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EXFORGE: A NEW
COMBINATION TO TREAT
HYPERTENSION

Rahil Lone, Pharm. D. Candidate


The prevalence of hypertension continues to be
unacceptably high in the United States and Europe,
with about 1 billion individuals affected world-
wide.1'2 Despite the availability of a variety of anti-
hypertensive medications, population-based surveys
indicate that an estimated 40-80% of treated patients
do not achieve their blood pressure (BP) goals3 for
reasons that include noncompliance and inadequate
dosing.4 Inadequately controlled hypertension has
serious consequences, causing and promoting the
progression of cardiovascular, renal and metabolic
disease. However, effective interventions to lower
BP can reduce the risk of cardiovascular events.2
Approximately two-thirds of all patients with hy-
pertension require multi-drug regimens to achieve
recommended BP targets.2 European and US treat-
ment guidelines recommend that therapy be initiated
with a combination of individual agents or fixed-
dose combinations in patients with a BP > 20/10 mm
Hg above goal2 or those at high risk for cardiovascu-
lar complications.5 Use of combination therapy with
> 2 agents having complementary mechanisms of
action such as an angiotensin-converting enzyme
(ACE) inhibitor plus a calcium channel blocker
(CCB), or a diuretic plus an ACE inhibitor or angio-
tensin II-receptor blocker (ARB), is more effective in


lowering BP than either agent alone and leads to
higher response rates versus monotherapy.2,5'6'7 Dual
therapy that blocks both calcium channels and angio-
tensin II type 1 (AT-1) receptors represent a new
therapeutic option.
In June 2007, Novartis Pharmaceuticals received
FDA approval for their new fixed combination prod-
uct, Exforge. The new product is a combination of
previously approved amlodipine and valsartan. The
combination of amlodipine + valsartanis approved
for the treatment of hypertension in patients who do
not respond to monotherapy of amlodipine or valsar-
tan as single agents. This article will review the
pharmacology and pharmacokinetics, clinical trials,
safety profile, drug interactions, dosing and admini-
stration and cost for amlodipine + valsartan.

Pharmacology and Pharmacokinetics
Amlodipine + valsartan contain two anti-
hypertensive medications that are effective in lower-
ing blood pressure. Both amlodipine and valsartan
lower blood pressure by reducing peripheral resis-
tance. Their mechanisms of action, calcium influx
blockade and reduction of angiotensin II vasocon-
striction, are complementary mechanisms.8



INSIDE THIS ISSUE:
El >lmli- :A NEW COMBINATION TO TREAT
HYPERTENSION
AND
MARAVIROC (SI I /1-\ I 14 ): A NOVEL
ANTIRETROVIRAL


mm


SPharmaNote


VOLUME 23, ISSUE 5 FEBRUARY 2008


Volume 23, Issue 5 February 2008


PharmaNote







Amlodipine inhibits the influx of extracellular
calcium across the myocardial and vascular smooth
muscle cell membranes. Serum calcium levels re-
main unchanged. The resultant decrease in intracellu-
lar calcium inhibits contractile processes of the myo-
cardial smooth muscle cells, resulting in dilation of
the coronary and systemic arteries. As with other
calcium-channel blockers of the dihydropyridine
class, amlodipine exerts its effects mainly on arterio-
lar vasculature.9
Valsartan antagonizes angiotensin II at the AT-1
receptor subtype. Valsartan has about a 20,000-fold
greater affinity for the AT-1 subtype than the AT-2
subtype. By selectively blocking the AT-1 receptor
in tissues such as vascular smooth muscle and the
adrenal gland, valsartan blocks the vasoconstrictor
and aldosterone-secreting effects of angiotensin II.
Thus, by blocking the effects of angiotensin II, val-
sartan decreases systemic vascular resistance without
a marked change in heart rate.9 Blockade of the an-
giotensin II receptor inhibits the negative regulatory
feedback of angiotensin II on renin secretion. Circu-
lating levels of both renin and angiotensin II rise 2-
to 3-fold in response to blockade of the AT-1 recep-
tor. The resulting increased plasma renin activity and
angiotensin II circulating levels however, do not ne-
gate the effect of valsartan on blood pressure.8
Concomitant administration of amlodipine with
valsartan has no effect on the bioavailability of either
drug. The rate and extent of absorption of each drug
administered in combination are the same as when
each drug is administered as individual tablets. Am-
lodipine is slowly but almost completely absorbed
after oral administration. Oral bioavailability ranges
from 64-90%. Peak plasma concentrations are
achieved between 6-12 hours post-dose, and maxi-
mum hypotensive effects are correspondingly de-
layed.8'9 Food does not appear to influence these pa-
Table 1. Pharmacokinetics of amlodipine and valsartan.8'9


rameters significantly; however, grapefruit juice may
increase bioavailability by inhibiting cytochrome
P450 enzymes. Like other calcium-channel block-
ers, amlodipine is primarily metabolized by CYP3A4
isoenzymes. The drug is approximately 93% bound
to plasma proteins, but drug interactions secondary
to displacement from binding sites have not been
documented.10 Amlodipine is extensively metabo-
lized to inactive compounds, and 10% of the parent
compound and 60% of the inactive metabolites are
excreted in the urine. The mean terminal half-life of
amlodipine is 35 hours following single dose admini-
stration, which is significantly longer than the other
dihydropyridines currently available.10
Valsartan is rapidly absorbed, with peak plasma con-
centrations occurring 2-4 hours after administra-
tion. Absolute bioavailability for the capsule formu-
lation is roughly 25% (range, 10-35%). Admini-
stration with food decreases the AUC by about 40%;
therapeutic effect is maintained despite the reduction
in bioavailability. AUC and Cmax of valsartan in-
crease linearly within the dosage range of 80-320
mg; however, the antihypertensive dose-response
curve is nonlinear, with proportionally small de-
creases in blood pressure attained with increased
dosage. Approximately 95% of valsartan is bound to
serum proteins, primarily albumin. The primary me-
tabolite of valsartan is valeryl-4-hydroxy valsartan,
which is inactive and accounts for about 9% of the
dose. The enzyme(s) responsible for the metabolism
of valsartan is unknown. Duration of antihyperten-
sive activity is approximately 24 hrs. Valsartan is
excreted primarily in the feces, most likely via the
biliary route. Only 13% of the dose is excreted un-
changed in urine. The elimination half-life of valsar-
tan averages 6 hrs.8'9 A summary of the pharmacoki-
netics of amlodipine and valsartan is presented in
Table 1.


