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Title: PharmaNote
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Publisher: College of Pharmacy
Place of Publication: Gainesville, Fla.
Publication Date: August 2010
Copyright Date: 2010
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LIRAGLUTIDE: A NEWLY
APPROVED INCRETIN MIMETIC

Scott Hochmuth, Pharm.D. candidate


Liraglutide acts as a GLP-1 receptor agonist, which
places it in the same class of medications as Byetta
(exenatide). GLP-1 receptor agonists stimulate glucose
-dependant insulin release from pancreatic beta-cells,
promote beta-cell proliferation, decrease postprandial
glucagon secretion, delay gastric emptying, and in-
crease satiety.5


PHARMACOKINETICS


he prevalence of type II diabetes mellitus (DM)
and obesity continue to increase in the United
States. According to National Health and Nutri-
tion Examination Survey (NHANES) data, the preva-
lence of obesity in adults has increased from 15% in
1980 to nearly 34% in 2008.1 DM is associated with
obesity, as almost 90% of patients newly diagnosed
with type II DM are overweight.2 Many patients are
uncontrolled on current available medications, and
often have an increase in weight or hypoglycemia due
to therapy. There remains a need for new treatment
options in DM that control glucose levels without caus-
ing the usual side effects.3
The Food and Drug Administration approved
liraglutide, an incretin mimetic, on January 25, 2010.
Novo Nordisk manufactures liraglutide and markets it
under the brand name Victoza. Liraglutide is ap-
proved for use in adults with type II DM in combina-
tion with diet and exercise to improve glycemic con-
trol.4 The objective of this article is to review liraglu-
tide with a focus on both efficacy and safety.

PHARMACOLOGY

The incretins are insulinotropic hormones re-
leased by the gastrointestinal tract in response to in-
creased glucose levels after meals. The two major in-
cretins are glucagon-like peptide-1 (GLP-1) and glu-
cose-dependent insulinotropic polypeptide (GIP).3


After subcutaneous administration, plasma con-
centrations reached their peak in 8-12 hours (Table
1). Liraglutide has a long elimination half-life of 13
hours.4,6 This extended half-life is a function of liraglu-
tide's resistance to dipeptidyl peptidase IV (DPP-IV),
which is responsible for GLP-1 metabolism. The resis-
tance to DPP-IV and other peptidases allows for once
daily dosing.6 Intact liraglutide is not found in urine or
feces, and only a small percentage of related metabo-
lites were recovered in each.

Special Populations
Approximately 20% of the patients enrolled in
phase III clinical trials were considered elderly (>65
years old). These trials found no changes in safety or
efficacy, so no dosage adjustment is necessary in the
elderly. Pediatric patients have not been included in

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PharmaNote Volume 25, Issue 11 August 2010


SPharmaNote


VOLUME 25, ISSUE 1 1 AUGUST 2010

i -i


INSIDE THIS ISSUE:

LIRAGLUTIDE: A NEWLY APPROVED
INCRETIN MIMETIC

PITAVASTATIN: A NEW STATION TO TREAT
HYPERLIPIDEMIA


" ''


PharmaNote


Volume 25, Issue 11


August 2010







Table 1. Pharmacokinetics of Liraglutide.
PROPERTY LIRAGLUTIDE
Peak Concentrations 8-12h
Vd ~13L
T1/2 13 h
Plasma Protein Binding > 98%
Absolute bioavailability 55%
Excretion Urine (6%) and Feces (5%)
T1/2 = elimination half-life; Vd = volume of distribution



studies, and recommended use is in adults only. Race
and gender also had minimal effects on liraglutide
pharmacokinetics. Body weight does alter the pharma-
cokinetic profile of liraglutide. As body weight in-
creases, the exposure to drug decreases. However, no
clinically significant change in exposure or outcomes
was associated with patients weighing less than 160
kg. Liraglutide does not require a dosage adjustment
based on weight, but patients weighing over 160 kg
were not included in any studies. Patients with varying
degrees of hepatic and renal disease were included in
clinical trials. While these patients had a slightly lower
AUC, it did not correlate to worse outcomes clinically.
Caution is advised, but no dosage adjustments are rec-
ommended.4

