract 075.
Telavancin for hospital-acquired pneumonia, includ-
ing ventilator-associated pneumonia: the ATTAIN
studies. Barcelona, Spain: In: 18th European Con-

PharmaNote


gress of Clinical Microbiology and Infectious Diseases
(ECCMID) April 19-22, 2008.
18. Stryjewski ME et al. Telavancin versus standard ther-
apy for treatment of complicated skin and skin struc-
ture infections caused by gram-positive bacteria:
FAST 2 study. Antimicrob Agents Chemother 2006;50
(3):862-7.
19. Corey GR, Stryjewski M, et al. P845 ATLAS 1: the first
phase 3 study evaluating the new lipoglycopeptide,
telavancin, for the treatment of patients with compli-
cated skin and skin structure infections. International
Journal of Antimicrobial Agents 2007;29(2):S216-
S217.
20. Corey GR, Stryjewski M, et al. P846 ATLAS 2: a dou-
ble-blind, randomized, active controlled, multina-
tional Phase 3 study comparing telavancin with van-
comycin for the treatment of patients with compli-
cated skin and skin structure infections. International
Journal of Antimicrobial Agents 2007;29(2):S216-
S217.
21. Corey R, Stryjewski M, et al. Telavancin for the treat-
ment of complicated skin and skin structure infec-
tions (cSSSI): results of the ATLAS I study. 44th Infec-
tious Disease Society of America. Toronto, Canada.
2006
22. Laohavaleeson et al. Cost-effectiveness of relavancin
vs. vancomycin for treatment of complicated skin
and skin structure infections. Pharmacotherapy
2008;28:1471-82.
23. Shaw et al. Pharmacokinetics, serum inhibitory and
bactericidal activity, and safety of telavancin in
healthy subjects. Antimicrob Agents Chemother
2005;49:195-201.
24. Odenholt I, Lowdin E, et al. Pharmacodynamic effects
of telavancin against methicillin-resistant and methi-
cillin-susceptible Staphylococcus aureus strains in
the presence of human albumin or serum and in an in
vitro kinetic model. Antimicrob Agents Chemother
2007; 51:3311-6.
25. Krause et al. In vitro activity of telavancin against
resistant gram-positive bacteria. Antimicrob Agents
Chemother 2008;52(7):2647-2652.
26. Rybak et al. Therapeutic monitoring of vancomycin
in adult patients: A consensus review of the Ameri-
can Society of Health-System Pharmacists, the Infec-
tious Diseases Society of America, and the Society of
Infectious Disease Pharmacists. Am J Health-Syst
Pharm 2009; 66:82-98.


Volume 25, Issue 9 June 2010










VALTURNA (ALISKIREN/
VALSARTAN): A NEW COMBI-
NATION RAAS INHIBITOR

Trishna Patel, Pharm.D.


Hypertension (HTN), known as the "silent kil-
ler," is common, affecting an estimated 73+
million Americans that require some type of
antihypertensive treatment' If left untreated, this dis-
ease can increase the risk of heart attack, heart failure,
stroke, and kidney disease, and lead to other complica-
tions. Almost 30% of patients are not aware that they
have HTN, and greater than 40% of patients who are
aware are not on any kind of treatment2 Several
classes of medications can be used in HTN treatment:
diuretics, alpha and beta blockers, calcium channel
blockers, angiotensin converting enzyme inhibitors
(ACE-I), angiotensin II receptor blockers (ARB), and
the newest addition, direct renin inhibitors (DRIs).
DRIs reduce blood pressure (BP) by suppressing renin
effects and reducing plasma renin activity.3 Valturna
(aliskiren/valsartan) was FDA approved on Septem-
ber 9, 2009 as the first combination DRI and ARB. It is
manufactured by Novartis for the treatment of HTN in
patients not controlled on monotherapy, substituted
for the titrated components, or as initial therapy in
patients who may need multiple medications to con-
trol their BP.4 This article will review the efficacy,
safety, and tolerability of aliskiren/valsartan.

