Pitavastatin

A new potent statin

(HMG-CoA reductase inhibitor).
Statins
Statins ที่มีจําหนายในปจจุบัน
- Lovastatin (Mevachor®)
- Simvastatin (Zocor®)
- Pravastatin (Mevalotin®)
- Fluvastatin (Lescol®)
- Atorvastatin (Lipitor®)
- Rosuvastatin (Crestor®)

- Pitavastatin (Livalo ®)

สวน Cerivastatin ถูกถอนออกจาก

ตลาดยาในป 2001 เนื่องจากพบอุบัติการณ
ของ Myopathy สูง
 Pitavastatin (Livalo®)
- “NK -104”
- Created by Nissan Chemical Industries
Ltd, Tokyo, Japan.
- Developed by Kowa Co. Ltd, Tokyo,
Japan.
- MW = 880.98
- Calcium salt of the active β-hydroxy
acid form.

Int J Clin Pract. 2005; 59(2):239-52.

 Pitavastatin: Pleiotropic effects
- Anti-inflammatory & Anti-atherogenic effects.

Endothelial function ↑ eNOS mRNA expression,

↓ ET-I mRNA expression
Monocyte activation ↓ Monocyte adhesion on endothelium
/Endothelium-adhesion/ ↓ MCP-1 mRNA expression
Migration ↓ IL-8 production / mRNA expression
↓ NF-κB transactivation
↓ ICAM-I mRNA expression
Foam cell ↓ SMC proliferation
formation/Cholesterol ↓ SMC migration
accumulation
↓ CD36 mRNA/protein expression
↓ Cholesterol accumulation in macrophage
↓ apoB48R expression

Vascular Health and Risk Management. 2009; 5:921-36.

 Pitavastatin: Pleiotropic effects
- Anti-inflammatory & Anti-atherogenic effects.
Plaque stabilization ↓ Accumulation of macrophages,
↑ Collagen, ↓ MMPs
Thrombosis formation ↓ TF mRNA/Protein expression,
↓ PAI-mRNA expression/antigen
secretion/activity
↑ t-PA mRNA expression/antigen secretion
↑ TM mRNA expression/cellular
antigen/transcription rate
Inflammatory markers ↓ CRP, ↓ PTX3 mRNA expression

Anti-oxidation ↓ ROS production, ↑ PONI promoter activity

Vascular Health and Risk Management. 2009; 5:921-36.

 Pitavastatin: Pharmacokinetics
 Lipophillic statin  Human studies
(log P* = 1.49)  Linear pharmacokinetics:
 Absorption dose-related Cmax and
AUC.
 Rapidly absorbed after oral  Cmax = 26.7 ng/mL
administration: reaching Cmax  AUC = 16.7 ng/mL
in 4 hrs.
(oral administration of
 Extent of oral absorption = pitavastatin 2.0 mg)
80%
 Repeated administration
 Bioavailability > 60%; for 5 days:
unaffected by food.
 Slightly increased Cmax on
Remark *: log P = N-octanol/water partition coefficient day 5.
 AUC increased by 20%

Int J Clin Pract. 2005; 59(2):239-52.

 Pitavastatin: Pharmacokinetics
 Distribution Tissue distribution
 Protein binding = 96% − The highest levels in the liver
 No drug-drug interaction base on (target organ): taken up through
the displacement of the binding OATP2
sites in plasma protein. combined with cyclosporine: AUC
increased by 4.6 fold.
− Followed by kidneys, heart and
adrenals
 Pregnancy
− Also found in skeletal muscle and
 Across the placenta: less than
that in the maternal plasma. brain, equivalent to or less than in
plasma.

Int J Clin Pract. 2005; 59(2):239-52.

 Pitavastatin: Pharmacokinetics
Pitavastatin

Glucuronidation by UGT

Hydrolysis
Pitavastatin glucuronide

Elmination reaction

Pitavastatin lactone
(inactive form)

Vascular Health and Risk Management 2009:5 921-36.

 Pitavastatin: Pharmacokinetics
 Elimination  Excretion
 Half-life = 11 hrs  Primarily in the feces via bile.
 A result of enterohepatic  Low urinary excretion.
circulation of the parent drug (< 2%)
and the lactone metabolite.
→ A long acting HMG-CoA
 Milk excretion
reductase inhibitor.  85 – 98% excreted with the
unchanged form.
 Long Tmax compared with plasma
(6 -7 hrs VS 0.5 – 4.0 hrs)
 Short elimination T1/2 compared
with plasma
(4.8 hrs VS 7.5 hrs)

Int J Clin Pract. 2005; 59(2):239-52.

