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Publication Date: May 2007
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POSACONAZOLE (NOXAFIL): A
NEW BROAD SPECTRUM TRIA-
ZOLE ANTIFUNGAL

Faryda Krynitskaya, Pharm.D. Candidate


Patients with cancer, AIDS, recipients of bone
marrow or solid organ transplant, and other immuno-
deficient patients are all at increased risk of acquir-
ing life-threatening invasive fungal infections (IFI)
caused by various pathogens, such as Candida spp,
Aspergillus spp, Cryptococcus, Mucormorales,
among others. Approximately 11 to 28% of trans-
plant recipients acquire fungal infections at some
point. Usually opportunistic fungal infections are not
life threatening, but in infected bone marrow trans-
plant patients mortality rates can be as high as 60 to
75%.1 Treatment options for IFI include four classes
of antifungal drugs: the polyenes (eg, amphotericin
B), the azoles ( eg, ketoconazole, itraconazole, flu-
conazole, and voriconazole), flucytosine, and the
echinocandins (eg, caspofungin). Emergence of drug
resistance, extensive side effect profile, and rela-
tively low efficacy of established antifungals created
a demand for a new agent in high-risk patients.
Posaconazole (po' so k6n' a z81], or Noxafil
(n6ks' a fil), a new molecular entity structurally re-
lated to a family of azole antifungals, was developed
by Schering Corporation and approved by the FDA
on September 18, 2006. Posaconazole is indicated
for prophylaxis of fungal infections caused by Asper-
gillus sp. and Candida sp. in immunocompromized


patients and treatment of oropharyngeal candidiasis.
This article will review the pharmacology, pharma-
cokinetics, dosing, toxicity, and clinical trials of
posaconazole.

Pharmacology and pharmacokinetics
Posaconazole works similar to other azole
agents by inhibiting 14-alpha-demethylase (CYP51
or Erg 1 lp) and blocking ergosterol synthesis. Ergos-
terol molecules serve as building blocks for the fun-
gal cell membrane and imbalance between its pro-
duction and degradation will results in growth inhibi-
tion and cell death. Posaconazole has an extended
side chain which makes it different from other az-
oles. This addition provides higher binding affinity
to 14-alpha-demethylase and potentially makes posa-
conazole less susceptible to mutations. Posaconazole
is eliminated by CDR1 and CDR2 encoded pumps,
but resistant to efflux by pumps encoded by FLU1
and MDR1.2

In vitro and in vivo activity
The minimum inhibitory concentration
(MIC90) is usually used to assess in vitro or in vivo
antifungal activity. In vitro activity does not always

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SPharmaNote


VOLUME 22, ISSUE 8 MAY 2007


INSIDE THIS ISSUE:
POSACONAZOLE (NOXAFIL*): A NEW BROAD
SPECTRUM TRIAZOLE ANTIFUNGAL


Volume 22, Issue 8 May 2007


PharmaNote







correctly reflect in vivo response and clinical effi-
cacy. Posaconazole has a broad and potent activity
against C. albicans and A. fumigatus in vitro. Its ac-
tivity is comparable to or better than that of voricona-
zole, itraconazole, and amphotericin B.3In vivo activ-
ity was studied in immunocompromised animal mod-
els to reflect a potential patient target population. Ad-
ministration of posaconazole resulted in reduction or
clearance of A. fumigatus, A. flavus, and C. albicans
and increased survival, which could be suggestive of
fungicidal activity. Similar finding were discovered
when posaconazole was used prophylactically.