PHARMACOLOGY & PHARMACOKINETICS


Valturna is a single tablet combination of al-
iskiren, a direct renin inhibitor, and valsartan, an an-
giotensin II antagonist at the AT1 receptor subtype.
Aliskiren blocks the conversion of angiotensinogen
to angiotensin (Ang) I. Suppressing Ang I decreases
the formation of Ang II which functions as a negative
inhibitory feedback to suppress renin release within
the renin-angiotensin-aldosterone system (RAAS). De-
creasing Ang II leads to an increase in plasma renin
concentration.5
Valsartan works by antagonizing Ang II at the AT1
receptor subtype. Four Ang II receptors have been
identified: AT1-4. However, only AT, and AT2 receptors
have been implicated in RAAS involvement in hyper-
tension. Valsartan has a 20,000-fold greater affinity for

PharmaNote


the AT1 receptor subtype.6 Ang II is a potent vasocon-
strictor and stimulates the synthesis and release of
aldosterone. Valsartan blocks the vasoconstrictor and
aldosterone-secreting effects of Ang II by selectively
blocking the AT1 receptors in the vascular smooth
muscle and adrenal gland. Blocking the AT1 receptors
leads to a 2-3 fold increase in the circulating levels of
renin and Ang II. The BP lowering effects are produced
by antagonizing ATl-induced vasoconstriction, aldos-
terone release, catecholamine release, arginine vaso-
pressin release, water intake, and hypertonic re-
sponses. In addition, shifting Ang II action to the AT2
receptor causes vasodilation.
The combination of aliskiren and valsartan blocks
the RAAS at different sites leading to a complimentary
mechanism in inhibiting the RAAS.5
The duration of action of both aliskiren and valsar-
tan are about 24 hours, thus allowing for once daily
dosing of aliskiren/valsartan. The rate and extent of
absorption of each drug when administered in combi-
nation are the same as when administered as individ-
ual agents. Aliskiren inhibits the RAAS in a dose-
dependent manner with the maximum reductions in
Ang II observed within 1 hour after oral administra-
tion. The maximum antihypertensive effect of aliskiren
occurs within 2 weeks of initiation. Absorption of al-
iskiren is poor and is further decreased by concomi-
tant administration with high fat meals. When taken
with food, the mean AUC is decreased by 76% and the
Cmax is decreased by 88%.6 Aliskiren is metabolized
via CYP3A4 enzymes, though the extent of metabolism
is unknown. One-fourth of the absorbed dose is ex-
creted unchanged in the urine, and it is excreted un-
changed in the feces via biliary excretion.
Valsartan has an onset of action of 2 hours and is
rapidly absorbed regardless of concomitant food in-
take. Valsartan is metabolized to valeryl-4-hydroxy
valsartan, the primary metabolite, which is inactive.
The enzyme responsible for the metabolism of valsar-
tan is unknown. It is also excreted as unchanged drug
in the urine (13%) and feces (83%).4,5,6 The pharma-
cokinetic (PK) profiles of aliskiren and valsartan are
presented in Table 1.

PHARMACOLOGY & PHARMACOKINETICS

Renal Impairment
Rate and extent of exposure (AUC and Cmax) of
aliskiren in patients with renal impairment did not
show a consistent correlation with the severity of re-
nal impairment No adjustment is needed in the start-
ing dose in these patients. Similarly, there is no appar-
ent correlation between renal function (measured by
creatinine clearance [CrCl]) and exposure (measured


Volume 25, Issue 9 June 2010







Table 1. Pharmacokinetics of aliskiren and valsartan.56


ALISKIREN


Onset of action
Duration of action
Time to peak
Bioavailability
Absorption
Metabolism

Excretion

Half-life elimination


Maximum antihypertensive effect: Within 2 weeks
Accumulation half-life: 24 hours
1-3 hours (plasma)
2.5%
Poor, decreased by high fat meals
Via CYP3A4; extent of metabolism unknown

Urine: 25% of absorbed dose unchanged
Feces: unchanged via biliary excretion


16 32 hours


~2 hours
24 hours
2-4 hours (serum)


Rapidly absorbed
To inactive metabolite

Feces (83%) & urine (13%) as unchanged drug


~6 hours


by AUC) to valsartan. In patients with mild-to-
moderate renal impairment, no dosage adjustment is
necessary. No studies have been performed in patients
with severe renal impairment (CrCl <10 mL/min).
Hemodialysis does not remove valsartan from the
plasma.4