Amlodipine Valsartan
Onset of action 30-50 min 2 weeks (maximal: 4 weeks)
Duration of action 24 hours 24 hours
Absorption (oral) Well absorbed Well absorbed
Distribution (Vd) 21 L/kg 17 L (adults)
Protein binding 93-98% 95%, mainly albumin
Metabolism Hepatic (>90%) to inactive metabolite Unknown pathway to inactive metabolite
Bioavailability 64-90% 25% (10-35%)
Half-life elimination 30-50 hours 6 hours
Time to peak (plasma) 6-12 hours 2-4 hours
Feces (83%) and urine (13%) as un-
Excretion Urine (10% as parent, 60% as metabolite) F and r
changed drug

PharmaNote ^5^ Volume 23, Issue 5 February 2008







Clinical Trials
Two studies were conducted to compare the effi-
cacy of various combinations of amlodipine and val-
sartan administered once daily with their individual
components and placebo in patients with mild to
moderate essential hypertension.11 The studies were
multinational, multi-center, 8-week, randomized,
double-blind, placebo-controlled, parallel-group tri-
als. The primary objective of both studies was to
compare the BP-lowering effects of a once-daily
regimen of various doses of amlodipine and valsartan
with those of their individual components and pla-
cebo in patients with a mean sitting diastolic blood
pressure [MSDBP] > 95 and < 110 mm Hg. A sec-
ondary objective was to evaluate safety and tolerabil-
ity. The primary efficacy variable in both studies
was the change from baseline in MSDBP at study
end in both the combination and monotherapy
groups. Secondary efficacy variables in both studies
included the change from baseline in mean sitting
systolic blood pressure (MSSBP) and response rates
(the proportion of patients achieving an MSDPB <
90 mm Hg or a > 10 mm Hg reduction from base-
line).
In Study 111, 1911 patients were randomized to
receive 1 of 15 treatments: amlodipine 2.5 or 5 mg
once daily, valsartan 40, 80, 160 or 320 mg once
daily, the combination of amlodipine + valsartan
2.5/40, 5/40, 2.5/80, 5/80, 2.5/160, 5/160, 2.5/320 or
5/320 mg once daily or placebo. Global assessment
of MSDBP reduction at study end indicated that both
monotherapies contributed to the overall BP-
lowering effects of combination treatment (p<0.001,
both amlodipine and valsartan). The greatest effects
were observed at the highest dose of combination
therapy, amlodipine 5 mg + valsartan 320 mg. Com-


bination treatments were associated with signifi-
cantly greater reductions in MSDBP at the end of the
study compared with their individual components
and placebo (p<0.05) (Table 2). There was an in-
creased reduction in MSDBP at each combination
dose starting at the lowest strength combination of
amlodipine 2.5 mg + valsartan 40 mg (MSDBP re-
duction of 10.8 mm Hg) to the highest strength com-
bination of amlodipine 5 mg + valsartan 320 mg
(MSDBP reduction of 15.9 mm Hg). Mostly all of
the combination doses were significant vs. placebo,
the same dose of valsartan monotherapy and the
same dose of amlodipine monotherapy, with the
highest reduction at the highest dose combination of
amlodipine 5 mg + valsartan 320 mg which would
justify a dose escalation from a combination of am-
lodipine 2.5 mg + valsartan 40 mg to amlodipine 5
mg + valsartan 320 mg. The MSDBP reduction of
amlodipine 2.5 mg + valsartan 320 mg was not sig-
nificant versus valsartan monotherapy although am-
lodipine 2.5 mg + valsartan 160 mg was significant
versus valsartan monotherapy. However, amlodipine
2.5 mg is not available in combination with valsar-
tan. The highest response rates were observed with
amlodipine 5 mg + valsartan 320 mg (91.3%) and the
lowest rates were observed with placebo (40.9%).
The response rate for amlodipine 5 mg + valsartan
320 mg group was significantly greater than those
for each monotherapy and placebo groups (all com-
parisons, p<0.05) (Table 3).
In Study 211, 1250 patients were randomized to
receive 1 of 6 treatments: amlodipine 10 mg once
daily, valsartan 160 or 320 mg once daily, the combi-
nation of amlodipine + valsartan 10/160 or 10/320
once daily or placebo. Similar to Study 1, global as-
sessment of MSDBP reduction at study end indicated


Table 2. Least squares mean reduction in sitting diastolic blood pressure (DBP) at end of Study 111


Valsartan dose (mg)


Omg

40mg

80mg

160mg

320mg


Amlodipine dose (mg)

Omg 2.5mg 5mg


7.0 (placebo)

10.1*

9.7*
11.0*

13.4*


10.8*

13.4*T
13.3*tT

14.2*"


11.5*

14.6*t

14.5*t
14.2*t

15.9*t


*p<0.05 vs. placebo; p<0.05 versus the same dose ofvalsartan monotherapy; p<0.05 versus the same dose of amlodipine monotherapy.