Drug Interactions
Liraglutide may decrease the absorption of some
oral medications by delaying gastric emptying. Clinical
trials failed to show a clinically relevant change in the
absorption of oral medications, but use caution with
oral medications in combination with liraglutide. In
vitro studies showed limited potential for relevant in-
teractions involving CYP enzymes and plasma protein
binding.4

CLINICAL TRIALS

The Liraglutide Effect and Action in Diabetes
(LEAD) trial series established both the clinical safety
and efficacy of liraglutide. The LEAD series consisted
of six phase III trials that investigated over 4,400 pa-
tients with DM. These trials compared liraglutide to
rosiglitazone, insulin glargine, glimepiride, and ex-
enatide. The two most decisive trials were liraglutide
versus glimepiride monotherapy for type 2 diabetes
(LEAD-3 Mono) and liraglutide once a day versus ex-
enatide twice a day for type 2 diabetes (LEAD-6).
LEAD-3 Mono proved safety and efficacy as a mono-
therapy, while LEAD-6 was a favorable direct compari-


son with exenatide. The rest of the LEAD trials studied
liraglutide as part of various combination therapies
(Table 2). Liraglutide was not studied in patients less
than 18 years old or in combination with insulin dur-
ing phase III clinical trials.3,4
LEAD-3 Mono was conducted as a 52 week, multi-
center, double-blind, randomized controlled trial that
included 746 early DM patients. The inclusion criteria
was 18-80 years, a body mass index (BMI) < 45 kg/m2,
and a previous diagnosis of DM. The study excluded
participants if they used insulin within the last 3
months, had a history of severe hypoglycemia, or had
impaired liver function. Groups were randomly as-
signed (1:1:1) to receive subcutaneous liraglutide 1.2
mg daily, subcutaneous liraglutide 1.8 mg daily, or oral
glimepiride 8 mg daily. The primary endpoint was a
change in hemoglobin Alc from baseline after 52 weeks
of treatment. Six patients treated with liraglutide dis-
continued treatment due to vomiting and no patients
were lost from the glimepiride group. Both liraglutide
treatment groups showed a significantly greater de-
crease in Aic than the glimepiride treatment group.
The decrease in the glimepiride group was 0.51%, in
comparison to the liraglutide 1.2 mg 0.84% decrease (-
0.33% difference, p=0.0014) and to liraglutide 1.8 mg
1.14% decrease ([-0.62 difference, p<0.0001). Liraglu-
tide patients overall showed weight loss of 2.3 kg,
while the glimepiride group increased 1.1 kg in weight.
The glimepiride treatment also led to more hypoglyce-
mia. The authors concluded that liraglutide is safe and
effective as initial monotherapy in DM treatment, and
produces greater reductions in Aic, weight, and hypo-
glycemia than glimepiride.7
LEAD-6 compared GLP-1 receptor agonists liraglu-
tide and exenatide. This trial had a 26 week random-
ized, open-label, multicenter, parallel group design.
Participants had to be aged 18-80 years, have DM with
an Aic between 7-11%, have a BMI < 45 kg/m2, and
being treated with maximal doses of metformin, a sul-
fonylurea, or both for at least 3 months. Patients were
excluded if previously treated with insulin, had cancer,
uncontrolled hypertension, impaired liver function, or
cardiovascular disease. The study randomly assigned
(1:1) all 464 participants to receive either subcutane-
ous liraglutide 1.8 mg daily or subcutaneous exenatide
10 tig twice daily. The primary endpoint was change in
Alc from baseline following 26 weeks of treatment. The
average decrease in Aic from baseline was significantly
greater in the liraglutide treated group than in the ex-
enatide treated group (-1.12% vs. -0.79%, p<0.0001).
Both drugs caused a comparable reduction in weight,
and patients generally tolerated both well, but there
was slightly less persistent nausea and minor hypogly-
cemia with liraglutide. The authors concluded that