Administration
Increases in single oral doses from 50 mg to 800
mg and multiple-daily doses from 50 mg BID to 400
mg BID resulted in proportional increases in plasma
concentrations and total drug exposure, expressed as
area under the curve (AUC). However, total daily
doses of pocasonazole exceeding 800 mg did not re-
sult in increased plasma concentrations. Posacona-
zole reaches peak plasma concentration (Cmax) in 3
to 5 hours and about 7 to 10 days for steady state
concentrations. Mean AUC and Cmax increased by 3-
fold when administered with nonfat meals and by 4-
fold with high-fat meals. Administration as a sus-
pension resulted in increased exposure by 37% com-
pared to the tablet form. Pocasonazole's oral
bioavailability increases when administered in di-
vided doses. Oral bioavailability is increased by 58%
when posaconazole was administered 200 mg 4 times
daily instead of 400 mg twice daily.3 Posaconazole is
significantly bound to plasma proteins (>98%), espe-
cially to albumin. Based on a volume of distribution
of 1774 L, it is highly likely that posaconazole dis-
tributes beyond the plasma and easily penetrates tis-
sues. Posaconazole is not extensively metabolized by
any of CYP P450 enzymes; however, it undergoes
glucuronidation mediated by UDP-
glucuronosyltransferase (UDP-G). Parent drug is the
major form found in circulation. About 17% of a
radiolabeled dose is metabolized and excreted pri-
marily as inactive glucuronide conjugates. Elimina-
tion of posaconazole occurs primarily via the fecal
route (71%) and to a smaller degree via renal (13%).3
After administering a single radiolabeled dose, 66%
was detected in feces as unchanged posaconazole,
13% was present in urine as glucuronide conjugates,
and trace amounts of parent form. Posaconazole has
a half-life of 35 hours (range, 20-66 hours) suggest-


ing slow elimination. Total body clearance is 32 L/h.
Posaconazole is a P-glycoprotein substrate, an ATP-
dependent drug efflux transporter. However, some
clinical data suggests that posaconazole could be re-
absorbed into the systemic circulation.3 Posacona-
zole inhibits CYP 3A4 and increases plasma concen-
trations of CYP 3A4 substrates. Inhibitors or induc-
ers of UDP-glucuronidation and P-glycoprotein ef-
flux could alter posaconazole pharmacokinetics. Ri-
fabutin and phenytoin cause UDP-G induction and
decrease posaconazole AUC by 49% and 50%. Ci-
metidine alters gastric pH and decreases AUC by
39%. The concomitant use of rifabutin, phenytoin, or
cimetidine with posaconazole should be avoided.
Posaconazole increases AUC of tacrolimus, rifabu-
tin, midazolam and phenytoin by 358%, 72%, 83%,
and 16%, respectively.3 A dose reduction of 29%
with cyclosporine is necessary with concomitant
posaconazole use. The increase of AUC in the eld-
erly and African American subjects is not clinically
significant and no dose adjustment is necessary.
Posaconazole is not removed by hemodialysis,
probably, due to high protein binding.3

Clinical trials
Posaconazole vs. fluconazole for prophylaxis in se-
vere graft-versus-host disease (GHVD)
An international, phase 3, randomized, dou-
ble-blind trial was conducted by Ullmann and col-
leagues to compare oral posaconazole and oral flu-
conazole for prophylaxis against invasive fungal in-
fections in patients with graft-versus-host disease
(GVHD) on immunosuppressive therapy.2 The pri-
mary outcome of the study was the incidence of
proven or probable invasive fungal infections from
randomization to the fixed 112th day of treatment.
The exposure period was identified as the period
from the first dose to 7 days after the last dose. Of a
total of 600 patients, 301 were randomized to receive
posaconazole oral suspension at a dose of 200 mg
three times daily and 299 to fluconazole 400 mg en-
capsulated tablet orally once daily. Posaconazole was
equally effective to fluconazole in preventing all in-
vasive fungal infections, and superior in preventing
proven or probable invasive aspergillosis (Table 1).
Fewer patients receiving posaconazole acquired
breakthrough invasive fungal infections during the
exposure period (Table 2). The Kaplan-Meier
method was used to analyze the time to IFI (Figure
1). There was a delay in the onset of infections in the


PharmaNote Volume 22, Issue 8 May 2007


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PharmaNote







Table 1. Posaconazole vs. fluconazole for prophylaxis against IFI in patients with graft-versus-host disease (GVHD)4

Pathogen or Pathogen Group Posaconazole Group Fluconazole Group Odds Ratio
(N=301) (0 P Value
Fixed treatment period No. () (N=299) No. (%) (95%CI)

