Title: PharmaNote
ALL VOLUMES CITATION PDF VIEWER THUMBNAILS PAGE IMAGE ZOOMABLE
Full Citation
STANDARD VIEW MARC VIEW
Permanent Link: http://ufdc.ufl.edu/UF00087345/00054
 Material Information
Title: PharmaNote
Series Title: PharmaNote
Physical Description: Serial
Creator: University of Florida College of Pharmacy
Publisher: College of Pharmacy, University of Florida
Publication Date: July 2007
 Record Information
Bibliographic ID: UF00087345
Volume ID: VID00054
Source Institution: University of Florida
Rights Management: All rights reserved by the source institution and holding location.

Downloads

This item has the following downloads:

July2007 ( PDF )


Full Text
















TOLVAPTAN: A NEW APPROACH
TO THE MANAGEMENT OF EU-
VOLEMIC AND HYPERVOLEMIC
HYPONATREMIA

Olamide Oshikoya, Pharm. D Candidate


Hyponatremia is the most common electro-
lyte disorder in the United States, occurring in ap-
proximately 15 to 20% of hospitalized patients.1 Hy-
ponatremia is classified as hypovolemic, euvolemic
or hypervolemic, depending on the amount of fluid
and solute. Hyponatremia is associated with morbid-
ity and mortality among patients with heart and liver
disease, neurological disorders, as well as syndrome
of inappropriate anti-diuretic hormone secretion
2
(SIADH).2 This is significant because correction of
the electrolyte imbalance in situations, such as
chronic heart failure (CHF), liver cirrhosis and
SIADH, can have drastic implications in the im-
provement and management of these disease states.
Chronic heart failure, liver cirrhosis, and
SIADH are examples of conditions that are charac-
terized by abnormal water retention mediated by ar-
ginine vasopressin (AVP) release inappropriate to
plasma tonicity.3 AVP produces its anti-diuretic ef-
fect on the kidneys through interactions with aq-
uaporin 2 channels.4 Systemic blood volume is an
important non-osmotic trigger for AVP secretion.4
Other non-osmotic triggers for AVP release include
nausea and hypoglycemia.4 Osmotic stimuli for AVP
release occur through osmoreceptor detection of
blood osmolality (Figure 1). Subsequently, low
plasma osmolality leads to the release of AVP, while
high plasma osmolality inhibits AVP secretion.4 An


osmotic stimulus for AVP release that may have sig-
nificant implications in CHF is atrial natriuretic pep-
tide (ANP). ANP is released upon atrial stretch re-
ceptor activation which occurs during periods of vol-
ume expansion. High levels of ANP have been ob-
served in hyponatremic patients and may contribute
to hyponatremia by increasing natriuresis and solute
depletion.5
Vasopressin mediates its effects through in-
teractions with several receptors that have multiple
actions throughout the body (Table 1). There are 3
receptor subtypes, VIA, ViB, and V2, which differ
based on localization and signal transduction path-
ways. AVP binds to VIA receptors on vascular
smooth muscle, leading to peripheral vasoconstric-
tion, an increase of intracellular calcium within myo-
cytes, and direct myocardial muscle stimulation.6
AVP activity at V1B receptors occurs at the pituitary
gland and mediates the release of adrenocorticotropic
hormone (ACTH).7 V2 receptors in the kidney are the
primary receptors responsible for the anti-diuretic
effects of vasopressin.
Tolvaptan (t61 vip' tin) is an oral, non-
peptide V2 receptor antagonist manufactured by
Otsuka Pharmaceutical Company. Tolvaptan is cur-
rently being studied for use in euvolemic and hyper-


mm


SPharmaNote


VOLUME 22, ISSUE 10 JULY 2007


INSIDE THIS ISSUE:
TOLVAPTAN: A NEW APPROACH TO THE
MANAGEMENT OF EUVOLEMIC AND
HYPERVOLEMIC HYPONATREMIA


Volume 22, Issue 10 July 2007


PharmaNote







Figure 1. Process of water regulation by vasopressin


Vascular smooth muscle + Collecting duct

Vasoconstriction receplois receplor


+ Water
Re-absorption


Osmoreceptors residing in the anteroventral third ventricle region of the hypothalamus detect increased serum osmolality thereby
stimulating the production of AVP. Baroreceptors located in the left atrium, carotid sinus, and aortic arch detect arterial underfilling
which stimulate neurons in the SON and PVN to produce AVP (the atrial receptors are mediated by the vagus nerve rather than
blood pressure). The neurons of the SON and PVN project into the posterior pituitary gland where AVP is initially stored and then
released into the circulation. Via receptors located in the vascular smooth muscle sense increased levels of AVP and cause vasocon-
striction. AVP also stimulates V2 receptors located in the collecting duct of the kidney which cause free water absorption.


