pitavastatin

Pitavastatin

A new potent statin(HMG-CoA reductase inhibitor).

Statins

Statins ท่ีมีจําหนายในปจจุบัน

- Lovastatin (Mevachor®)

- Simvastatin (Zocor®)

- Pravastatin (Mevalotin®)

- Fluvastatin (Lescol®)

- Atorvastatin (Lipitor®)

- Rosuvastatin (Crestor®)

- Pitavastatin (Livalo ®)

สวน Cerivastatin ถูกถอนออกจากตลาดยาในป 2001 เน่ืองจากพบอุบัติการณของ 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-hydroxyacid form.

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

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

↓ SMC proliferation↓ SMC migration↓ CD36 mRNA/protein expression↓ Cholesterol accumulation in macrophage↓ apoB48R expression

Foam cell formation/Cholesterol accumulation

↓ Monocyte adhesion on endothelium↓ MCP-1 mRNA expression↓ IL-8 production / mRNA expression↓ NF-κB transactivation↓ ICAM-I mRNA expression

Monocyte activation /Endothelium-adhesion/ Migration

↑ eNOS mRNA expression, ↓ ET-I mRNA expression

Endothelial function

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

↓ ROS production, ↑ PONI promoter activityAnti-oxidation

↓ CRP, ↓ PTX3 mRNA expressionInflammatory markers

↓ TF mRNA/Protein expression,↓ PAI-mRNA expression/antigen secretion/activity↑ t-PA mRNA expression/antigen secretion↑ TM mRNA expression/cellular antigen/transcription rate

Thrombosis formation

↓ Accumulation of macrophages,↑ Collagen, ↓ MMPs

Plaque stabilization


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

Pitavastatin: Pharmacokinetics Lipophillic statin

(log P* = 1.49)

Absorption Rapidly absorbed after oral

administration: reaching Cmaxin 4 hrs.

Extent of oral absorption = 80%

Bioavailability > 60%; unaffected by food.

Human studies Linear pharmacokinetics:

dose-related Cmax and AUC. Cmax = 26.7 ng/mL AUC = 16.7 ng/mL(oral administration of

pitavastatin 2.0 mg) Repeated administration

for 5 days: Slightly increased Cmax on

day 5. AUC increased by 20%

Remark *: log P = N-octanol/water partition coefficient

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

Distribution Protein binding = 96% No drug-drug interaction base on

the displacement of the binding sites in plasma protein.

Pregnancy Across the placenta: less than

that in the maternal plasma.

Pitavastatin: PharmacokineticsTissue distribution− The highest levels in the liver (target organ): taken up through OATP2combined with cyclosporine: AUC increased by 4.6 fold.− Followed by kidneys, heart and adrenals

− Also found in skeletal muscle and brain, equivalent to or less than in plasma.

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

Pitavastatin: Pharmacokinetics

Glucuronidation by UGT

Elmination reaction

Hydrolysis

Pitavastatin

Pitavastatin glucuronide

Pitavastatin lactone

(inactive form)

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

Elimination Half-life = 11 hrs A result of enterohepatic

circulation of the parent drug and the lactone metabolite.

→ A long acting HMG-CoAreductase inhibitor.

Excretion Primarily in the feces via bile. Low urinary excretion.

(< 2%)

Milk excretion 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)

Pitavastatin: Pharmacokinetics

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

LipophillicHydrophillicHydrophillicLipophillicLipophillicLipophillicLipophillic

NoNoYes (↓30)

Yes (↑50)

Yes (↓15-25)

Yes (↓13)

NoEffect ofFood on

BA(%)

<52017<510-3512>60BA (%)

78-879066> 7068> 70NAHepaticexcretion

(%)

65-85503731983080Absorption (%)