All proven and probable invasive 16(5.3) 27(9.0) 0.5607
fungal infections (0.30-1.07)
0.31
All invasive aspergillosis 7(2.3) 21(7.0) 0.13 0.006
(0.13-0.75)

IFI: invasive fungal infections

Table 2. Posaconazole vs. fluconazole for prophylaxis against IFI in patients with graft-versus-host disease (GVHD)4

Pathogen or Pathogen Group Posaconazole Group Fluconazole Group Odds Ratio
Exposure period No. (N ) (N=288) No. (%) (95%CI)alue
No. (%)
All proven and probable invasive 7 2.4 22 7.6 0.30 0.
7 (2.4) 22 (7.6) 0.004
fungal infections (0.12-0.71)
0.17
All invasive aspergillosis 3 (1.0) 17 (5.9) 0.057) 0.001
(0.05-0.57)IFI: invasive fungal infections
IFI: invasive fungal infections


posaconazole group versus the fluconazole group
during the fixed treatment period (P=0.048).4 Overall
mortality and the incidence of treatment-related ad-
verse events were similar between groups.

Posaconazole vs. fluconazole or itraconazole pro-
phylaxis in patients / ith neutropenia.


Figure 1. Posaconazole vs fluconazole: Time to proven or
probable IFI


Fluconazole group


Comely et. al. compared the efficacy and
safety of posaconazole, fluconazole or intraconazole
for prophylaxis in patients with prolonged neutro-
penia.5 A total of 602 patients participated in this
prospective, randomized, evaluator-blinded, multi-
center study. Patients (n=304) received 200 mg of
posaconazole oral suspension TID and 298 patients
received 400 mg of fluconazole oral suspension once
daily (240 patients) or 200 mg of itraconazole oral
solution BID (58 patients). The primary endpoint of
the study was the incidence of proven or probable IFI
during treatment. Prophylaxis was administered with
each cycle of chemotherapy until recovery from neu-
tropenia and complete remission, until occurrence of
an invasive fungal infection, or for up to 12 weeks,
whichever came first. Proven or probable IFI, espe-
cially invasive aspergillosis, occurred in fewer posa-
conazole recipients than in the fluconazole or itra-
conazole group (Table 3). Administration of posa-
conazole resulted in significantly longer survival
(P=0.004). According to the Kaplan-Meier analysis
for time to death from any cause at the end of the
100-day period after randomization, posaconazole
resulted in a significant survival benefit (P=0.04)
(Figure 2).
Posaconazole versus fluconazole for the treatment of
oropharyngeal candidiasis in subjects ith// HIV/
AIDS


PharmaNote Volume 22, Issue 8 May 2007


0 10 20 30 40 50 60 70 80 90 100
Days after First Dose of Study Drug
Adopted from Ullmann et al.4 IFI: invasive fungal infections


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PharmaNote








Table 3. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia


PosFluconazole or
Posaconazole
IFI during treatment (N ) Itraconazole Fluconazole Itraconazole ..
phase* No. (N=298) (N=240) (N=58)alue 95
No.No. (%)


-9.7 to
Proven or probable 7(2) 25(8) 19(8) 6(10) <0.001 -2.5
-2.5

-9.1 to
Invasive aspergillosis 2(1) 20 (7) 15 (6) 5(9) <0.001 -3.1
-3.1

Adopted from Comely et al.5 *The treatment phase was defined as the period from randomization to 7 days after the last dose of the study drug had been administered
during the last cycle of chemotherapy. *P values and 95% confidence intervals (CIs) are reported for the posaconazole group compared with the pooled fluconazole
and itraconazole groups.; IFI: invasive fungal infections


Figure 2. Kaplan-Meier curves for time to IFI (Panel A),
death from any cause (Panel B), and IFI or death (Panel C)
over the 100-day period after randomization

A
. 015-,
So Fluconazole
0.10- oritraconazole P=
005 PoscP=0.003

IV C. Posaconazole
So.os-
0.00 ,


Days after Randomization


B













C

IL.5
;t
U

:E
'S .2
9i
P


Ds after Random ization


0 20 40 60 80 100
Days after Randomization
Adopted from Comely et al. ; IFI: invasive fungal infections