volemic hyponatremia associated with CHF, cirrho-
sis, or SIADH. Ultimately, tolvaptan increases ex-
cretion of free water resulting in serum sodium con-
centration increases.2 Tolvaptan is different from its
AVP receptor antagonist predecessor, conivaptan
(Travisol), in that it is selective for V2 receptors and
is able to be given orally. This article will discuss the
clinical pharmacology, efficacy and tolerability of
tolvaptan.


Clinical Pharmacology
AVP receptor antagonism provides a promis-
ing mechanism for a new class of drugs designed to
manage hyponatremic disorders. This class of drugs
increases serum sodium concentrations and promotes
aquaresis with good tolerability.8 Tolvaptan exerts its
effects through V2 receptors of the distal nephron. V2
receptors are coupled to aquaporin channels in the
apical membrane of the renal collecting ducts. These


Table 1. Vasopressin receptor location and function

Receptor Localization Function

Vasoconstriction,
VIA Vascular smooth muscle Vaocotrictio,
myocardial hypertrophy

V1B Anterior pituitary ACTH release



Basolateral membrane of collecting tubule Insertion of AQP2 water channels into apical
membrane, induction of AQP2 synthesis
V2 Vascular endothelium and vascular smooth
muscle Vasodilation



Termed V3 in some references ACTH, adrenocorticotropin hormone; AQP2, aquaporin-2 Adapted from Janicic N, et al.'

PharmaNote 10 Volume 22, Issue 10 July 2007


[.


_1







receptors are integral to maintain plasma osmolality
within the normal range. As expected from this class
of drugs, the primary pharmacodynamic effect of V2
antagonism is excretion of free water.

Clinical Evidence
Tolvaptan in CHF, cirrhosis and SIADH
In the Study of Ascending Levels of Tolvap-
tan in Hyponatremia 1 and 2 (SALT 1 and SALT 2)2,
patients with serum sodium concentrations < 135
mmol/L were randomly assigned to tolvaptan or pla-
cebo for 30 days. The study was double-blinded with
15 mg of tolvaptan administered orally with dose
adjustments to 30 mg or 60 mg as needed. The mean
age was 62 years, 42% of the patients were women,
and the 2 groups were roughly equal at 225 and 223
subjects for tolvaptan and placebo, respectively. The
source of hyponatremia could be linked to CHF in
31% of patients, cirrhosis in 27% of patients and
SIADH or other causes in 42% of patients. Mean
baseline serum sodium concentrations in the two
groups was 129 mmol/L. Serum sodium levels were
measured on days 4 and 30, revealing an increase in
serum sodium of 4 mmol/L and 6 mmol/L, on re-
spective days, in the tolvaptan treated group. The
placebo treated group showed no increase in serum
sodium at day 4 and an increase of 2 mmol/L at day
30 (p<0.001). Results further showed that in the tol-
vaptan group, > 40% of patients had a normal serum
sodium by day 4 and approximately 55% of patients
by day 30. The placebo treated group had approxi-
mately 10% of patients reach normal serum sodium
levels by day 4 and 25% by day 30 (p<0.001).2


Figure 2. Changes in body weight
0.8
0.6
S0.4
-c 0.2 -


S-0.2
0 0

." -0.2
-0.4
I -0.6
-0.8
-1
-1 9


The most prevalent adverse effects were dry
mouth and thirst. There were 14 deaths in the tolvap-
tan group and 13 deaths in the placebo group during
a mean follow-up of 37 days. The authors concluded
that vasopressin antagonists can correct hyponatre-
mia, but the effect on mortality should still be ex-
plored.2

Tolvaptan in CHF NYHA class II and III
Gheorghiade et al.9 studied the efficacy of
tolvaptan in 254 patients with CHF NYHA class II or
III, who were not on fluid restriction. Patients were
maintained on stable doses of furosemide and ran-
domized to receive 30, 45, or 60 mg tolvaptan or pla-
cebo once daily for 25 days. After 24 hours, the tol-
vaptan treated patients lost 0.8 kg on average versus
the placebo group who gained 0.32 kg. (Figure 2)
The weight loss was similar in all dosage groups and
continued with no added weight loss over the re-
mainder of the study period. At the conclusion of the
25 day study period, tolvaptan was shown to have
significantly increased urine output, reduce body
weight, and improve clinical signs and symptoms of
heart failure. Additionally, the tolvaptan treated
group demonstrated normalization of serum sodium
levels and reduction of edema, whereas the placebo
group did not. Hypernatremia was documented in 5,
6, 11, and 13% of patients in the placebo, tolvaptan
30 mg, 45 mg, and 60 mg groups. Polyuria, thirst,
and dry mouth were the most common adverse ef-
fects. The authors concluded that tolvaptan provided
a moderate effect on weight loss and demonstrated a
normalization of serum sodium levels without sig-