 Vascular Health and Risk Management. 2009; 5:921-36.

Statins: Pharmacokinetic parameters

Pi A F L Pr R S
MW 881 1209 433.5 405 446.5 1001 418.15

Origin Synthetic Synthetic Synthetic Microbial Semi- Synthetic Semi-

synthetic synthetic
Racemic No No Yes No No No No

Prodrug No No No Yes No No No

Log P 1.49 1.11 1.27 1.70 -0.84 -0.33 1.60

Lipophillic Lipophillic Lipophillic Lipophillic Hydrophillic Hydrophillic Lipophillic

Absorption 80 30 98 31 37 50 65-85
(%)
Hepatic NA > 70 68 > 70 66 90 78-87
excretion
(%)
BA (%) >60 12 10-35 <5 17 20 <5

Effect of No Yes Yes Yes Yes No No

Food on (↓13) (↓15-25) (↑50) (↓30)
BA
(%)

Pi = Pitavastatin, A = Atorvastatin, F = Fluvastatin, L = Lovastatin, Pr = Pravastatin, R = Rosuvastatin, S = Simvastatin

 Vascular Health and Risk Management. 2009; 5:921-36.

Statins: Pharmacokinetic parameters

Pi A F L Pr R S
Protein binding 96 >98 >98 96 – 98.5 43 – 54 88 >95
(%)
Tmax (h) 0.5 – 0.8 2.0 – 0.5 – 1.5 2.8 0.9 – 1.6 3 1.3 – 2.4
4.0

T1/2 (h) 11 11 – 30 0.5 – 2.3 2.5 – 3.0 0.8 – 3.0 20 1.9 – 3.0

Renal excretion <2 2 6 30 60 10 13

IC50 (nmol/L) 6.8 15.2 17.9 2.7 – 55.1 12 18.1

11.1

Lipid-lowering No Yes, Yes, Yes Yes, mainly No Yes

metabolites active mainly active
active

Range of dose 1-4 10 – 80 20 – 80 10 – 80 5 – 40 5 – 80 5 - 80

(mg)
CYP isoforms CYP2C9 CYP3A4 CYP2C9 CYP3A4 CYP3A4 CYP2C9 CYP3A4
minimally minimally minimally
primarily
involving with
metabolic
pathway

Pi = Pitavastatin, A = Atorvastatin, F = Fluvastatin, L = Lovastatin, Pr = Pravastatin, R = Rosuvastatin, S = Simvastatin

Statins: Indications
Pi A F L Pr R S

Primary hypercholesterolemia √ √ √ √ √ √
Mixed dyslipidemia √ √ √ √ √
Hypertriglyceridemia √ √ √ √
Primary dysbetalipoproteinemia √ √ √
Homozygous familial hyperlipidemia √ √ √
Primary prevention of coronary events √ √ √
Secondary prevention of cardiovascular √ √ √ √ √
events
Heterozygous familial hypercholesterolemia √ √ √ √ √
in adolescents
Hyperlipidemia √ √
Clinically evident coronary heart disease √
 Endocrinol Metab Clin North Am. 2009 Mar; 38(1):79-97.
Vascular Health and Risk Management 2009:5 921-36.

Statins: Comparative efficacy

Pi A F L Pr R S
Dose range (mg) 1-4 10-80 20-80 10-80 10-80 5-40 5-80

Effect on LDL-C 34-48 39-60 22-35 21-42 22-37 45-63 26-47

(% decrease)
Effect on HDL-C 4-9 5-9 3-11 2-8 2-12 8-10 10-16
(% increase)
Effect on 20-42 19-37 17-21 6-21 15-24 10-30 12-33
Triglycerides
(% decrease)

Pi = Pitavastatin, A = Atorvastatin, F = Fluvastatin, L = Lovastatin, Pr = Pravastatin, R = Rosuvastatin, S = Simvastatin

 Endocrinol Metab Clin North Am. 2009 Mar; 38(1):79-97.
Vascular Health and Risk Management 2009:5 921-36.

Typical LDL-C reductions (% change from baseline)

by statin doses.
Reduction by dose (% Change from baseline)
5 mg 10 mg 20 mg 40 mg 80 mg
 depending on the drug,
A -- -37 -43 -48 -51 the dosage, and, in the
case of triglycerides,
baseline levels.
F -- -- -22 -25 -35
 varying among patients

L -- -21 -27 -31 -40

 each doubling of the
dose typically produces an
Pr -- -20 -24 -30 -36 additional 6% further
reduction of LDL-C.