Pharm~oteVolum 23,Issu 5 Feruar 200


Volume 23, Issue 5 February 2008


PharmaNote







Table 3. Proportions of responders (mean sitting diastolic blood pressure < 90 mm Hg or a > 10 mm Hg reduction from
baseline) at the end of Study 1 and 211


Placebo 49.3

*p<0.05 vs. placebo; p<0.05 versus the same dose of valsartan monotherapy; p 0.05 versus the same dose of amlodipine monotherapy


that both monotherapies contributed to the overall
BP-lowering effects of combination treatment
(p<0.001, both valsartan and amlodipine). Between-
treatment comparisons of MSDBP indicated that
both combination treatments were associated with
significantly greater reductions in MSDBP compared
with their individual components and placebo at
study end (p<0.05) (Table 4). The highest response
rates were observed with amlodipine 10 mg + valsar-
tan 160 mg (88.5%) and the lowest with placebo


(49.3%) (Table 3). The response rates with am-
lodipine 10 mg + valsartan 160 mg and amlodipine
10 mg + valsartan 320 mg were significantly greater
than those with valsartan monotherapy (p<0.05) and
with placebo (p<0.05); however, they did not differ
significantly from the response rate with amlodipine
monotherapy (Table 3).
In Study 2, the response rates for amlodipine 10 mg
+ valsartan 320 mg was actually lower (87.5%) than
amlodipine 10 mg + valsartan 160 mg (88.5%) and


Table 4. Least squares mean reduction in sitting diastolic blood pressure (DBP) at end of Study 211

Amlodipine dose (mg)
Valsartan dose (mg) Omg 10mg

Omg 8.7 (placebo) 15.6*
160mg 13.3* 17.6*t

320mg 13.3* 18.6*t

*p<0.05 vs. placebo; Tp<0.05 versus the same dose of valsartan monotherapy; p<0.05 versus the same dose of amlodipine monotherapy

PharmaNote Volume 23, Issue 5 February 2008


Study 1
Amlodipine 5mg + valsartan 320mg
Amlodipine 5mg + valsartan 160mg
Amlodipine 5mg + valsartan 80mg
Amlodipine 5mg + valsartan 40mg
Amlodipine 2.5mg + valsartan 320mg
Amlodipine 2.5mg + valsartan 160mg
Amlodipine 2.5mg + valsartan 80mg
Amlodipine 2.5mg + valsartan 40mg
Amlodipine 5mg
Amlodipine 2.5mg
Valsartan 320mg
Valsartan 160mg
Valsartan 80mg
Valsartan 40mg
Placebo
Study 2
Amlodipine 10mg + valsartan 320mg
Amlodipine 10mg + valsartan 160mg
Amlodipine 10mg
Valsartan 320mg
Valsartan 160mg


Response Rate, %
91.3*"
81.1*"
84.9*"?
83.7*"?
79.7*"
74.4*"
77.5*"?
57.0*
71.9*
60.3*
73.4*
67.7*
57.7*
59.1*
40.9
Response Rate, %
87.5*?
88.5*?
86.9*
72.0*
74.9*







amlodipine 5 mg + valsartan 320 mg (91.3%, Study
1). However, the response rates were still significant
vs. both placebo and the same dose of valsartan
monotherapy in Study 2. The highest decrease in
MSDBP was seen at the highest dose combination of
amlodipine 10 mg + valsartan 320 mg (18.6 mm
Hg). However, this was not significant versus the
amlodipine 10 mg + valsartan 160 mg. Therefore,
increasing the dose above the combination of am-
lodipine 5 mg + valsartan 320 mg is probably not a
reasonable option.

Safety
Combination therapy of amlodipine + valsartan
was generally well tolerated regardless of age, race
or sex.11 In the combined safety evaluation from
both studies which included 1437 patients in the am-
lodipine + valsartan combination group and 337 pa-
tients in the placebo group, the most common ad-
verse events (AEs), regardless of their relation to
treatment, were peripheral edema (5.4%), headache
(4.3%), nasopharyngitis (4.3%), upper respiratory
tract infection (2.9%) and dizziness (2.1%). Adverse
events associated with low BP, such as syncope, hy-
potension/orthostatic hypotension, postural dizziness
and lightheadedness either did not occur or occurred
at very low frequencies (< 0.3% of patients).
Amlodipine + valsartan is contraindicated in pa-
tients with known hypersensitivity to either of its
components including dihydropyridine hypersensi-
tivity. Amlodipine + valsartan should be used with
caution in patients with coronary artery disease. Pa-
tients have rarely developed documented increased
frequency, duration, and/or severity of angina or
acute myocardial infarction on starting calcium chan-
nel blocker therapy or at the time of dosage increase.
Caution is also warranted with impaired renal func-
tion as valsartan affects the renin-angiotensin-
aldosterone system (RAS) and has caused increases
in serum creatinine. Amlodipine + valsartan should
also be used with caution in patients with hepatic dis-
ease. The clearance of both amlodipine and valsar-
tan is prolonged in these patients. Amlodipine + val-
sartan has caused excessive hypotension in 0.4% of
patients with uncomplicated hypertension during pla-
cebo-controlled trials. Angiotensin receptor blockers
may cause symptomatic hypotension in patients with
an activated renin-angiotensin system such as pa-
tients with hypovolemia and/or salt-depletion receiv-
ing high doses of diuretics. Intravascular volume


depletion increases the risk of symptomatic hypoten-
sion. These conditions should be corrected prior to
starting therapy, or therapy should be started under
close medical supervision. Amlodipine + valsartan
should be used with caution in patients whose renal
function is critically dependent on the activity of the
renin-angiotensin-aldosterone system (RAS) (e.g.,
patients with heart failure) and in patients undergo-
ing surgery or dialysis. Amlodipine + valsartan
should not be used during the second or third trimes-
ter of pregnancy (FDA pregnancy risk category D),
unless the benefits outweigh the potential risks.
Drugs which affect the renin-angiotensin system
have been associated with fetal and neonatal injury
when administered to pregnant women.