1.60-0.33-0.841.701.271.111.49Log P

NoNoNoYesNoNoNoProdrug

NoNoNoNoYesNoNoRacemic

Semi-synthetic

SyntheticSemi-synthetic

MicrobialSyntheticSyntheticSyntheticOrigin

418.151001446.5405433.51209881MW

SRPrLFAPi


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

Statins: Pharmacokinetic parameters

SRPrLFAPi

CYP3A4CYP2C9 minimally

CYP3A4 minimally

CYP3A4CYP2C9CYP3A4CYP2C9minimally

CYP isoformsprimarily

involving with metabolic pathway

5 - 805 – 805 – 4010 – 8020 – 8010 – 801-4Range of dose (mg)

YesNoYes, mainly active

YesYes, mainly active

Yes, active

NoLipid-lowering metabolites

18.11255.12.7 –11.1

17.915.26.8IC50 (nmol/L)

1310603062<2Renal excretion

1.9 – 3.0200.8 – 3.02.5 – 3.00.5 – 2.311 – 3011T1/2 (h)

1.3 – 2.430.9 – 1.62.80.5 – 1.52.0 –4.0

0.5 – 0.8Tmax (h)

>958843 – 5496 – 98.5>98>9896Protein binding (%)


Statins: Pharmacokinetic parameters


Statins: Indications

√Clinically evident coronary heart disease

√√Hyperlipidemia

√√√√√Heterozygous familial hypercholesterolemia in adolescents

√√√√√Secondary prevention of cardiovascular events

√√

√√

√

S

√√√Primary prevention of coronary events

√√Homozygous familial hyperlipidemia

√√Primary dysbetalipoproteinemia

√√√Hypertriglyceridemia

√√√√Mixed dyslipidemia

√√√√√Primary hypercholesterolemia

RPrLFAPi

Statins: Comparative efficacy

12-33

10-16

26-47

5-80

S

10-3015-246-2117-2119-3720-42Effect on Triglycerides (% decrease)

8-102-122-83-115-94-9Effect on HDL-C (% increase)

45-6322-3721-4222-3539-6034-48Effect on LDL-C (% decrease)

5-4010-8010-8020-8010-801-4Dose range (mg)

RPrLFAPi


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.

depending on the drug, the dosage, and, in the case of triglycerides, baseline levels.

varying among patients

each doubling of the dose typically produces an additional 6% further reduction of LDL-C.

-47-42-34Pi

4 mg2 mg1 mg

-47-41-38-30-26S

---55-52-46-40R

-36-30-24-20--Pr

-40-31-27-21--L

-35-25-22----F

-51-48-43-37--A80 mg40 mg20 mg10 mg5 mg

Reduction by dose (% Change from baseline)

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

Statins: Safety

Higher systemic

exposure in hepatic and

severe renal

function impairment.

↑Conc with severe renal

function impairment and hepatic

disease.

Potential drug accumulation with hepatic

function impairment

Potential drug accumulation with renal/

hepatic function impairment

Plasma levels:

markedly ↑with chronic

liver disease.

↑Concwith

severe renal

disease.

↑Cmax in renal/hepatic impariment

Effects of renal/hepatic function impairment

Category: XPregnancy category

Transaminase: <1% in patients treated with intermediate doses, about 2%–3% at higher doses;dose-dependent manner

Aminotransferase: about 1% of patients taking statins.

Liver enzyme elevation (>3 time of ULN.)

Abdominal pain, constipation, flatulence, nausea, headache, fatigue, diarrhea, and muscle complaints. Infrequent: About 5% of patients Dose-dependent manner.

Common side effects:

Very low incidence (rare)Occur at any dose level; dose-dependent manner

Rhabdomyoly-sis

< 1 in 10,000 patients at standard dosesdose-dependent manner

Myopathy

SRPrLFAPi

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

NA

NA

NA

1.5 – 2.6

1.5 – 3.6

<5%

NA

NA

NA

Pi

1.33.4/≥ 17.31.9 - 4.73.2≥ 2/< 2Nausea/Vomiting

1.9≥ 13.33.7 - 6.42.61.1 - 2.8Flatulence

1.13.4-1.3 - 3.97.91.3 - 2.8Dyspepsia

1.93.46.22.6 - 5.54.92.7 - 5.3Diarrhea

2.3≥ 242 - 4.93.11.1 -2.5Constipation

3.2≥ 25.42 - 5.74.92.1 - 3.8Abdominal

pain/cramps

GI

3.55.56.22.6 -9.38.92.5 - 16.7Headache

-≥ 23.30.7 - 22.2≥ 2Dizziness

1.62.7---2.2 - 3.8Asthenia

CNS

SRPRLFAAdversereactions

HMG-CoA Reductase Inhibitor Adverse Reactions (≥ 3%)