-*- Placebo (n=62)

--- Tolvaptan 30 mg qd
(n=64)
- Tolvaptan 45 mg qd
(n=62)
- Tolvaptan 60 mg qd
(n=61)


Significant (P=0.001) decreases in body weight were observed primarily on the first day of treatment with all three doses of tolvap-
tan compared with placebo. These reductions persisted throughout the 25 days of the study. Adapted from ref. Gheorghiade et al.9
Pharma~~~~ot 1 Voue2,Ise1-uy20


Volume 22, Issue 10 July 2007


PharmaNote







nificant hypematremia.9


Tolvaptan in CHF exacerbation
In the Acute and Chronic Therapeutic Impact
of a Vasopressin Antagonist in Congestive Heart
Failure trial (ACTIV in CHF), 319 patients from
multiple centers across the United States were ran-
domized to receive tolvaptan at doses of 30, 60, or
90 mg per day or placebo for 60 days. The patients
had ejection fractions < 40% and were hospitalized
for acute CHF exacerbation. The primary endpoint
was in-hospital weight loss at 24 hours. The tolvap-
tan treated group demonstrated greater weight loss
than the placebo group: -1.80 (-3.85 to -0.50),
-2.10 (-3.10 to -0.85), -2.05 (-2.80 to -0.60), and
-0.60 (-1.60 to 0.00) kg for the groups receiving tol-
vaptan 30, 60, and 90 mg, and placebo (p=.002, .002,
and .009 for the 3 tolvaptan groups compared with
the placebo group) Additional secondary endpoints
were worsening heart failure or unexpected hospital
visits for CHF exacerbations over the 60 day period.
These endpoints were not significantly different.10

Tolvaptan versus fluid restriction
Fluid restriction has served as a fundamental
strategy in the correction of hyponatremia. In a ran-
domized, double-blind study by Gheorghiade et al.11,
treatment with tolvaptan was compared to fluid re-
striction when attempting to achieve normal serum
sodium concentrations, defined as concentrations
>135 mmol/L or > 10% increase from baseline. The
treatment group received tolvaptan alone at 10 mg/
day with increases to 60 mg/day as needed, whereas
the fluid restriction group did not consume more than
1,200 ml/day in addition to placebo. Treatment con-
tinued for 27 days with a total of 65 days of follow
up. At the last in-patient visit, the tolvaptan group
demonstrated an increase in serum sodium of 5.7
mmol/L compared to 1.0 mmol/L in the fluid restric-
tion group (p=0.006). Tolvaptan appeared to be more
effective than fluid restriction in the normalization of
serum sodium. Adverse effects were similar in both
groups."

Tolvaptan and cardiovascular mortality
In one of the more anticipated studies to in-
clude tolvaptan, Konstam et al.12 investigated the
mortality benefits in The Efficacy of Vasopressin
Antagonism in Heart Failure Outcome Study with
Tolvaptan (EVEREST). The trial consisted of 4,133


patients who were randomized to tolvaptan 30 mg
daily or placebo within 48 hours of hospital admis-
sion, for a minimum of 60 days in addition to stan-
dard therapy. The primary endpoints were all-cause
mortality (superiority and noninferiority) and cardio-
vascular death or hospitalization for heart failure
(superiority only). Data was collected for 28 months
with a median follow-up of 9.9 months. During the
follow-up period, 537 patients (25.9%) in the tolvap-
tan treated group and 543 patients (26.3%) in the pla-
cebo group died (HR 0.98; 95% confidence interval
[CI], 0.87-1.11; p=.68). The rate of cardiovascular
death or hospitalization for heart failure occurred in
871 (42%) patients in the tolvaptan group and 829
(40.2%) patients in the placebo group (HR 1.04; 95%
CI, 0.95-1.14; p=.55). There were also no differ-
ences in the secondary endpoints of cardiovascular
death, cardiovascular hospitalization and worsening
heart failure. However, in the short term, tolvaptan
did provide added body weight reduction and relief
of dyspnea on days 1 and 7 after admission, in lieu of
discharge.13 Adverse effects were similar between
tolvaptan and placebo groups, and no signs of hy-
potension or worsening renal dysfunction were re-
ported.13

Adverse Effects
Tolvaptan was generally well tolerated during
clinical trials. The most common adverse effects
were dry mouth, thirst and polyuria. A summary of
the important adverse effects is included in Table 2.