AM


In this multicenter, evaluator-blinded study,
Vasquez et. al. randomized 350 patients with HIV
infection and oropharyngeal candidiasis to two
groups: 178 in the posaconazole group and 172 in the
fluconazole group.6 Patients received either 200 mg
of posaconazole or fluconazole oral suspension on
day 1, followed by 100 mg/day for 13 days. The pri-
mary outcome was clinical cure or improvement on
day 14. The robustness of the data was evaluated on
day 42. Clinical success occurred in 155 (91.7%) of
169 posaconazole recipients and in 148 (92.5%) of
160 fluconazole recipients (95% confidence interval,
6.61% to 5.04%), indicating that posaconazole was
not inferior to fluconazole. Posaconazole was more
effective in sustaining clinical success after treatment
was discontinued. On day 14, mycological success
was 68% in both arms, but by day 42, significantly
more posaconazole recipients continued to have my-
cological success (40.6% vs. 26.4%).

Pooled data from other recent clinical trials reflect-
ingposaconazole use in refractory treatment patients
Studies suggest that resistant fungi can be
successfully treated with posaconazole, despite the
cross-resistance between posaconazole and the older
generation azoles.8-13 Skiest et al. showed in an
open-label trial that posaconazole was effective in
75% of HIV-infected patients with oropharyngeal
and oesophageal candidiasis refractory to flucona-
zole or itraconazole.8 Posaconazole could be used as
alternative therapy for invasive aspergillosis caused
by A fumigatis and A terreus refractory to ampho-
tericin B. An open-label trial performed by Walsh et
al. showed that the overall success rate was 42% in
refractory or intolerant to conventional therapy pa-


"%P


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PharmaNote







Table 4. Recent clinical trials of posaconazole as salvage therapy against difficult-to-treat fungal infections.

Number of
efe e F l Ifeon p Predominant underlying condition Response
Reference Fungal Infection patients
treated (proportion of patients affected ) Rate (%)


Skiest et al.8 Oropharyngeal and oesophag- 199 HIV/AIDS (100%) 75
eal candidiasis
Walsh et al.9 Invasive aspergillosis 107 Haematological malignancy (74%) 42
Hahm et a.110 Invasive aspergillosis due to
Hachem et al. Invasive aspergillosis due to 8 Haematological malignancy (100%) 50
Aspergillus fumigatus

HaThe et a.1 Invasive aspergillosis due to
Hachem et al. Invasive aspergillosis 9 Haematological malignancy (100%) 44
Aspergillus terreus
Raad et al." Fusariosis 20 Haematological malignancy (75%) 45
Greenberg et al.12 Zygomycosis 23 Haematological malignancy (61%) 70
Restrepo et al.13 Histoplasmosis 7 HIV/AIDS (43%) 83
Adopted from Torres et al


tients treated with posaconazole compared with 26%
in the control group.9 Posaconazole appears to be a
valuable therapeutic option in patients with fusario-
sis, zygomycosis and histoplasmosis.11-13 A sum-
mary of posaconazole use as salvage therapy is lo-
cated in Table 4.

Dosing and Administration
Posaconazole is supplied as a cherry-flavored
suspension containing 40 mg of posaconazole per
ml. Each dose of posaconazole should be adminis-
tered with a full meal or a liquid nutritional supple-
ment. Patients with diarrhea, vomiting, and concomi-
tant medications should be monitored for break-
through fungal infections. The duration of treatment
depends on recovery from neutropenia or immuno-
suppression. Posaconazole is indicated for prophy-
laxis of invasive Aspergillus and Candida infections
at dose of 200 mg (5 ml) TID in patients 13 years of
age or older, who are severely immunocompromised.
An additional indication is for the treatment of oro-
pharyngeal candidiasis for which posaconazole is
administered on the first day at a loading dose of 200
mg once a day, then 100 mg once a day for 13 days.
For oropharyngeal candidiasis refractory to itracona-
zole and fluconazole, the dose is higher at 400 mg
twice a day. The duration of treatment for oropharyn-
geal candidiasis should be based on the severity of
the patient's underlying disease and clinical re-
sponse. In patients with hepatic impairment, posa-


conazole should be used with caution. No dose ad-
justment is warranted in patients with renal insuffi-
ciency.3