Hepatic Impairment
Aliskiren PKs were not significantly affected in pa-
tients with mild-to-moderate liver disease. Patients
with mild-to-moderate chronic liver disease have
twice the exposure (measured by AUC values) to val-
sartan compared to healthy volunteers; however, no
dosage adjustment is needed in these patients.4

Geriatric Populations
PKs of aliskiren and valsartan were studied in pa-
tients > 65 years. Exposure of aliskiren (measured by
AUC) is increased in this population, but does not war-
rant adjustment of the starting dose. The exposure of
valsartan is 70% higher and the half-life is 35%
longer, but no dosage adjustment is necessary.4

CLINICAL TRIALS

Efficacy & Safety Studies
Oparil, et al. conducted an 8 week, randomized,


double-blind, parallel-group, placebo controlled, dose
escalation study to assess the BP lowering effects of
dual renin system intervention with the combination
of aliskiren and valsartan at their maximum doses.
The study was conducted in men and women
(n=1792) aged 18 years or older with stage 1-2 essen-
tial HTN (mean sitting diastolic blood pressure
(MSDBP) of 95 to <110 mmHg). The primary outcome
was change in MSDBP from baseline to week 8. One of
the secondary outcomes included changes from base-
line to week 8 in mean sitting systolic blood pressure
(MSSBP).
Patients were randomly assigned to receive once
daily aliskiren 150 mg, valsartan 160 mg, combination
aliskiren/valsartan 150/160mg, or placebo for 4
weeks. After 4 weeks, all patients underwent a forced
titration to double the dose of their treatment for an-
other 4 weeks. Sitting BP was assessed at baseline and
at weeks 2, 4, 6, and 8 (or at discontinuation) of the
double-blind period.
At week 8, treatment with the combination of al-
iskiren and valsartan reduced MSSBP and MSSDBP
from baseline significantly more than did aliskiren
(p<0.0001) or valsartan (p<0.0001) monotherapy, or
placebo (p<0.0001) (Table 2 & 3).
Monotherapy with aliskiren or valsartan provided
significantly greater reductions in MSDBP and MSSBP


Table 2. Least Squares Mean Changes in Mean Sitting Diastolic and Systolic Blood Pressure at Week 8.8

Placebo Aliskiren 300 mg Valsartan 320 mg Aliskiren/Valsartan 300/320 mg
(n=459) (n=437) (n=455) (n=446)

A MSDBP, mmHg -4.1 -9.0* -9.7* -12.2'

A MSSBP, mmHg -4.6 -13.0* -12.8* -17.2t
*p<0.0001 vs. placebo. tp<0.0001 vs. placebo, aliskiren, and valsartan.
LSM = least squares mean; MSDBP = mean sitting diastolic blood pressure; MSSBP = mean sitting systolic blood pressure

Dhl N V l 2 I n I J 201
ri---i------I-----------


VALSARTAN


I JUIeC H l.J


rm ii iIC ULC


oume ssue







Table 3. Summary of Clinical Trials Involving Aliskiren and Valsartan.


STUDY
Oparil, et al.8
(2007)

n = 1797


Chrysant, et al.9
(2008)

n = 601


Yarows, et al.10
(2008)

n = 581



Pool, et al."
(2007)

n = 1123



Geiger, et al.12
(2008)

n = 641


DESIGN
. 8-week R, DB, PG, PCB-controlled,
dose escalation study
. Primary outcome: A in MSDBP from
baseline to week 8 endpoint


. 54-week, OL, MC
. Primary outcome: assess the safety
of combo therapy; K' elevations were
a predefined safety outcome


. Post-hoc analysis of an 8-week, R,
DB, PCB-controlled, MC study in pts
with stage 2 HTN
. Primary outcome: A in MSDBP from
BL to week 8 endpoint


. MC, R, PCB-controlled, 8-week trial
. Primary outcome: A from BL in
MSDBP at endpoint