Drug Interactions
Amlodipine is a CYP3A4 substrate and its me-
tabolism may theoretically be affected by CYP3A4
inducers (barbiturates, carbamezapine, phenytoin,
etc) or inhibitors (amiodarone, antifungals, ci-
metidine, macrolides, etc). No pharmacokinetic drug
interactions were observed when amlodipine was
given with atorvastatin, cimetidine, digoxin, antac-
ids, sildenafil, or warfarin.9 One study demonstrated
no significant affinity of valsartan for CYP2C9 or
CYP2C19 isoenzymes.12 No pharmacokinetic drug
interactions were observed when valsartan was ad-
ministered concomitantly with amlodipine, atenolol,
cimetidine, digoxin, furosemide, glyburide, hydro-
chlorothiazide, or indomethacin. The concomitant
administration of valsartan and warfarin did not
change the pharmacokinetics of valsartan or the
time-course of the anticoagulant properties of war-
farin.9 Valsartan tends to reverse potassium loss, but
not the serum uric acid rise associated with hydro-
chlorothiazide monotherapy.9

Dosing and Administration
To minimize dose-independent hazards, it is usu-
ally appropriate to begin therapy with amlodipine +
valsartan only after a patient has failed to achieve the
desired antihypertensive effect with monotherapy.
Although, initial combination therapy may be appro-
priate in patients with stage 2 hypertension. A pa-
tient whose blood pressure is not adequately con-
trolled with amlodipine (or another dihydropyridine
CCB) alone or with valsartan (or another ARB)
alone may be switched to combination therapy with
amlodipine + valsartan. The dosage for a patient


PharmaNote Volume 23, Issue 5 February 2008


Volume 23, Issue 5 February 2008


PharmaNote







should first be individualized by dose titration of
both amlodipine and valsartan. The combination
product is available as 5/160 mg, 5/320 mg, 10/160
mg, or 10/320 mg tablets of amlodipine/valsartan.
The dosage of one or both drug components may be
increased after 3-4 weeks depending on the clinical
response. The maximum dosage per day is 10 mg
amlodipine and 320 mg valsartan. Volume and/or
sodium depletion should be corrected prior to ad-
ministration.8 Amlodipine + valsartanmay be ad-
ministered without regard to meals. Patients should
be instructed to either not significantly alter grape-
fruit juice intake or to avoid grapefruit juice, if possi-
ble, while taking this drug.

Cost
Pricing data for Exforge was obtained for a one
month prescription from three community pharma-
cies located in Gainesville, FL. The average
monthly cost (30 tablets) for all strengths was $84.45
(range $79.99-$95.68). This monthly cost is cheaper
than the separate combinations of the two medica-
tions. An average one month prescription cost for
amlodipine (30 tablets) for both strengths is $62.53
(generic; range $53.59-67.39) and $88.22 (as Nor-
vasc; range $80.99-95.68). An average one month
prescription for valsartan (30 tablets) for all strengths
is $75.28 (range $71.88-78.99).

Summary
Exforge (amlodipine + valsartan) is the newest
addition to the anti-hypertensive drug market. It of-
fers adequate BP lowering effects through a combi-
nation of two antihypertensive medications, amlodip-
ine and valsartan, each with their own distinct but
complementary mechanisms of action. The fixed-
dose combination is more effective than monother-
apy and may improve patient compliance by simpli-
fying the drug regimen. Amlodipine + valsartan is
not indicated for initial high blood pressure therapy.
It is a viable option and should be considered for
high blood pressure in patients who have not been
controlled through the use of monotherapy with an
angiotensin receptor blocker or calcium channel
blocker and for patients who have experienced dose-
limiting side effects on either valsartan or amlodipine
monotherapy.

References
1. Hajjar I, Kotchen TA. Trends in prevalence,


PharmaNote


awareness, treatment and control of hypertension
in the United States, 1998-2000. JAMA 2003;
290:199-206.
2. Chobanian AV, Bakris GL, Black HR, et al., for
the Joint National Committee on Prevention, De-
tection, Evaluation, and Treatment of High Blood
Pressure; the National Heart, Lung and Blood
Institute; and the National High Blood Pressure
Education Program Coordinating Committee.
Seventh report of the Joint National Committee
on Prevention, Detection, Evaluation, and Treat-
ment of High Blood Pressure. Hypertension
2003; 42:1206-52.
3. Wolf-Maier K, Cooper RS, Kramer H, et al. Hy-
pertension treatment and control in five European
countries, Canada and the United States. Hyper-
tension 2004; 43:10-7.
4. Kulkarni SP, Alexander KP, Lytle B, et al. Long-
term adherence with cardiovascular drug regi-
mens. Am Heart J 2006; 151: 185-91.
5. European Society of Hypertension European
Society of Cardiology Guidelines Committee.
2003 European Society of Hypertension Euro-
pean Society of Cardiology guidelines for the
management of arterial hypertension. J Hyper-
tens 2003; 21: 1011-53.
6. Sica DA. Rationale for fixed-dose combinations
in the treatment of hypertension: The cycle re-
peats. Drugs 2002; 62: 442-62.
7. Weber MA. Creating a combination antihyper-
tensive regimen: What does the research show? J
Clin Hypertens 2003; 5: 12-20.
8. Exforge (amlodipine and valsartan) [package
insert]. Novartis Pharmaceuticals Corp., East
Hanover, NJ; April 2007.
9. Exforge Drug Monograph. Clinical Pharmacol-
ogy 2007 July. Gold Standard Media.
10. Abernethy DR. The pharmacokinetic profile of
amlodipine. Am Heart J 1989; 118: 1100-3
11. Philipp T, Smith T, Glazer R, et al. Two multi-
center, 8-week, randomized, double-blind, pla-
cebo-controlled, parallel-group studies evaluating
the efficacy and tolerability of amlodipine and
valsartan in combination and as monotherapy in
adult patients with mild to moderate essential hy-
pertension. Clin Ther 2007; 29: 563-80.
12. Brookman LJ, Rolan PE, Benjamin IS, et al.
Pharmacokinetics of valsartan in patients with
liver disease. Clin Pharmacol Ther 1997; 62:272-
8.