Toxicity and Safety
The safety of posaconazole has been evalu-
ated in 605 patients in the prophylaxis studies and
1239 patients treated for other indications. In the pro-
phylaxis study of patients with neutropenia, the
safety and tolerability of the study drugs were evalu-
ated in 602 patients.5 Investigators found that 34% of
patients in posaconazole group experienced an ad-
verse event related to the study drug. Gastrointestinal
adverse events such as diarrhea, nausea, and vomit-
ing were reported most frequently. Rash and QTc
prolongation were also commonly reported side ef-
fects. Another prophylaxis study was conducted in
HSCT recipients with GVHD.4 In the posaconazole
group, 36% of patients experienced a treatment-
related adverse event. Gastrointestinal adverse events
were the most frequently reported. Hypertension
(1%), tremor (1%) and sensory disturbances such as
blurred vision and taste perversion (both 1%) were
reported by HSCT recipients.3 Side effects that oc-
curred in > 2% of patients in both prophylaxis stud-
ies are presented in Table 5.
The most common adverse events associated
with both prophylaxis studies were bilirubinemia,
increased hepatic enzyme levels, hepatocellular dam-
age, nausea and vomiting.3 Serious and medically


PharmaNote Volume 22, Issue 8 May 2007


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PharmaNote







Table 5. Treatment-related adverse events with a 2 % or greater incidence

Patients with Neutropenia5 HSCT Recipients with GVHD4
N (%) N (%)
Posaconazole Fluconazole/Itraconazole Posaconazole Fluconasole
Adverse Events8) (N=301) (N=299)
(N=304) (N=298) (N=301) (N=299)


Subjects reporting any ad-
verse event.


Body as a whole: general disorders
Headache

GI system disorders


102 (34)


101 (34)


5 (2)


Nausea 22 (7)
Diarrhea 20 (7)
Vomiting 14 (5)
Abdominal Pain 9 (3)

Heart Rate and rhythm disorders
QT/QTc prolongation 12 (4)

CV Disorders, general
HTN

Liver and biliary system disorders
Bilirubinemia 7 (2)
Hepatic Enzymes increased 7 (2)

Metabolic and nutritional disorders
Hypokalemia 9 (3)
Alkaline phosphatase

Skin and subcutaneous tissue disorders
Rash 9 (3)

Renal and urinary system disorders
Serum creatinine increase


1(<1)



25 (8)
21(7)
20 (7)
9 (3)


107 (36)


3 (1)


22 (7)
8 (3)
13 (4)
4 (1)


115 (38)


8 (3)


28 (9)
12(4)
15(5)
7 (2)


9 (3)


8(3)
3 (1)



6 (2)


2 (1)



8(3)
8(3)


5 (2)



5 (2)
7 (2)


5 (2)


5 (2)


11(4)


6 (2)


5 (2)


significant adverse events such as adrenal insuffi-
ciency, allergic and/or hypersensitivity reactions are
uncommon and rare. Patients on concomitant cyc-
losporine or tacrolimus therapy were reported to
have rare cases of hemolytic uremic syndrome,
thrombotic thrombocytopenic purpura, and pulmo-
nary embolus.3

Cost
Posaconazole is supplied as a 4-ounce (123 mL)
bottle containing 105 mL of suspension (200 mg of


posaconazole per 5
average retail price
($676 $692), or
dose.


mL). As of April of 2007, the
of Noxafil is $685 per bottle
approximately $27.40/200 mg


Summary
Posaconazole is a new triazole antifungal that
blocks ergosterol synthesis. Posaconazole is indi-
cated for prophylaxis of IFI primarily caused by As-
pergillus sp. and Candida sp. in immunocompro-
mised patients. Posaconazole represents a valuable