R -40 -46 -52 -55 --

S -26 -30 -38 -41 -47

1 mg 2 mg 4 mg

Pi -34 -42 -47

 Endocrinol Metab Clin North Am. 2009 Mar; 38(1):79-97.
Vasc Health Risk Manag. 2008 June; 4(5):525–33.

Statins: Safety
Pi A F L Pr R S
Common side  Abdominal pain, constipation, flatulence, nausea, headache, fatigue, diarrhea, and muscle
effects: complaints.
 Infrequent: About 5% of patients
 Dose-dependent manner.

Myopathy < 1 in 10,000 patients at standard doses

dose-dependent manner

Rhabdomyoly- Very low incidence (rare)

sis Occur at any dose level; dose-dependent manner

Liver enzyme Transaminase: <1% in patients treated with intermediate doses,

elevation (>3 about 2%–3% at higher doses;
time of ULN.)
dose-dependent manner
Aminotransferase: about 1% of patients taking statins.

Pregnancy Category: X
category

Effects of ↑Cmax in Plasma Potential drug ↑Conc Potential drug ↑Conc with Higher
renal/hepatic renal/hepatic levels: accumulation with accumulation severe renal systemic
function impariment markedly with hepatic severe with renal/ function exposure in
impairment ↑with function renal hepatic function impairment hepatic and
chronic impairment disease. impairment and hepatic severe
liver disease. renal
disease. function
impairment.
 HMG-CoA Reductase Inhibitor Adverse Reactions (≥ 3%)
Adverse
reactions Pi A F L PR R S
CNS

Asthenia NA 2.2 - 3.8 - - - 2.7 1.6

Dizziness NA ≥2 2.2 0.7 - 2 3.3 ≥2 -

Headache NA 2.5 - 16.7 8.9 2.6 -9.3 6.2 5.5 3.5

GI
Abdominal
pain/cramps <5% 2.1 - 3.8 4.9 2 - 5.7 5.4 ≥2 3.2

Constipation 1.5 – 3.6 1.1 -2.5 3.1 2 - 4.9 4 ≥2 2.3

Diarrhea 1.5 – 2.6 2.7 - 5.3 4.9 2.6 - 5.5 6.2 3.4 1.9

Dyspepsia NA 1.3 - 2.8 7.9 1.3 - 3.9 - 3.4 1.1

Flatulence NA 1.1 - 2.8 2.6 3.7 - 6.4 3.3 ≥1 1.9

Nausea/
Vomiting NA ≥ 2/< 2 3.2 1.9 - 4.7 7.3 3.4/≥ 1 1.3
 HMG-CoA Reductase Inhibitor Adverse Reactions (≥ 3%)

Adverse reactions Pi A F L PR R S
Musculoskeletal
Arthralgia NA 2 - 5.1 4 0.5 - 1 - ≥2 -

Back pain 1.4 – 3.9 1.1 - 3.8 5.7 - - 2.6 -

Localized pain NA - - 0.5 - 1 10 - -

Myalgia 1.9 – 3.1 1.3 - 5.6 5 2.4 - 2.6 2.7 2.8 -

Respiratory

Common cold NA - - - 7 - -

Pharyngitis NA 1.3 - 2.5 3.8 - - - -

Rhinitis NA ≥2 4.7 - 4 2.2 -
Sinusitis NA 2.5 - 6.4 2.6 - - 2 -

Upper respiratory NA
tract infection - 16.2 - - - 2.1

Pi = Pitavastatin, A = Atorvastatin, F = Fluvastatin, L = Lovastatin, Pr = Pravastatin, R = Rosuvastatin, S = Simvastatin

 •A 12-month, multi-certer, prospective, open-label study.
•Inclusion criteria: TC ≥ 220 mg/mL, TG < 400 mg/mL
•178 cases
•Blood samples: obtained at the beginning and 3, 6 and 12
months after the administration of pitavastatin

J Atheroscler Thromb 2008; 15(6):345-50.

 KISHIMEN investigators
Effects of Pitavastatin on lipid levels in all subjects.

Total cholesterol and LDL-cholesterol. Triglyceride.

J Atheroscler Thromb 2008; 15(6):345-50.

 KISHIMEN investigators
Effects of Pitavastatin on lipid levels in all subjects.

HDL-cholesterol. Remnant-like particle cholesterol

J Atheroscler Thromb 2008; 15(6):345-50.