. R, DB, PG, active-control, dose-
escalation study
. Primary efficacy variable: A in DBP
from BL to week 8
. Primary objective: comparison at
week 8 for the triple combination of
. A/V/HCTZ 300/320/25 mg with both
double combinations of A/HCTZ
300/25 mg and V/HCTZ 320/25 mg


DOSE
A 150 mg; V 160 mg; A/V 150/160 mg; or
PCB x 4 weeks, followed by forced titration
to A 300 mg; V 320 mg; A/V 300/320 mg or
PCB x 4 weeks


. A/V 150/160 mg x 2 weeks, followed by
forced titration to A/V 300/320 mg x 52
weeks
. After 2 months from start of A/V 300/320
mg, HCTZ 12.5 mg titratedd to 25 mg) was
permitted in pts w/ MSSBP 140 mmHg
and/or MSDBP 90 mmHg at 2 consecu-
tive visits

A 150 mg; V 160 mg; A/V 150/160 mg; or
PCB x 4 weeks, followed by 4 weeks at dou-
ble the initial dose




3-4 week SB PCB run-in, then R in a modified
factorial study design to receive once-daily,
DB oral treatment with PCB, A (75, 150, or
300 mg), V (80, 160, or 320 mg), A/V combo
(150/160 and 300/320 mg), or V/HCTZ
(160/12.5 mg)

Following 4-week, SB HCTZ (12.5 mg for 1
week; 25 mg for 3 weeks), qualified pts (DBP
_ 95 mmHg) were R to the equal ratio to
receive
A/V/HCTZ 150/160/25 mg x 4 weeks,
300/320/25 mg x another 4 weeks; A/HCTZ
150/25 mg x 4 weeks, 300/25 mg x another 4
weeks; V/HCTZ 160/25 mg x 4 weeks, 320/25
mg x another 4 weeks; or HCTZ 25 mg x 8
weeks


RESULTS
At week 8 endpoint combo A/V 300/320 mg lowered
MSDBP from BL by 12.2 mmHg significantly more than
monotherapy (A 300 mg, 9.0 mm Hg decrease, P<0.0001; V
320 mg, 9.7 mm Hg decrease, P<0.0001), or with PCB (4.1
mm Hg decrease, P<0.0001)

. 66.2% of patients reported at least one AE during the long
-term combo treatment
. The most freq. reported AEs were: headache, dizziness,
and nasopharyngitis
. 12 pts (out of 588; 2%) experienced K+ levels > 5.5 mmol/L
at any post-BL visit
. Overall, 4 pts (0.7%) were recorded with an AE of hyper-
kalemia

SA/V 300/320 mg reduced BP from BL by 22.5/11.4 mmHg
at week-8 endpoint
. BP reduction with combo were sig. greater than with A
300 mg (17.3/8.9 mmHg, P<0.05), V 320 mg (15.5/8.3
mmHg, P<0.01), or with PCB (7.9/3.7 mmHg, P<0.0001).


. Aliskiren monotherapy provides antihypertensive efficacy
and PCB-like tolerability in pts with HTN
. A/V combo may provide additive BP-lowering effects with
maintained tolerability



. A/V/HCTZ produced statistically significant additional re-
ductions in SBP/DBP when compared with other groups
(P<.001 vs. A/HCTZ; P<.01 vs. V/HCTZ; P<.001 vs. HCTZ)
. At week 8, reductions in SBP/DBP in the treatment groups
were 22/16 (A/V/HCTZ), 15/11 (A/HCTZ), 18/14 (V/HCTZ),
or 6/6 (HCTZ alone) mmHg
. A/V/HCTZ produced significantly better BP control (SBP/
DBP <140/90 mm Hg; 66.7%) compared with other treat-
ment groups (20.5%-48.7%, P<.001)