Volume 23, Issue 5 February 2008










MARAVIROC (SELZENTRY): A
NOVEL ANTIRETROVIRAL

Daniel Dobrian, Pharm. D. Candidate


HIV/AIDS represents a significant health problem
in the United States. By the end of 2003, approxi-
mately 2 million persons in the United States were
living with HIV/AIDS, an estimated 24-27% of
whom were unaware of their infection.1 The CDC
reports close to 85,000 deaths from AIDS from
2001-2005. Survival has increased for diagnoses
made during 1997-1999 while year-to-year gains in
survival were small during 2000-2004.2 Treatment
options for HIV/AIDS include four classes of antiret-
roviral therapy: protease inhibitors (PI), nucleoside/
nucleotide reverse transcriptase inhibitors (NRTIs),
non-nucleoside reverse transcriptase inhibitors
(NNRTIs), and a fusion inhibitor. While these drugs
have had a major factor on survival, not all patients
have realized the benefits of these therapies due to
drug intolerance and viral resistance.
Maraviroc (Selzentry) is the first of a new phar-
macological class of antiretroviral agents known as
chemokine receptor 5 (CCR5) antagonists. It is a
small molecule acting on a human cellular target to
prevent infection; in other words, HIV-1 fusion and
entry are inhibited. Developed by Pfizer Corpora-
tion, it was approved by the FDA on August 6, 2007.
It is indicated in combination with other antiretrovi-
ral medications for patients who show evidence of
viral replication and exhibit HIV-1 CCR5 tropism.
This article will review the pharmacology, pharma-
cokinetics, dosing, cost, toxicity, and clinical trials of
maraviroc.

Pharmacology
Maraviroc has a novel mechanism of action. It
binds to CCR5 coreceptors on CD4 cells blocking
entry of HIV into these cells. This first step of HIV-
1 cell entry is the specific binding of viral gpl20 to
CD4, the primary receptor for HIV-1. This binding
alone is not sufficient for HIV-1 entry. The binding
of gpl20 to CD4 causes a conformational change in


gpl20 that exposes the bridging sheet and forms a
co-receptor binding site.3 Once this has occurred,
co-receptor binding triggers conformational changes
in gp41, which drives the remaining steps in fusion
and entry of the viral core.4 The chemokine recep-
tors most commonly utilized by HIV-1 in vivo are
(CCR5) and/or CX chemokine receptor 4 (CXCR4).5
The ability of gpl20 to bind to either one or both re-
ceptors defines the tropism of the virus. HIV-1
strains are therefore categorized as R5 (CCR5-
tropic), X4 (CXCR4-tropic) or R5X4 (strains using
both CCR5 and CXCR4; also referred to as 'dual-
tropic').6 The ability of maraviroc to prevent infec-
tion by inhibiting viral entry provides another treat-
ment mechanism in a oral dosage form compared to
enfurvitide which requires an subcutaneous injection.
Maraviroc selectively inhibits CCR5-tropic HIV-
1 replication in vitro. Maraviroc inhibited replica-
tion of 43 CCR5-tropic primary isolates in human
peripheral blood lymphocytes containing primarily
CD4+ T-cells, which represent the major cellular res-
ervoir for HIV-1 replication in vivo. The unbound in
vitro antiviral IC90 (inhibitory concentration of drug
needed to suppress 90% of HIV replication) for
maraviroc is estimated to be approximately 1.0 nM
(0.5 ng/mL).2

Pharmacokinetics
Peak maraviroc plasma concentrations (Cmax) are
attained 0.5-4 h following single oral doses of 1-
1200 mg in healthy volunteers. The pharmacokinet-
ics of oral maraviroc are not dose proportional over
the dose range.2 The bioavailability of maraviroc is
23% after a single dose of 150 mg and is predicted to
have a bioavailability of 33% after a single 300 mg
dose.7 Maraviroc is a substrate for the efflux trans-
porter P-glycoprotein (Pgp). The effect of food re-
sulted in a decreased Cmax by 33% to 60%, and area
under the curve (AUC) by 33% to 50% although
there was no difference in the reduction of viral load
at day 11 between groups who received maraviroc
150 mg orally twice daily in the fasted or fed state.8
The terminal half-life (ti/) of maraviroc is between
14 and 18 h healthy subjects.2
Multiple dosing of maraviroc at 300 mg achieved
steady state within 7 days and resulted in limited ac-
cumulation. The actual distribution in human tissue
is unknown. Maraviroc is 76% bound to plasma pro-
teins showing moderate affinity for albumin and al-
pha-1-glycoprotein. It is predominately confined to