 KISHIMEN investigators
Effects of pitavastatin on hs-CRP levels.

All subjects Subjects with Type2 DM.

- 39.0%
- 34.8%

Pitavastain may have direct anti-inflammatory effects which are independent

of improved lipid profiles.

J Atheroscler Thromb 2008; 15(6):345-50. Remark: hs-CRP = high-sensitivity C-Reactive Protein

 Using the database of LIVES study, to analyze:
-The effects of pitavastatin: HDL-C, LDL-C, TG
- The clinical factors that might affect HDL-C elevation.

J Atheroscler Thromb. 2009; 16(5):654-61.

J Atheroscler Thromb. 2009; 16(5):654-61.
J Atheroscler Thromb. 2009; 16(5):654-61.
J Atheroscler Thromb. 2009; 16(5):654-61.
 The primary objective: to assess the
long-term safety and tolerability of
pitavastatin 4mg once daily.
The secondary objective: to assess the
long-term efficacy of pitavastatin 4mg once
daily on lipid and lipoprotein fractions and
ratios and LDL-C target attainment.

Patients in this study:

- Previously received pitavastatin (2 mg or 4 mg once daily), atorvastatin (10mg or
20mg daily) or simvastatin (20 mg or 40 mg daily) for 12 weeks during one of two
double-blind phase III studies that assessed the efficacy and tolerability of pitavastatin.
- At the end of these studies, received open-label treatment with pitavastatin 4mg once
daily for a further 52 weeks. (The extension phase)
-Nine visits during the extension phase: weeks 0, 4, 8, 16, 24, 32, 40, 48 and 52 or end
of treatment (EOT) following early termination

Atherosclerosis. 2009 Dec 11. [Epub ahead of print]

 A gradual increase in HDL-C concentration over the extension phase.
• +14.3% above the intial baseline of the double-blind studies;
A sustained reduction in mean LDL-C concentration throughout the extension study.
• At the end of the extension study: -42.89%, compared to the baseline of the double-blind study.

Atherosclerosis. 2009 Dec 11. [Epub ahead of print]

 Safety & tolerability
 Treatment emergent adverse events (TEAEs): 12% related to pitavastatin
 The most common TEAEs: increased blood creatine phosphokinase
(CPK) (5.8%), nasopharyngitis (5.4%), myalgia/myalgia intercostal (4.1%)
 The values of CPK did not exceed 10 times the upper limit of normal,
these patients did not meet the criteria for myopathy.
 No cases of rhabdomyolysis.
 No clinically significant abnormalities raising safety concerns in routine
laboratory, variables, urinalysis, vital signs or 12-lead ECG measurements

Atherosclerosis. 2009 Dec 11. [Epub ahead of print]

J Atheroscler Thromb, 2003;10(2):109-16.
J Atheroscler Thromb, 2003;10(2):109-16.
J Atheroscler Thromb, 2003;10(2):109-16.
 Pharmacokinetic study in
patients with liver
dysfunction.
Results:
A significant increase in the
following pharmacokinetic
parameters of Pitavastatin
between patients with liver
cirrhosis:
- Cmax (p = 0.010)
- AUCt (p = 0.003)
- AUCinf (p = 0.002)
A significant decrease in the Cmax
of Pitavastatin lactone.
(p = 0.008)

Br J Clin Pharmacol. 2005; 59(3):291-7.

 Pitavastatin

The metabolism of
Pitavastatin is
affected by the degree
of hepatic
impairment.
-The increase in blood
Pitavastatin lactone concentration of
Pitavastatin and the
decrease in blood
concentration of
Pitavastatin lactone: In
relation to the degree of
liver dysfunction because
of reduced uptake by liver.

■ Volunteers without liver disease; ○ Child-Pugh A patients; ▲Child-Pugh B patients

Br J Clin Pharmacol. 2005; 59(3):291-7.

 •Multi-centre study Double-blind medication:
•12-week treatment period • Pitavastatin 2 mg tablets and Pravastatin-matched
•Inclusion criteria: TC ≥ 220 mg/mL, placebo

TG < 400 mg/mL • Pravastatin 10 mg tablets and Pitavastatin-matched

plavebo
•240 randomized patients

Atherosclerosis. 2002; 162:373-9.

 Statins: substrates of CYP
3A4 (major)
Grapefruit juice: a potent
CYP 3A4 inhibitor.