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Table 3. Adverse Events of Selected Diabetic Therapies During Clinical Trials.7'8'10

Liraglutide + Glimepiride + Placebo +
Liraglutidea Glimepiridea Metforminb Metforminb Metforminb Liraglutidec Exenatidec
Adverse Event (n=497) (n=248) (n=724) (n=242) (n=121) (n=235) (n=232)
Nausea 28.4 8.5 15.2 3.3 4.1 25.5 28
Diarrhea 17.1 8.9 10.9 3.7 4.1 12.3 12.1
Vomiting 10.9 3.6 6.5 0.4 0.8 6.0 9.9
Constipation 9.9 4.8 NR NR NR 12.0 6.0
Headache 9.1 9.3 9.0 9.5 6.6 8.9 10.3
Hypoglycemia 9.7 25 3.6 22.3 2.5 25.5 33.6
Data expressed as percentages. Bolded terms reported as significantly different from comparator or placebo.
NR = Not Recorded.
a LEAD-3
b LEAD-2
c LEAD-6


when weight loss and hypoglycemia are concerns,
liraglutide might be a treatment option for type II DM.8

SAFETY

Liraglutide carries a black box warning for an in-
creased risk of thyroid C-cell tumors. The FDA as-
signed this warning due to two 104-week carcino-
genicity studies conducted on both rats and mice. The
studies showed a duration and dose-dependent in-
crease in C-cell carcinomas. The statistically significant
increase risk was evident in both sexes of rodents, but
males showed a higher rate. All of the clinical trials
reported four cases of thyroid C-cell tumors for human
patients using liraglutide, while comparators had one
reported case. Based on current evidence the FDA was
unable to determine if the increased risk actually
translates to humans. Liraglutide is contraindicated in
patients diagnosed with or having a family history of
medullary thyroid carcinoma (MTC) and multiple en-
docrine neoplasia syndrome type 2 (MEN 2).4-9
The total frequency of withdrawal as a result of
side effects was 7.8% during phase III clinical trials."P
The majority of these patients withdrew due to gastro-
intestinal adverse events. The most commonly re-
ported adverse events during monotherapy were nau-
sea, diarrhea, vomiting, and constipation (Table 3).7,8
Table 3 provides a summary of the most common ad-
verse events during the relevant clinical trials.


DOSING & ADMINISTRATION


the abdomen, the upper thigh, and the upper arm.
Liraglutide comes as a pre-filled, disposable, multi-
dose pen. Each pen contains 3 mL of solution, and the
concentration is 6 mg/mL. Patients can give the injec-
tion without regards to meals or the time of day. The
starting dose is 0.6 mg once daily for the first week to
lessen the gastrointestinal side effects. After one week,
the dose should be increased to 1.2 mg daily. If 1.2 mg
is not providing effective glycemic control, it can be
increased to the maximum dose of 1.8 mg once daily.4

COST

The available pack sizes for Victoza are two pens
and three pens. The average price for two pens is
$291.63 ($283.95-$302.95) and the average price for
the three-pen pack is $469.62 ($435.95-$515.95).
These prices represent the monthly cost for patients
on 1.2 mg once daily and 1.8 mg once daily respec-
tively.


SUMMARY


Liraglutide, a new GLP-1 receptor agonist, pro-
vides clinicians an alternative to current DM treatment
options. This agent proved safe and effective as mono-
therapy and as an add-on to current treatment options
when used with diet and exercise for glycemic control.
Liraglutide provides convenient once daily dosing, has
relatively few drug interactions, causes a clinically sig-
nificant reduction in Alc with minimal hypoglycemia,
and potentially reduces body weight.