PharmaNote Volume 22, Issue 8 May 2007


)
)


Volume 22, Issue 8 May 2007


PharmaNote







therapeutic alternative to fluconazole and itracona-
zole in refractory patients with oropharyngeal can-
didiasis. Posaconazole has been studied in patients
with human immunodeficiency virus (HIV), hemato-
poietic stem cell transplantation (HSCT) recipients
with GHVD, and neutropenic patients and consid-
ered to be equally effective to fluconazole in these
patient populations. Posaconazole changes the me-
tabolism of CYP 3A4 substrates and itself is subject
to changes from inducers or inhibitors of UDP-G
and/or P-glycoprotein. The adverse event profile of
posaconazole includes common side effects such as
bilirubinemia, increased hepatic enzyme levels,
hepatocellular damage, nausea and vomiting. Serious
and rare treatment-related adverse events are adrenal
insufficiency, allergic and/or hypersensitivity reac-
tions.

References
1. Saad AH, DePestel DD, Carver PL. Factors in-
fluencing the magnitude and clinical significance
of drug interactions between azole antifungals
and select immunosuppressants. Pharmacother-
apy 2006; 26: 1730-44.
2. Keating GM. Posaconazole. Drugs 2005; 65:
1553-67.
3. Noxafil (posaconazole) oral suspension Pre-
scribing Information. Schering Corporation; Ken-
ilworth, NJ; October 2006.
4. Ullmann AJ, Lipton JH, Vesole DH, et al. Posa-
conazole or fluconazole for prophylaxis in severe
graft-versus-host disease. N Engl J Med 2007;
356: 335-47.
5. Comely OA, Maertens J, Drew J, et al. Posa-
conazole vs. fluconazole or itraconazole prophy-
laxis in patients with neutropenia. N Engl J Med
2007; 356: 348-59.
6. Vasquez JA, Skiest DJ, Nieto L, et al. A multi-
center randomized trial evaluating posaconazole
versus fluconazole for the treatment of oro-
pharyngeal candidiasis in subjects with HIV/
AIDS. Clin Infect Dis 2006. 42:1179-86.
7. Torres HA, Hachem RY, Chemaly RF, et al.
Posaconazole: a broad-spectrum triazole antifun-
gal. Lancet Infect Dis 2005; 5:775-85.
8. Skiest DJ, Vazquez JA, Graybill JR, et al. Open-
label trial of posaconazole (POS) for azole-
refractory oropharyngeal and esophageal candidi-
asis in HIV/AIDS patients: final analysis. 44th
Interscience Conference on Antimicrobial Agents


and Chemotherapy; Washington, DC, USA; Oct
30-Nov 2, 2004.
9. Walsh TJ, Raad I, Patterson TF, et al. Treatment
of invasive aspergillosis in patients who are re-
fractory to or intolerant of conventional therapy:
an externally controlled blinded trial. Clin Infect
Dis 2007; 44: 2-12.
10. Hachem RY, Kontoyiannis DP, Boktour MR, et
al. Aspergillus terreus: an emerging amphotericin
B-resistant opportunistic mold in patients with
hematologic malignancies. Cancer 2004; 101:
1594-1600.
11. Raad I, Hachem R, Herbrecht R, et al. Experi-
ence of posaconazole in patients with fusariosis.
13th International Symposium on Infections in
the Immunocompromised Host; Granada, Spain;
June 27-30, 2004.
12. Greenberg RN, Anstead G, Herbrecht R, et al.
Posaconazole experience in the treatment of zy-
gomycosis. 43rd Interscience Conference on An-
timicrobial Agents and Chemotherapy; Chicago,
IL, USA; Sept 14-17, 2003.
13. Restrepo A, Clark B, Graham D, et al. Treatment
of histoplasmosis with posaconazole. 43rd Inter-
science Conference on Antimicrobial Agents and
Chemotherapy; Chicago, IL, USA; Sept 14-17,
2003.



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




John G. Gums Editor
Pharm.D.

R. Whit Curry, M.D. Associate Editor

Shawn Anderson Assistant Editor
Pharm.D.


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