A = change; A = aliskiren; AE = adverse event; A/V = aliskiren/valsartan; BL = baseline; BP = blood pressure; DB = double blind; DBP = diastolic blood pressure; HCTZ = hydrochlorothiazide; HTN
= hypertension; MC = multicenter; MSDBP/SBP = mean sitting diastolic blood pressure/systolic blood pressure; OL = open-label; PCB = placebo; PG = parallel group; pts = patients; R = random-
ized; SB = single-blind; SBP = systolic blood pressure; V = valsartan







than did placebo at week 8 endpoint (all p<0.0001).
Combination therapy provided additional reductions
of 4.2/3.2 mmHg over aliskiren monotherapy and
4.4/2.5 mmHg over valsartan monotherapy.
Adverse events occurred at similar frequencies in
both monotherapy groups, the combination group,
and placebo. The most common adverse events in the
aliskiren, valsartan, and the combined aliskiren/
valsartan treatment groups were headache, naso-
pharyngitis, and dizziness (Table 4).
The proportion of patients with a serum K+ con-
centration over 5.5 mmol/L at any point after baseline
was higher in the combination group (4.5%) than ei-
ther monotherapy group (aliskiren 4%; valsartan 4%)
or placebo group (4%). A clinically relevant increase
in serum creatinine (> 2.0 mg/dL) was seen in four
patients receiving combination treatment, two pa-
tients receiving valsartan, and one patient receiving
aliskiren. The increases were not associated with a
notable increase in the blood urea nitrogen. Neither of
the serum K+ nor creatinine concentration increases


was associated with AEs or led to patient discontinua-
tion from the study.8
Chrysant et al. conducted a six month interim
analysis on the long-term safety, tolerability, and effi-
cacy of aliskiren used in combination with valsartan
for HTN. In this 54-week, open-label, multicenter
study, 601 patients with HTN received a combination
of aliskiren/valsartan 150/160 mg for 2 weeks fol-
lowed by forced titration to aliskiren/valsartan
300/320 mg once daily. The addition of optional hy-
drochlorothiazide (HCTZ) was allowed from week 8
for inadequate BP control (_ 140/90 mmHg). The pri-
mary objective was to assess the safety of combination
therapy; potassium elevations were a predefined
safety outcome.
At the 6 month cut-off date, 512 patients (85.2%)
were still on study treatment, and 192 patients
(31.9%) had received at least one dose of HCTZ during
this period. Combination therapy (aliskiren/valsartan
300/320 mg with or without HCTZ) was generally
well tolerated, and the most commonly reported AEs


Table 4. Safety and Tolerability of Study Treatments.8
Placebo* Aliskiren Valsartan Aliskiren/Valsartan
(n=458) (n=437) (n=455) (n=446)
AE
Any AE 168 (37%) 149 (34%) 167 (37%) 156 (35%)
Any Serious AE 5 (1%) 8 (2%) 6 (1%) 3 (0.7%)
Discontinuation due to AE 10 (2%) 11 (3%) 11 (2%) 7 (2%)
Most Frequent AEs (> 2% in Any Group)
Headache 41(9%) 14 (3%) 25 (5%) 19 (4%)
Nasopharyngitis 9 (2%) 16 (4%) 20 (4%) 12 (3%)
Dizziness 9 (2%) 8 (2%) 11(2%) 8 (2%)
Fatigue 11(2%) 6 (1%) 7 (2%) 7 (2%)
Nausea 41(9%) 14 (3%) 25 (5%) 19 (4%)
Laboratory Abnormalities
Serum Potassiumt
< 3.5 mmol/L 17 (4%) 11(3%) 20 (4%) 12 (3%)
> 5.5 mmol/L* 12 (3%) 7 (2%) 7 (2%) 18 (4%)
> 6.0 mmol/L 6 (1%) 4 (1%) 5 (1%) 2 (0.5%)
Creatinine
> 176.8 pmol/L (2.0 mg/dL) 0 1 (0.2%) 2 (0.4%) 4 (0.9%)
Blood Urea Nitrogen
> 14.3 mmol/L 0 1 (0.2%) 1 (0.2%) 0
Data are n (%); AE = adverse event
*One randomized patient did not take double-blind medication before discontinuation.
tn=445 for placebo, 416 for aliskiren, 443 for valsartan, 424 for aliskiren/valsartan.
SOf the 18 patients with increases in serum potassium >5.5 mmol/L during double-blind treatment, 13 had potassium concentrations within the
normal range at the end of the study without the need for treatment disruption.
n=446 for placebo, 417 for aliskiren, 445 for valsartan, 426 for aliskiren/valsartan.
Pha rma Note Volume 25, Issue 9 I June 2010___________________


Volume 25, Issue 9 1 June 2010


PharmaNote







Table 5. Retail Pricing for a 1 month supply (30 tablets).