Liraglutide is approved for once daily subcutane-
ous administration. The available injection sites are


w
PharmaNote Volume 25, Issue 11 August 2010


PharmaNote


Volume 25, Issue 11


August 2010







REFERENCES

1. National Center for Health Statistics (NCHS). Na-
tional Health and Nutrition Examination Survey
Data. Hyatsville, MD: U.S. Department of Health
and Human Services, CDC, 2008. Available from:
http://www.cdc.gov/obesity/data/trends.html.
2. Centers for Disease Control and Prevention. Na-
tional diabetes fact sheet: general information and
national estimates on diabetes in the United States,
2007. Atlanta, GA; U.S. DHHS, 2008.
3. Neumiller JJ, Campbell RK. Liraglutide: A Once-
Daily Incretin Mimetic for the Treatment of Type 2
Diabetes Mellitus. Ann Pharmacother
2009;43:1433-44.
4. Novo Nordisk. Victoza (liraglutide) package in-
sert. Princeton, New Jersey; 2010.
5. Holst JJ. The physiology of glucagon-like peptide 1.
Physiol Rev 2007;87:1409-39.
6. Elbr0nd B, Jakobsen G, Larsen S, et al. Pharmacoki-
netics, pharmacodynamics, safety, and tolerability
of a single-dose of NN2211, a long-acting glucagon
-like peptide 1 derivative, in healthy male subjects.
Diabetes Care 2002;25:1398-404.
7. Garber A, Henry R, Ratner R, et al. Liraglutide ver-
sus glimepiride monotherapy for type 2 diabetes
(LEAD-3 Mono): a randomised, 52-week, phase III,
double-blind, parallel-treatment trial. Lancet
2009;373(9662):473-81.
8. Buse JB, Rosenstock J, Sesti G, et al. Liraglutide
once a day versus exenatide twice a day for type 2
diabetes: a 26-week randomised, parallel-group,
multinational, open-label trial (LEAD-6). Lancet
2009;374:39-47.
9. Bjerre Knudsen L, Madsen LW, Andersen S, et al.
Glucagon-like Peptide-1 receptor agonists activate
rodent thyroid C-cells causing calcitonin release
and C-cell proliferation. Endocrinology
2010;151:1473-86.
10. Nauck M, Frid A, Hermansen K, et al. Efficacy and
safety comparison of liraglutide, glimepiride, and
placebo, all in combination with metformin in type
2 diabetes mellitus (LEAD-2 Met). Diabetes Care
2009; 32:84-90.
11. Vilsb0ll T, Zdravkovic M, Le-Thi T, et al. Liraglu-
tide, a long-acting human glucagon-like peptide-1
analog, given as monotherapy significantly im-
proves glycemic control and lowers body weight
without risk of hypoglycemia in patients with type
2 diabetes. Diabetes Care 2007;30:1608-10.
12. Marre M, Shaw J, Brandle M, et al. Liraglutide, a
once-daily human GLP-1 analogue, added to a sul-
phonylurea over 26 weeks produces greater im-
provements in glycaemic and weight control com-


pared with adding rosiglitazone or placebo in sub-
jects with type 2 diabetes (LEAD-1 SU). Diabet
Med 2009;26:268-78.
13. Zinman B, Gerich J, Buse JB, et al. Efficacy and
safety of the human GLP-1 analog liraglutide in
combination with metformin and TZD in patients
with type 2 diabetes mellitus (LEAD-4 Met+TZD).
Diabetes Care 2009;32:1224-30.
14. Russell-Jones D, Vaag A, Schmitz 0, et al. Liraglu-
tide vs insulin glargine and placebo in combination
with metformin and sulphonylurea therapy in type
2 diabetes mellitus: a randomised controlled trial
(LEAD-5 met+SU). Diabetologia 2009;52:2046-55.