Cost and Dosing
Tolvaptan is currently not marketed in the
United States and is undergoing phase III clinical
trials. Specifics pertaining to cost and availability are
not available at this time. In two clinical trials for the
treatment of euvolemic and hypervolemic hyponatre-
mia, tolvaptan was initiated at 15 mg by mouth once
daily. The dose can be increased to 30 mg, then 60
mg per day as needed based on serum sodium lev-
els.2 In addition, patients hospitalized with acute de-
compensated heart failure were randomized to re-
ceive 30 mg by mouth daily within 48 hours of ad-
mission for a minimum of 60 days.

Summary
Tolvaptan is a new approach to the manage-
ment of hyponatremia. It provides an effective and
tolerable alternative to the current utilization of fluid


PharmaNote Volume 22, Issue 10 July 2007


Volume 22, Issue 10 July 2007


PharmaNote






Table 2. Summary of adverse events in clinical trials
Adverse event Tolvaptan (%) Placebo (%)
Thirst 14 5
Dry Mouth 13 4
Ascites 6 6
Constipation 7 2
Diarrhea 5 6
Nausea 8 6
Vomiting 3 9
Fatigue 5 5
Peripheral edema 7 7
Weakness 9 5
Urinary tract infections 6 4
Hyperglycemia 5 1
Hyperkalemia 5 5
Dizziness 7 5
Headache 7 7
Urinary frequency 7 3
Hypotension 7 6


retention, hypertonic 3% saline and pharmacological
modalities such as demeclocycline, urea and lithium
which are often associated with poor patient compli-
ance and limited variability.14 The evidence supports
the short term benefits of symptom relief associated
with diuresis; however, reduction in mortality and
CHF-related morbidity have not been elucidated. If
approved, it remains to be seen where tolvaptan will
reside within the armamentarium of strategies em-
ployed to combat CHF. Further research is needed
to uncover the benefits that this class of drugs may
provide.

References
1. Janicic N and Verbalis JG. Evaluation and man-
agement of hypo-osmolality in hospitalized pa-
tients. Endocrinology Metab Clin North Am
2003; 32: 459-81.
2. Schrier RW, Gross P, Gheorghiade M, et al., Tol-
vaptan, a selective oral vasopressin V2-receptor
antagonist, for hyponatremia. N Engl J Med
2006; 355: 2099-112.
3. Greenberg A and Verbalis JG. Vasopressin re-
ceptor antagonists. Kidney International 2006:
69: 2124-30.
4. Cawley M. Hyponatremia: Current treatment
strategies and the role of vasopressin antagonists.
Ann Pharmacother 2007;41:840-50.
5. Siragy HM. Hyponatremia, fluid-electrolyte dis-
orders, and the syndrome of inappropriate antidi-
uretic hormone secretion: diagnosis and treat-


ment options. Endocr Pract 2006; 12: 446-57.
6. Knoers N. Hyperactive vasopressin receptors and
disturbed water homeostasis. N Engl J Med
2005; 352: 1847-50.
7. Thibonnier M, Preston JA, Dulin N, et al. The
human V3 pituitary vasopressin receptor: ligand
binding profile and density-dependent signaling
pathways. Endocrinology 1997; 1: 4109-22.
8. Arai Y, Fujimori A, Sudoh K, Sasamata M.
Vasopressin receptor antagonists: potential indi-
cations and clinical results. Curr Opin Pharmacol
2007; 7: 124-9.
9. Gheorghiade M, Niazi I, Ouyang J, et al. Vaso-
pressin V2 receptor blockade with tolvaptan in
patients with chronic heart failure: results from a
double-blind, randomized trial. Circulation 2003;
107: 2690-6.
10. Gheorghiade M, Gattis WA, O'Connor CM, et al.
Effects of tolvaptan, a vasopressin antagonist, in
patients hospitalized with worsening heart fail-
ure: a randomized controlled trial (ACTIV in
CHF). JAMA 2004; 291:1963-71.
11. Gheorghiade M, Gottlieb SS, Udelson JE, et al.
Vasopressin V2-receptor blockade with tolvaptan
versus fluid restriction in the treatment of hypo-
natremia. Am J Cardiol 2006; 97:1064-7.
12. Konstam MA, Gheorghiade M, Burnett JC, et al.
Effects of oral tolvaptan in patients hospitalized
for worseing heart failure: The EVEREST Out-
come Trial. JAMA 2007; 297: 1319-31
13. Gheorghiade M, Konstam MA, Burnett JC, et al.