Phrm~oe olme23 sse Fbrar 20


Volume 23, Issue 5 February 2008


PharmaNote







plasma with little penetration into erythrocytes. It has
a volume of distribution (Vd) of 194L or 2.8L/kg.2
The main route of metabolism of maraviroc is pri-
marily by CYP 3A4 and it is not significantly me-
tabolized by any polymorphic enzymes. Maraviroc
is the major circulating component (42%) after a sin-
gle 300 mg dose. Circulating metabolites include a
secondary amine formed by N-dealkylation (22%)
and other metabolites produced from mono-
oxidation. Metabolites of maraviroc do not have
pharmacologic activity. The pharmacokinetics of
maraviroc have not been sufficiently studied in pa-
tients with hepatic impairment. Because maraviroc is
metabolized by the liver, concentrations are likely to
be increased in these patients.
After a single radiolabeled dose, elimination of
maraviroc is primarily via the fecal route (76%) and
to a smaller degree really (20%). Total body clear-
ance is 10.5 mL/min/kg.2 The safety and efficacy of
maraviroc have not been specifically studied in pa-
tients with renal impairment; therefore maraviroc
should be used with caution in this population.
Maraviroc concentrations may be increased in pa-
tients with renal impairment, especially when
CYP3A inhibitors are coadministered. Patients with
a creatinine clearance of less than 50 mL/min who
receive maraviroc and a CYP3A inhibitor may be at
an increased risk of adverse effects related to in-
creased maraviroc concentrations.
The safety and efficacy of maraviroc in patients <
16 or > 65 years of age have not been established.
Therefore, maraviroc should be used cautiously in
these patients. In addition, maraviroc has not been
studied in pregnant women; thus, other alternatives
must be explored.2

Drug Interactions
Maraviroc has been evaluated for its effect on
other drugs. It had no clinically relevant effect on
midazolam with an increase in the AUC of 18%.


Maraviroc showed no effect on lamivudine, zi-
dovudine, or oral contraceptives.
Drug concentrations of maraviroc will be affected
by inducers or inhibitors of CYP 3A4/Pgp. Dosing
recommendations have been issued surrounding
pharmacokinetic interactions (Table 1). The
CYP3A/Pgp inhibitors ketoconazole, lopinavir/
ritonavir, ritonavir, saquinavir and atazanavir all in-
creased the Cmax and AUC of maraviroc. These drugs
increased maraviroc exposure that ranged from an
AUC increase of 2.6 fold (ritonavir 100 mg bid) to
8.3-9.7 fold with saquinavir/ritonavir. CYP3A induc-
ers rifampin and efavirenz decreased Cmax and AUC
of maraviroc. Both drugs reduced maraviroc expo-
sure by 45% or more. Doubling the maraviroc dose
restored exposure (AUC) to approximately 100%.
The combination of tipranavir/ritonavir, a CYP3A
inhibitor and Pgp inducer respectively, did not affect
the steady state pharmacokinetics of maraviroc

Clinical Trials
The clinical efficacy and safety of maraviroc is
derived from analyses of 24-week data from two on-
going multi-center, double-blind studies, A4001027
and A4001028 in antiretroviral-treated adult subjects
infected with CCR5-tropic HIV-1.7'8 A total of 1049
subjects participated in both studies with the majority
of subjects being male (89%), Caucasian (84%) and
with mean age of 46 years. Eligible patients were
required to have CCR5-trophic HIV-1 infection and
an HIV-1 viral load of greater than 5000 copies de-
spite at least 6 months of prior antiretroviral therapy
with at least one agent from three of the four antiret-
roviral drug classes; > 1 NRTI, > 1 NNRTI, > 2 PIs,
and/or enfuvirtide, or documented resistance or intol-
erance to at least one member of each class. All sub-
jects received an optimized background regimen
(OBT) consisting of 3 to 6 antiretroviral agents
(excluding low-dose ritonavir). OBT was selected
on the basis of the subject's prior treatment history


Table 1. Maraviroc dosing schedule with interacting medications9
CYP3A4 inhibitor or inducer Interacting medication Adjusted maraviroc dose
Protease inhibitors (except tipranavir/
ritonavir), delavirdine, ketoconazole, itra-
Strong inhibitors (with or without an inducer) ritonavir), delavirdine, ketoconazole, itra- 150 mg twice daily
conazole, clarithromycin, nefazadone,
telithromycin
Weak inhibitor or inducer, or neutral Tipranavir/ritonavir, nevirapine, all NRTIs 300 mg twice daily
Weak inhibitor or inducer, or neutral 300 mg twice daily
and enfuvirtide
Efavirenz, rifampin, carbamazepine, pheno-
Strong inducer (without a strong inhibitor) Efaviren, rifapin, carbaazepine, pheno- 600 mg twice daily
barbital, phenytoin
In r S. J s wt Concomitant use not recom-
Inducer St. John's wort m
mended
NRTIs = nucleoside reverse transcriptase inhibitors
PharmaNote Volume 23, Issue 5 February 2008