PITAVASTATIN:
A NEW STATION TO TREAT
HYPERLIPIDEMIA

Pamela Giordano, Pharm.D. candidate


T he American Heart Association estimates that
102.3 million American adults have total blood
cholesterol levels of 200 mg/dl or higher.1 The
main aim of anti-hyperlipidemic therapy is a reduction
in low density lipoprotein cholesterol (LDL-C) which is
a significant cardiovascular risk factor. Moreover,
studies have shown for every one percent reduction in
LDL cholesterol there is a one percent reduction in
CHD events.2 Due to the superior LDL lowering effi-
cacy of stations as compared to other therapies, this
class of medications is considered first line treatment
for hyperlipidemia.3 In August 2009, the Food and
Drug Administration approved another station pitavas-
tatin (Livalo) which is manufactured by Kowa phar-


Table 1. Pharmacokinetics of Pitavastatin.4
PROPERTY PITAVASTATIN
Volume of Distribution 148 L
Protein Binding > 99%
Bioavailability 51%
Time to peak in serum 1 hour
Elimination Half life 12 hours
Metabolism Primarily UGT 1A3 and UGT 2B7
Metabolismsmall extent CYP2C8, CYP 2C9

Excretion 79% fecal 15% urine


P o VA


Volue 25 Isse 1 i Agust201


PharmaNote







Table 2. Mean Percent Change from Baseline to Week 12 in Dose-Ranging Studies.4
TREATMENT N LDL APO-B TG TC HDL
Placebo 53 -3 -2 1 -2 0
Pitavastatin 1mg 52 -32 -25 -15 -23 8
Pitavastatin 2mg 49 -36 -30 -19 -26 7
Pitavastatin 4 mg 51 -43 -35 -18 -31 5


maceuticals. Although new to the United States this
station has been in use in Asian countries since 2003.
The intent of this article is to discuss the pharmacol-
ogy, pharmacokinetics, efficacy, and safety of pitavas-
tatin.

PHARMACOLOGY

Similar to the other currently available stations, pi-
tavastatin affects the rate limiting step of cholesterol
synthesis by inhibiting HMG-CoA reductase. Pitavas-
tatin is approved as an adjunctive therapy to diet to
reduce elevated total cholesterol (TC), low-density
lipoprotein cholesterol (LDL-C), apolipoprotein B
(ApoB), triglycerides (TG), and to increase high den-
sity lipoprotein cholesterol (HDL-C) in adult patients
with primary hyperlipidemia and mixed dyslipide-
mia.4

PHARMACOKINETICS

The main pharmacokinetic parameters of pitavas-
tatin are summarized in Table 1. Pitavastatin under-
goes carrier-mediated uptake in hepatocytes by or-
ganic anionic transporting polypeptide 1B1.5 Pitavas-
tatin undergoes hepatic metabolism primarily by UGT
metabolism (UGT1A3 and UGT2B7) and minimally
CYP-mediated (CYP2C9 and CYP2C8). This property
may reduce the occurrence of drug-drug interactions.
However, non-CYP-mediated metabolism does not
make pitavastatin unique for other stations
(pravastatin and rosuvatatin) also share this charac-


teristic.


CLINICAL TRIALS

Dose-Ranging Study
A multicenter randomized, double- blind, placebo-
controlled study involving 251 participants with pri-
mary hyperlipidemia was performed to ascertain ap-
propriate dosing.4 Participants were given pitavastatin
or matching placebo once daily for 12 weeks. The ef-
fects on LDL, TC, TG, Apo-B and HDL are summarized
below in Table 2. At a dose of pitavastatin 1 mg daily
the average reduction in LDL was 32% (Table 2).4

Pitavastatin vs. Atorvastatin
During a phase 3 trial pitavastatin was compared
to atorvastatin in a randomized, multicenter, double-
blind, active comparator, non-inferiority study. The
study included 817 participants with primary hyper-
lipidemia or mixed dyslipidemia. All of the partici-
pants first underwent a 6-8 week washout period. The
participants were then assigned to either pitavastatin
2 mg, pitavastatin 4mg, atorvastatin 10mg or atorvas-
tatin 20 mg daily for 12 weeks. Non-inferiority was
demonstrated for both pitavastatin 2 mg vs. atorvas-
tatin 10 mg and pitavastatin 4 mg vs. atorvastatin 20
mg (Tables 3 & 4).4

Pitavastatin vs. Simvastatin
A similar study by Ose et al. compared the effects
of pitavastatin against simvastatin in participants with
primary hypercholesterolemia or combined dyslipide-