Phara~oe Voume22, ssu 10 uly200


Volume 22, Issue 10 July 2007


PharmaNote







Short term clinical effects of tolvaptan, an oral
vasopressin antagonist, in patients hospitalized
for heart failure: The EVEREST Clinical Status
Trials. JAMA 2007; 297: 1332-43.
14. Sanghi P, Uretsky BF, Schwarz ER. Vasopressin
antagonism: a future treatment option in heart
failure. European Heart Journal 2005;26:538-
543.
15. Wong LL, Verbalis JG. Systemic diseases associ-
ated with disorders of water homeostatis. Endo-
crinol Metab Clin North Am 2002; 31: 121-40.


: DRUG UPDATE



Pregbailin (Lyrica )-- I'i:e,, 1/11

In June 2007, pregabalin was the first druu,
Approved by the FDA for the management of fi-
Sbromyalgia. Pregabalin is a structural analogue of
gamma-aminobutyric acid (GABA) that acls
through binding to the U2-6 subunit of calcium
channels. Pregabalin has anxiolytic, analgesic, and 5
Santiepileptic properties. As such, pregabalin is also
indicated for neuropathic pain associated with dia-
Sbetic peripheral neuropathy, post-herpetic neural-
gia, and adjuctive therapy for adults with partial
Sunset seizures. Starting dose for the treatment of4
fibromyalgia is 150 mg daily in divided doses
Target dose is 300 to 450 mg per day in 2 divided
doses. The dose should be adjusted in patients with
k reduced renal function. The most common adverse ,
Effects include dizziness, somnolence, dry mouth,
edema, blurred vision, and weight gain. Pregabalin
is a Schedule V controlled substance.


Budesonide:Formoterol (Symbicort) -
AstraZeneca

Budesonide:formoterol is now available for
, use. Budesonide:formoterol is a combination of a
Scorticosteroid and a long acting beta-2 agonist ad-
Sministered by oral inhalation via metered-dose in-
haler (MDI) approved by the FDA in July 2006.
SHistorically, budesonide (Pulmicort) and for-
Smoterol (Foradil') have been administered as dry
Powder inhalers, but this combination product is
a dministeied as a MlDI Budesomnde foimoterol is
4. /--/-//*/-//-//*/-//*/-//-/**//*--//- /-*//


Indicated for long-term maintenance treatment of
asthma. Depending on asthma severity, the recom-
mended dose is 2 inhalations of Symbicort 80/4.5
S(80 mg of budesonide and 4.5 mcg of formoterol
per inhalation) or Symbicort 160/4.5 (160 mg of
budesonide and 4.5 mcg of formoterol per inhala-
Stion) twice daily. Budesonide:formoterol has not $
Been proven safe and effective in children less than ,
, 12 \eadFs

1
SArmiiod(Irinil (Nu igil ) '( ',phaIl, 1/

Armodafinil is a single isomer of the parent
drug, modafanil (Provigil), that was recently ap-
Sproved by the FDA for treating excessive sleepi-
ness associated with narcolepsy, shift work sleep
disorder (SWSD), or obstructive sleep apnea/
hypopnea syndrome (OSA/HS). Armodafinil is
Classified as a C-IV controlled substance. Armo-
dafinil may increase excitatory glutaminergic trans-
mission in the thalamus and hippocampus, thus
promoting wakefulness. The approved dose is 150
mg or 250 mg daily in the morning for OSA/HS
and narcolepsy; for SWSD, 150 mg 1 hour before
Shift work starts. The most common adverse effects
Sin clinical trials were headache, nausea, dizziness,
Insomnia, and anxiety.




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


John G. Gums Editor
Pharm.D.


R. Whit Curry, M.D. Associate Editor


Shawn Anderson Assistant Editor
Pharm.D.

:. WWK^WS WS^V ^WSW S^KA


PharmaNote Volume 22, Issue 10 July 2007


Volume 22, Issue 10 July 2007


PharmaNote




University of Florida Home Page
© 2004 - 2010 University of Florida George A. Smathers Libraries.
All rights reserved.

Acceptable Use, Copyright, and Disclaimer Statement
Last updated October 10, 2010 - - mvs