Tekturna (aliskiren)


150 mg
300 mg
Diovan (valsartan)
160 mg
320 mg
Valturna (aliskiren/valsartan)
150/160 mg
300/320 mg


$92.02
$119.32


$95.32
$120.15


$90.15
$109.32


$89.99 $94.49
$118.99 -$119.99


$86.99 -$100.99
$107.49 $126.99


$82.99 -93.99
$103.99 -$113.99


Prices were obtained from three community pharmacies in Gainesville, FL.
Valsartan is expected to become available generically in September 2012 when the patent expires


were headache, dizziness, and nasopharyngitis. Serum
potassium elevations > 5.5 mmol/L occurred in 10 pa-
tients receiving aliskiren/valsartan and 2 patients re-
ceiving aliskiren/valsartan/HCTZ. Only one patient
treated with aliskiren/valsartan exhibited potassium
levels > 6.0 mmol/L during this period. Aliskiren/
valsartan combination therapy (with or without HCTZ
add-on) provided mean reductions in MSSBP/DBP
from baseline of 22.3/14.4 mmHg at the 6-month end-
point. Combination therapy (aliskiren/valsartan) pro-
vided effective BP lowering which was maintained
over the 6 month treatment period.9

Stage II Hypertension Subgroup Analysis
Yarows et al. conducted a post-hoc analysis on the
efficacy of aliskiren/valsartan in reducing BP in pa-
tients with stage 2 HTN. This subgroup analysis comes
from the previous study conducted by Oparil, et al.
Aliskiren/valsartan 300/320 mg reduced MSSBP/DBP
from baseline by 22.5/11.4 mmHg after 8 weeks. BP
reductions with combination therapy were signifi-
cantly greater than with aliskiren 300 mg (17.3/8.9
mmHg P<0.05), valsartan 320 mg (15.5/8.3 mmHg
P<0.01), or with placebo (7.9/3.7 mmHg, P<0.0001).
BP control rates (<140/90 mmHg) were also signifi-
cantly higher (P<0.05) with aliskiren/valsartan
300/320 mg (29.8%) compared with either aliskiren
300 mg (19.0%) or valsartan 320 mg (13.8%) mono-
therapy, or placebo (8.9%). All treatments were gener-
ally well tolerated. The authors concluded that al-
iskiren/valsartan combination therapy is an appropri-
ate option for management of BP in patients with
stage 2 HTN.10 See Table 3 for a summary of the clini-
cal trials involving aliskiren and valsartan.


DRUG INTERACTIONS

Aliskiren is a substrate of P-glycoprotein (Pgp);
concurrent use of Pgp inhibitors may increase absorp-
tion.5 Cyclosporine is a highly potent Pgp inhibitor.
Concomitant administration of cyclosporine and al-
iskiren results in a 2.5-fold increase in Cmax and 5-
fold increase in AUC of aliskiren; therefore, it is not
recommended.
Concomitant use of K+ sparing diuretics
(spironolactone, triamterene, amiloride), K+ supple-
ments, or salt substitutes containing K+ with valsartan
may lead to increases in serum K+. In heart failure pa-
tients, valsartan can lead to increases in serum
creatinine.4

DOSING & ADMINISTRATION

The recommended doses of aliskiren/valsartan
are 150/160 mg daily or 300/320 mg daily. For pa-
tients initiating therapy with aliskiren/valsartan, the
recommended starting dose is 150/160 mg daily. The
dose can be titrated up to 300/320 mg once daily after
2-4 weeks of therapy.
Patients who are currently receiving either al-
iskiren or valsartan alone may be switched to combi-
nation therapy if their BP is not adequately controlled
on monotherapy. The recommended starting dose is
150/160 mg daily. Similarly, patients receiving al-
iskiren and valsartan as separate pills may be
switched to single tablet aliskiren/valsartan contain-
ing the same component doses for convenience.
Aliskiren/valsartan can be administered with or
without food and should be administered at the same
time each day.4


-


AVERAGE


RANGE


Volume 25, Issue 9 1 June 2010


PharmaNote







COST


The average retail prices, for a one month supply
(30 tablets), of aliskiren, valsartan, and aliskiren/
valsartan are shown in Table 5. The individual com-
ponents of Valturna, aliskiren and valsartan, are not
currently available generically. However, the patent
on valsartan is set to expire in September 2012, mak-
ing generic valsartan available in approximately 2-2.5
years. Aliskiren is marketed as Tekturna, and valsar-
tan is marketed as Diovan.