Table 3. Mean Percent Change in Lipid Parameters for Pitavastatin vs. Atorvastatin from Baseline to Week 12.4

Pitavastatin 2 mg Atorvastatin 10 mg Pitavastatin 4 mg Atorvastatin 20 mg
Parameter (n=315) (n=102) (n=298) (n=102)
LDL-C -38 -38 -45 -44
TC -28 -28 -32 -33
TG -14 -18 -19 -22
HDL-C 4 3 5 2

ri ii I I~~1U~ I~5U~ ~J.L&


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Table 4. Summary of Pitavastatin Clinical Trials.49
REFERENCE DESIGN RESULTS


Package Insert4


Package Insert4




Package Insert4





Saito (2002)s,7





Park (2005)5s8




Lee (2007)5-9





Sasaki (2008)s





Ose (2009)6


AC = active controlled;
domized.


DB = double-blind; DD = double-dummy; M = multicenter; NI = non-inferiority; OL = open-label; P = prospective; R = ran-


mia (Table 4). The study was a prospective, random-
ized, active-controlled, double-blind, double-dummy
trial which lasted 12 weeks. Eligible participants were
men and women (non-pregnant and non-lactating)
aged 18-75 years. The study enrolled 857 participants.
Prior to randomization, participants followed the


European Atherosclerosis Society diet for 6 weeks.
Participants receiving previous lipid-lowering therapy
underwent a wash-out period and followed the diet
for 8 weeks prior to randomization. At the end of the
diet participants were diagnosed with hyperlipidiemia
if LDL-C levels were >160 mg/dl and < 220 mg/dl and


PharmaNote Volume 25, Issue 11 I August 2010


* 12 week, R, DB, NI
* Participants with primary Hyperlipide-
mia or mixed dyslipidemia (N=817)
* Primary endpoint: Mean treatment
differences in LDL-C reduction

* 12 week, R,M, DB, DD, AC, NI
* Participants with Dyslipidemia and 2 or
more coronary risk factors (N=351)
* Primary endpoint: LDL-C reduction

* 12 week, R,M, DB,DD,AC, NI
* Participants with Dyslipidemia and Type
2 DM (N=410)
* Primary endpoint: Mean LDL-C%
change from baseline at Week 12

* 12 week, R, DB, AC
* Participants with Primary Hyperlipide-
mia (N=236)
* Primary endpoint: Percent change in TC,
LCL-C, and TG

*8 week, OL, AC
* Participants with Hypercholesterolemia
(N=95)
* Primary endpoint: LDL-C% change

. 8 week, R, OL,AC
* Participants with Hypercholesterolemia
(N=268)
* Primary endpoint: Proportion of partici-
pants achieving LDL-C goal

. 52 week, R, OL, AC
* Participants with elevated LDL-density
lipoprotein and glucose intolerance
(N=207)
* Primary endpoint:HDL-C% change

* 12 week, P, R, AC, DB, DD, NI
* Participants with primary Hypercholes-
terolemia or mixed dyslipidemia
(N=843)
* Primary endpoint: LDL-C reduction


No difference in LDL-C reduction between pitavastatin 2 mg vs.
atorvastatin 10mg or between pitavastatin 4 mg vs.
atorvastatin 20 mg.



No difference in LDL-C reduction between pitavastatin 4mg
(44% reduction) vs. simvastatin 40 mg (44% reduction)



Significantly greater reduction in LDL-C for atorvastatin 20 mg
(43% reduction) vs. pitavastatin 4 mg (41% reduction)




Significantly greater reduction in TC (additional 14% reduction)
and LDL-C (additional 18.4% reduction) with pitavastatin 2 mg
compared with pravastatin 10 mg; p<0.001



No significant difference between % change in LDL-C for pita-
vastatin 2 mg (38.2% reduction) vs. simvastatin 20 mg (39.4%
reduction)


No significant difference in proportion of patients achieving LDL
-C goal between pitavastatin 2 mg (92.7% of patients) vs. ator-
vastatin 10 mg (92% of patients)