SRPRLFAPiAdverse reactions

HMG-CoA Reductase Inhibitor Adverse Reactions (≥ 3%)

2.1---16.2-Upper respiratory NAtract infection

-2--2.62.5 - 6.4Sinusitis NA

-2.24-4.7≥ 2Rhinitis NA

----3.81.3 - 2.5Pharyngitis NA

--7---Common cold NA

Respiratory

-2.82.72.4 - 2.651.3 - 5.6Myalgia 1.9 – 3.1

--100.5 - 1--Localized pain NA

-2.6--5.71.1 - 3.8Back pain 1.4 – 3.9

-≥ 2-0.5 - 142 - 5.1Arthralgia NA

Musculoskeletal


•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 investigatorsEffects of Pitavastatin on lipid levels in all subjects.

Total cholesterol and LDL-cholesterol. Triglyceride.


HDL-cholesterol. Remnant-like particle cholesterol


KISHIMEN investigatorsEffects of Pitavastatin on lipid levels in all subjects.

KISHIMEN investigatorsEffects of pitavastatin on hs-CRP levels.

All subjects

- 34.8%

Subjects with Type2 DM.

- 39.0%

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

Pitavastain may have direct anti-inflammatory effects which are independent of improved lipid profiles.

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.

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

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.

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.


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


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 Pitavastatinbetween patients with liver cirrhosis:

- Cmax (p = 0.010)

- AUCt (p = 0.003)

- AUCinf (p = 0.002)

A significant decrease in the Cmaxof Pitavastatin lactone.

(p = 0.008)

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

Pitavastatin

Pitavastatin lactone

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

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

The metabolism of Pitavastatin is affected by the degree of hepatic impairment.-The increase in blood 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.

•Multi-centre study

•12-week treatment period

•Inclusion criteria: TC ≥ 220 mg/mL,

TG < 400 mg/mL

•240 randomized patients

Double-blind medication:

• Pitavastatin 2 mg tablets and Pravastatin-matched placebo

• Pravastatin 10 mg tablets and Pitavastatin-matched plavebo

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.


■ Pitavastatin 2 mg □ Pravastatin 10 mg

-28.0%

-13.8%

-37.6%

-18.4%

P < 0.001

P = 0.001


Total Cholesterol

LDL-C

Patients achieving TC target (TC < 220 mg/dL):

72% (Pitavastatin group) VS 36% (Pravastatin group)

Patients achieving LDL-C target (LDL-C < 140 mg/dL):

75% (Pitavastatin group) VS 36% (Pravastatin group)

■ 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 pitavastatingroup (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%)


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

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

HDL-C

Apo A-I

■ Pitavastatin 2 mg □ Atorvastatin 10 mg

PCI = Percutaneous Coronary Intervention; IVUS = Intravascular UltrasoundJ Am Coll Cardiol. 2009;54:293–302.

To examine the effect 8 to 12 months’ treatment with pitavastatin (4 mg) versus atorvastatin (20 mg) in coronary plaque regression in non-percutaneous coronary intervention (PCI) sites of the culprit vessel in patients with ACS.

ACS: Unstable angina pectoris, STEMI, NSTEMI

End point:

Primary - The percent change in coronary plaque volume (PV).

Secondary – The Nominal change inpercent PV (%PV) and the nominal change in normalized plaque volume (NPV)

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.

Japan-ACS study.

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

pitavastatin

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