SUMMARY


Aliskiren/valsartan, a combination direct renin
inhibitor and angiotensin receptor blocker, is one of
the newest treatment options for hypertension. It is a
therapeutic, cost-effective medication, compared to its
individual components, for patients initiated on dual
therapy or whose hypertension is not controlled with
a single agent Combination therapy is more effective
in reducing blood pressure than monotherapy with
either medication. It is dosed once daily with few ad-
verse reactions. However, the efficacy of dual RAAS
inhibition has not been shown to be superior com-
pared to a single RAAS inhibitor plus another anti-
hypertensive agent (i.e. diuretic, CCB, etc.). Results of
the recent ONTARGET trial suggest little additional
advantage from the combination of an ARB and an ACE
-I over either agent alone when used in patients who
have vascular disease or high-risk diabetes, but do not
have heart failure.12 Furthermore, this combination
can be associated with an increased risk for AEs.12 Un-
til more data become available with dual RAAS inhibi-
tion using direct renin inhibitors, potential candidates
for aliskiren/valsartan should be carefully selected to
minimize the potential for adverse effects.




REFERENCES

1. Institute of Medicine. "A Population-Based Policy and
Systems Change Approach to Prevent and Control
Hypertension." 2010.
2. Chobanian A et al. 7th report of the Joint National
Committee on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure. Hypertension
2003;42(6):1206-52.
3. Sanoski C. Aliskiren: An oral direct renin inhibitor for
the treatment of hypertension. 21 Aug 2009. Med-
scape.
4. FDA. "Label Information: Valturna". Aug 2009.
http://www.accessdata.fda.gov/drugsatfda_docs/


label/2009/0222171bl.pdf
5. Lexi-Comp OnlineTM, Lexi-Drugs OnlineTM, Hudson,
Ohio: Lexi-Comp, Inc.; 2009; February 05, 2010.
6. Clinical Pharmacology [database online]. Tampa, FL:
Gold Standard, Inc.; 2006. http://cp.gsm.com.
7. Anticipated availability of first-time generics. Phar-
macist's Letter/Prescriber's Letter 2009; 25
(10):251011.
8. Oparil S et al. Efficacy and safety of combined use of
aliskiren and valsartan in patients with hyperten-
sion: A randomized, double-blind trial. Lancet
2007;370:221-9.
9. Chrysant, et al. Long-term safety, tolerability and effi-
cacy of aliskiren in combination with valsartan in
patients with hypertension: a 6-month interim analy-
sis. Curr Med Res Opin 2008;24(4):1039-47.
10. Yarows, et al. Aliskiren and valsartan in stage 2 hy-
pertension: subgroup analysis of a randomized, dou-
ble-blind study. Adv Ther 2008; 25(12):1288-302.
11. Pool J et al. Aliskiren, an orally effective renin inhibi-
tor, provides antihypertensive efficacy alone and in
combination with valsartan. Am J Hypertens
2007;20:11-20.
12. Geiger H et al. Combination therapy with various
combinations of aliskiren, valsartan, and hydro-
chlorothiazide in hypertensive patients not ade-
quately responsive to hydrochlorothiazide alone. J
Clin Hypertens (Greenwich) 2009;11(6):324-32.
13. Yusuf S, et al. Telmisartan, ramipril, or both in pa-
tients at high risk for vascular events. NEJM
2008;358:1547-59.


r-


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


John G. Gums Editor
PharmD, FCCP

R. Whit Curry, MD Associate Editor

Steven M. Smith Assistant Editor
PharmD

1- 2yv~w ww w


Volume 25, Issue 9 1 June 2010


PharmaNote




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