Significantly greater increase in HDL-C with pitavastatin 2 mg
daily (8.2% increase) vs. atorvastatin 10 mg daily (2.9% in-
crease); p=0.031



No significant difference in LDL-C reduction between pitavas-
tatin 2 mg (39% reduction) vs. simvastatin 20 mg (35% reduc-
tion) or between pitavastatin 4 mg (44% reduction) vs. simvas-
tatin 40 mg (43% reduction)


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Table 5. Adverse Reactions Reported by >2.0% of Participants Treated with Pitavastatin and Placebo.4
Placebo Pitavastatin 1 mg Pitavastatin 2 mg Pitavastatin 4 mg
Adverse Reactions (n=208) (n=309) (n=951) (n=1540)
Myalgia 1.4% 1.9% 2.8% 3.1%
Pain in Extremity 1.9% 2.3% 0.6% 0.9%
Diarrhea 1.9% 2.6% 1.5% 1.9%
Constipation 1.9% 3.6% 1.5% 1.9%
Back Pain 2.9% 3.9% 1.8% 1.4%


mean trigelyceride levels were < 400 mg/dl. The par-
ticipants who met this criteria were allocated in a
3:3:1:1 ratio to treatment with pitavastatin 2 mg/day,
pitavastatin 4 mg/day, simvastatin 20 mg/day, or sim-
vastatin 40mg/day. Mean LDL levels were reduced by
39% in the pitavastatin 2 mg group, 35% in the sim-
vastatin 20 mg group, 44% in the pitavastatin 4 mg
group, and 43% in the simvastatin 40 mg group. The
authors concluded pitavastatin to be noninferioir to
simvastatin and found the adverse event profiles to be
similar. Musculoskeletal and gastrointestinal side ef-
fects were the most common reason for discontinua-
tion for both agents.5

ADVERSE REACTIONS

Myaligia is the most common adverse event ex-
perienced by participants treated with pitavastatin
(Table 5). Other reported adverse reactions include
arthralgia, headache, influenza, nasopharyngitis, and
hypersensitivity reactions such as rash and pruritus.
Pitavastatin may lead to laboratory abnormalities
such as elevated creatine phosphokinse, glucose, alka-
line phosphatase, bilirubin, and transaminases.

DRUG INTERACTIONS

Although pitavastatin undergoes minimal CYP-
mediated metabolism significant drug interactions still
exist. Several medications can increase the AUC of pi-
tavastatin. The manufacturer recommends avoiding
concomitant use of the anti-retroviral drugs lopinvir/
ritonavir if possible. Likewise, when co-administering
erythromycin therapy, the pitavastatin dose should be
limited to 1 mg daily.
As with other stations, combination therapy with
fibrates and niacin can lead to an increased risk of
musculoskeletal side effects. The manufacturer does
suggest a reduction in pitavastatin dosing when initi-
ating niacin therapy and suggests using caution with


fibrate therapy.
As mentioned previously, pitavastatin is metabo-
lized to a small extent by the enzyme CYP2C9 which is
responsible for the majority of warfarin metabolism.
Participants receiving concomitant pitavastatin and
warfarin therapy in clinical trials did not have a sig-
nificant altered INR or PT. However, the manufacturer
suggests monitoring patients PT and INR when initiat-
ing pitavastatin.4