Table 2. Change in HIV-1 RNA from baseline to week 24 (combined studies A4001027 and A4001028)2
Treatment Number of pa- Change from baseline to week 24 in HIV-1 RNA Treatment difference
group tients logoo copies/ml) (maraviroc minus placebo)
Adjusted mean
Raw median Raw mean (se) se e Estimate (se) 97.5% CI
(se)
Maraviroc
aai 414 -2.27 -1.87 (0.069) -1.88 (0.069) -0.89 (0.118) -1.15, -0.62
300 mg daily
Maraviroc
vir 426 -2.42 -1.96 (0.069) -1.96 (0.068) -0.973 (0.118) -1.24, -0.71
300 mg bid
Placebo 209 0.00 -0.99 (0.097) -0.99 (0.097) NC NC
Missing values have been imputed as the baseline value for subjects who discontinued blinded therapy
CI = confidence interval; NC = not calculated; se = standard error
and baseline genotypic and phenotypic viral resis- Mean change from baseline to week 24 in HIV-1
tance. In addition to OBT, subjects were then ran- RNA for subjects taking maraviroc daily + OBT,
domized in a 2:2:1 ratio to maraviroc 300 mg once maraviroc bid + OBT, and placebo (OBT) were -1.87
daily, maraviroc 300 mg twice daily, or placebo. loglo copies/mL, -1.96 loglo copies/mL, and -0.987
Doses were adjusted based on background therapy as logo copies/mL, respectively. Both dosing regimens
described in Table 1. demonstrated superiority compared to placebo. After
The primary endpoint for these studies was 24 weeks the proportion of subjects who had < 400
change from baseline in loglo HIV-1 RNA level at copies/mL taking maraviroc daily + OBT, maraviroc
Week 24. The secondary endpoints compared each bid + OBT, and placebo (OBT) were 69.2% for both
of the two maraviroc dosing regimens (300 mg daily dosing regimens and 27.8% for placebo.
and 300 mg bid) to the placebo regimen at week 24 The evaluation of the secondary endpoint that
in eight categories. The secondary endpoints con- looked at CD4 cell count at baseline and week 24
sisted of: 1) % of subjects with an HIV-1 RNA < 400 showed a greater increase for both maraviroc dosing
copies/mL; 2) % of subjects with an HIV-1 RNA < regimens compared to placebo. The adjusted mean
50 copies/mL; 3) % of subjects who achieved at least increase of CD4 cells was 108.6 cells/pL and 106.3
a 0.5 logo reduction in HIV-1 RNA from baseline or cells/aL for maraviroc daily and bid, compared with
< 400 copies/mL; 4) % of subjects who achieved at 57.4 cells/pL for placebo. These results are summa-
least a 1.0 loglo reduction in HIV-1 RNA from base- rized in Table 3.
line or <4 00 copies/mL; 5) differences in the magni-
tude of change in CD4 cell count from baseline; 6) Toxicity and Safety
differences in the magnitude of change in CD8 cell Warnings and Precautions
count; 7) time-averaged difference (TAD) in logo Maraviroc has a black box warning for potential
HIV-1 RNA; 8) assess HIV-1 genotype and pheno- hepatotoxicity, which has been reported with its use.
type at baseline and at the time of failure. The pri- Symptoms of a systemic allergic reaction such as
mary endpoint results are summarized in Table 2. pruritic rash, eosinophilia or elevations in IgE may

Table 3. Change in CD4 cell count from baseline to week 24 (combined studies A4001027 and A4001028)2
Treatment Number of pa- Change from baseline to week 24 in CD4 cell count Treatment difference
group tients (cells/pL) (maraviroc minus placebo)

Raw median Raw mean (se) Adjusted mean Estimate (se) 97.5% CI
(se)
Maraviroc
Maraviroc 407 86 109 (6.0) 108.6 (5.3) 51.2 (9.2) 33.3, 69.2
300 mg daily
Maraviroc
M virc 418 88 106 (4.9) 106.3 (5.3) 49.0 (9.1) 31.1, 66.9
300 mg bid
Placebo 206 31 56 (6.7) 57.4 (7.5) NC NC
Missing values have been imputed as the baseline value for subjects who discontinued blinded therapy
CI = confidence interval; NC = not calculated; se = standard error

PharmaNote Volume 23, Issue 5 February 2008







occur prior to the development of hepatotoxicity.
Patients with signs or symptoms of hepatitis or aller-
gic reaction following use of maraviroc should be
evaluated immediately.2 Use caution when adminis-
tering maraviroc to patients with liver dysfunction or
who are coinfected with viral hepatitis B or C.
Use maraviroc cautiously in patients with in-
creased risk for cardiovascular events. In Phase 3
clinical trials, 11 patients (1.3%) who received
maraviroc experienced a cardiovascular event includ-
ing myocardial infarction and/or ischemia while no
events were reported in the placebo group. The rela-
tive contribution of the drug to the events is not
known. Although symptomatic postural hypotension
occurred at similar rates between treatment and pla-
cebo groups in phase III clinical trials, earlier clinical
trials showed higher rates as compared to placebo at
higher than recommended doses.2 Therefore, use
caution when maraviroc is administered to patients
with a history of postural hypotension or medications
that are known to lower blood pressure.

Adverse Events
Safety data was based on 840 HIV-infected sub-
jects who received at least one dose of maraviroc


during two phase III trials. Data was evaluated for
safety in a 24-week interim analysis. A total of 426
participants received bid dosing and greater than
75% of participants received a dose of 150 mg be-
cause of concurrent OBT.2
The most common treatment-related adverse
events reported during the phase III studies were di-
arrhea (21.8%), nausea (17.6%), headache (13.7%),
and fatigue (11.8%). The most common adverse
events reported with maraviroc twice daily therapy
with frequency higher than placebo were cough, py-
rexia, upper respiratory tract infections, rash, muscu-
loskeletal symptoms, abdominal pain and dizziness.
In participants receiving once daily therapy, diarrhea,
edema, influenza, esophageal candidiasis, sleep dis-
orders, rhinitis, and urinary abnormalities were re-
ported at rates higher than placebo. Treatment-
emergent adverse events, regardless of causality,
from A4001027 and A4001028 are summarized in
Table 4. Serious and medically significant adverse
events such as myocardial infarction, myocardial
ischemia, cirrhosis of liver, cholestatic jaundice syn-
drome, liver failure, immune reconstitution syn-
drome are uncommon and rare.