>> To investigate the effects of a repeated intake of grapefruit juice (GFJ), a potent CYP3A4 inhibitor on
the pharmacokinetics of pitavastatin and atorvastatin in healthy subjects.

GFJ: ↑ The mean AUC0-24 of atorvastatin acid by 83%.

(from 21.3 to 39.0 ng mL-1 h; 95% CI for difference, 4.8–30.7; p<0.005)
↑ The mean AUC0-24 of pitavastatin acid only by 13%.
(from 194.2 to 220.1 ng mL-1 h; 95% CI for difference, -5.0 to 56.9; p<0.005)

The repeated intake of GFJ affected the

pharmacokinetics of atorvastatin, but had minimal effect
on pitavastatin acid.

Br J Clin Pharmacol. 2005;60(5):494–497.

 Pitavastatin in comparison with Pravastatin:
• Greater mean percent reductions from baseline in TC and LDL-C value (p<0.001 and 0.001)
• Greater mean percent reductions of Apo B, Apo C-II, Apo C-III and Apo-E.

Atherosclerosis. 2002; 162:373-9.

 Total Cholesterol
-13.8%
P < 0.001

-28.0% Patients achieving TC target (TC

< 220 mg/dL):
72% (Pitavastatin group) VS
36% (Pravastatin group)

LDL-C
Patients achieving LDL-C -18.4%
target (LDL-C < 140 mg/dL): P = 0.001

75% (Pitavastatin group) VS -37.6%

36% (Pravastatin group)

Atherosclerosis. 2002; 162:373-9. ■ Pitavastatin 2 mg □ Pravastatin 10 mg

 Triglyceride

• In the cases of a baseline TG level of ≥ 150 mg/dl, The mean percent reduction of TG in the pitavastatin
group (23.3%) showed non-inferiority to that observed in the pravastatin group (20.2%) (P=0.024).
• In TG of all patients, there was no linear trend of reduction over time. Pitavastatin-induced reductions of TG
over time (14.1%) were significantly greater than those observed in the pravastatin group (5.0%)

Atherosclerosis. 2002; 162:373-9. ■ Pitavastatin 2 mg □ Pravastatin 10 mg

 Inclusion criteria
•LDL-C levels ≥140 mg/dL, HDL-C levels <80
mg/dL, and TG levels <500 mg/dL
• Glucose intolerance:
FBG ≥110 mg/dL
1-hour blood glucose ≥180 mg/dL
2-hour blood glucose ≥140 mg/dL after
OGTT
a casual blood glucose level ≥140
mg/dL

Clin Ther. 2008 Jun; 30(6):1089-101

 Pitavastatin in comparison with Atorvastatin:
•Greater percent increase in HDL-C level
•Greater percent change in Apo A-I
(with the significant level.)

Clin Ther. 2008 Jun; 30(6):1089-101

 HDL-C

Apo A-I

Clin Ther. 2008 Jun; 30(6):1089-101 ■ Pitavastatin 2 mg □ Atorvastatin 10 mg

 To examine the effect 8 to 12 months’ treatment with End point:
pitavastatin (4 mg) versus atorvastatin (20 mg) in
Primary - The percent change in coronary
coronary plaque regression in non-percutaneous coronary plaque volume (PV).
intervention (PCI) sites of the culprit vessel in patients with
ACS. Secondary – The Nominal change in
percent PV (%PV) and the nominal change
in normalized plaque volume (NPV)

ACS: Unstable angina pectoris, STEMI, NSTEMI

J Am Coll Cardiol. 2009;54:293–302. PCI = Percutaneous Coronary Intervention; IVUS = Intravascular Ultrasound
 Japan-ACS study.
Results
• A primary end point: a significant regression in the percent change in coronary PV for both groups
• 16.9 ± 13.9% in the pitavastatin group,
• 18.1 ± 14.2% in the atorvastatin group
• 17.5 ± 14.0% for total patients
• Noninferiority of pitavastatin to atorvastatin and also atorvastatin to pitavastatin in terms of percent change
in PV
• No significant correlations between LDL-C level as well as percent change in LDL-C level at follow-up or at
baseline and percent change in PV.

J Am Coll Cardiol. 2009;54:293–302.

Pitavastatin: Conclusion
 A strong statin associated with minimal
drug–drug interactions.
 TG-lowering and HDL-elevating effects
 Improving the overall lipid profle.

 Pleiotropic effects: anti-inflammatory & anti-

atherogenic effects

 Strongly expected to become a standard agent for

the treatment of dyslipidemia.
Thank you for
your attention