DOSING & PRECAUTIONS

Pitavastatin is available in 1 mg, 2 mg, and 4 mg
tablets.4 The pricing information has not yet been pub-
lished. Pitavastatin will likely provide little economic
benefit considering the brand- only status of the medi-
cation and the availability of several generic stations 5
Pitavastatin can be administered anytime of the
day with or without food. Daily doses should not ex-
ceed 4 mg due to an association with an increased risk
of severe myopathy.
Pitavastatin is contraindicated in patients receiv-
ing cyclosporine. When participants on 2mg of pita-
vastatin were administered 2 mg/kg of cyclosporine
for 6 days, the Cmax of pitavastatin increased by 6.6-
fold. Pitavastatin is also contraindicated in patients
with active liver disease and those with unexplained
persistent elevations of serum transaminases.
Like other members of the station class, pitavas-
tatin is a category X during pregnancy and therapy
should be discontinued. Pitavastatin has not been
shown to be excreted in breast milk. However, the
manufacturer recommends against breastfeeding or to
consider alternative therapies.4
Renal dose adjustments are necessary for this
medication. Patients with moderate renal impairment
or end-stage renal disease should receive a lower
starting dose of 1 mg daily and should not exceed a
maximum dose of 2 mg daily. In patients who are not
receiving dialysis with creatinine clearances of less


VuA


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than 30 ml/min the use of pitavastatin is not recom-
mended for this population has not yet been studied.4

SUMMARY

Statin therapy remains first line for patients with
hyperlipidemia.3 Pitavastatin is the newest member of
this class. This agent has similar efficacy to low-to-
moderate doses of both atorvastatin and simvastatin
when comparing LDL-C reduction. However, data
showing a reduction in mortality and CHD remains to
be seen.4 Pitavastatin undergoes both minimal CYP -
mediated metabolism and renal elimination. However,
as already discussed these features are not unique to
this agent. Also, due to the brand only status of this
medication it is unlikely to be less expensive than cur-
rently available generic stations. Overall, the exact role
of this station in clinical practice may be limited due to
all of these factors.


REFERENCES


1. Lloyd-Jones D, Adams R, Carnethon M, et al. Heart
disease and stroke statistics-2010 update: a re-
port from the American Heart Association Statis-
tics Committee and Stroke Statistics Subcommit-
tee. Circulation 2010;121:e46-e215.
2. Gould AL, Rossouw JE, Santanello NC, Heyse JF,
Furberg CD. Cholesterol reduction yields clinical
benefit: impact of station trials. Circulation 1998;97
(10):946-52.
3. Expert Panel on Detection, Evaluation, and Treat-
ment of High Blood Cholesterol in Adults. Execu-
tive Summary of The Third Report of The National
Cholesterol Education Program (NCEP) Expert
Panel on Detection, Evaluation, and Treatment of
High Blood Cholesterol in Adults (Adult Treatment
Panel III). JAMA 2001;285(19):2486-97.
4. Package insert. Livalo (pitavastatin). Montgomery,
AL: Kowa Pharmaceuticals America, Inc., August
2009. Available from: http://
www.kowapharma.com/docs/LIVALO_Final%/0
201abeling%20NDA%20022363%2008-09.pdf.
Accessed 2010 March 8.
5. Wensel T, Waldrop B, Wensel B. Pitavastatin: A
new HMG-CoA reductase inhibitor. Ann Pharmaco-
ther 2010;507-13
6. Ose L, Budinski D, Hounslow N, Arneson V. Long-
term treatment with pitavastatin is effective and


well tolerated by patients with primary hypercho-
lesterolemia or combined dyslipidemia. Athero-
sclerosis 2010; 210(1):202-8.
7. Saito Y, Yamada N, Teramoto T, et al. A
randomized, double-blind trial comparing the
efficacy and safety of pitavastatin versus
pravastatin in participants with primary
hypercholesterolemia. Atherosclerosis
2002;162:373-9.
8. Park S, Kang HJ, Rim SJ, et al. A randomized, open-
label study to evaluate the efficacy and safety of
pitavastatin compared with simvastatin in Korean
participants with hypercholesterolemia. Clin Ther
2005;27:1074-82.
9. The most common adverse events experienced by
Lee SH, Chung N, Kwan J, et al. Comparison of the
efficacy and tolerability of pitavastatin and ator-
vastatin: an 8-week, multicenter, randomized,
open-label, dose-titration study in Korean partici-
pants with hypercholesterolemia. Clin Ther
2007;29:2365-73.


-Sm
PharmaNote Volume 25, Issue 11 August 2010


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

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PharmaNote


Volume 25, Issue 11


August 2010




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