Table 4. Adverse events (AE) reported in phase III studies A4001027 and A40010282
Maraviroc daily Maraviroc bid Placebo
N (%) N (%) N (%)
Total patients with AEs (> 2%) 366 (88.4) 383 (89.9) 175 (83.7)
Specific adverse events (> 5%)
Constipation 19 (4.6) 23 (5.4) 6 (2.9)
Diarrhea 94 (22.7) 89 (20.9) 45 (21.5)
Nausea 75 (18.1) 73 (17.1) 39 (18.7)
Vomiting 38 (9.2) 31(7.3) 20 (9.6)
Fatigue 45 (10.9) 54 (12.7) 31(14.8)
Injection site reaction 28 (6.8) 31(7.3) 18 (8.6)
Pyrexia 30 (7.2) 51(12.0) 17 (8.1)
Upper respiratory tract infection 38 (9.2) 44 (10.3) 11(5.3)
Arthralgia 18 (4.3) 22 (5.2) 6 (2.9)
Back pain 22 (5.3) 21(4.9) 6 (2.9)
Dizziness 39 (9.4) 34 (8.0) 14 (6.7)
Headache 61(14.7) 54 (12.7) 32 (15.3)
Insomnia 23 (5.6) 29 (6.8) 9 (4.3)
Cough 35 (8.5) 48 (11.3) 10 (4.8)
Rash 27 (6.5) 34 (8.0) 8 (3.8)
*Does not include adverse events experienced by patients who switched to open label bid treatment

PharmaNote Volume 23, Issue 5 February 2008







Dosage and Administration
Maraviroc is supplied as blue, biconvex, oval
film-coated tablet that is available in 150 mg and 300
mg strengths. The recommended dose of maraviroc
differs based on concomitant medications due to
drug interactions (Table 1). Maraviroc can be taken
with or without food.2 Maraviroc must be given in
combination with other antiretroviral medications
and duration of treatment is indefinite or as long as
treatment is safe and effective.
In patients with hepatic impairment, maraviroc
should be used with caution. The safety and efficacy
of maraviroc have not been specifically studied in
patients with renal impairment; therefore, maraviroc
should be used with caution in this population.2

Cost
Maraviroc retail cost from three community phar-
macies located in Gainesville, FL is identical for 150
mg and 300 mg tablets. The average cost for 60 tab-
lets of 150 mg or 300 mg is $1070 with a range be-
tween $1069 and $1080.

Summary
Maraviroc provides a novel drug for the treatment
of HIV/AIDS. By blocking the binding of the viral
envelope to CCR5 receptor, maraviroc prevents viral
entry into the T-lymphocytes by a method distinct
from all other HIV medications. When treating
CCR5 tropic, HIV-1 patients, maraviroc with OBT
shows greater efficacy than OBT therapy alone in
short term studies. For those patients who have
failed or have become resistant to current therapies,
maraviroc provides a potential alternative. Maravi-
roc treatment doses are affected by concomitant
medications that impact the CYP3A4 isoenzymes
which will require dosing modifications. The ad-
verse event profile of maraviroc includes common
side effects such as diarrhea, nausea, headache, and
fatigue. Maraviroc has a black box warning for hep-
tatotoxicity that may be accompanied by allergic fea-
tures. Serious and medically significant adverse
events such as myocardial infarction, myocardial
ischemia, cirrhosis of liver, cholestatic jaundice syn-
drome, liver failure, immune reconstitution syn-
drome are uncommon and rare.

References:
1. Glynn M, Rhodes P. Estimated Prevalence in the
US at the end of 2003. National HIV Prevention


Conference; June 2005; Atlanta. Abstract 595
2. Selzentry (maraviroc) [prescribing information]
Pfizer Labs, New York, NY; 2007.
3. Kwong PD, Wyatt R, Robinson J, et al. Structure
of an HIV gpl20 envelope glycoprotein in com-
plex with the CD4 receptor and a neutralizing
human antibody. Nature 1998; 393: 648-59.
4. Chan DC, Kim PS. HIV entry and its inhibition.
Cell 1998; 93: 681-4.
5. Choe H, Farzan M, Sun Y, et al. The beta-
chemokine receptors CCR3 and CCR5 facilitate
infection by primary HIV-1 isolates. Cell 1996;
85: 1135-48.
6. Berger EA, Doms RW, Fenyo EM, et al. A new
classification for HIV-1. Nature 1998; 391: 240.
7. Nelson M. Efficacy and safety of maraviroc plus
optimized background therapy in viremic, ART-
experienced patients infected with CCR5-tropic
HIV-1 in Europe. Australia, and North America:
24-Week Results [Abstract 104aLB]. Conference
on Retroviruses and Opportunistic Infections.
Alexandria, VA. 2007.
8. Lalezari J. Efficacy and safety of maraviroc plus
optimized background therapy in viremic ART-
experienced Patients Infected with CCR5-tropic
HIV-1: 24-week results of a phase 2b/3 study in
the US and Canada [Abstract 104bLB]. Confer-
ence on Retroviruses and Opportunistic Infec-
tions. Alexandria, VA. 2007.
9. Maraviroc. DRUGDEX Evaluations. Thomson
MICROMEDEX 1 974-2006.
www.library.health.ufl.edu. Accessed November
28, 2007.


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.
:. WWyW! W!WW ^W!W !^4y


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