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Livalo

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Livalo

Livalo

CLINICAL PHARMACOLOGY

Mechanism of Action

Pitavastatin competitively inhibits HMG-CoA reductase, which is a rate-determining enzyme involved with biosynthesis of cholesterol, in a manner of competition with the substrate so that it inhibits cholesterol synthesis in the liver. As a result, the expression of LDL-receptors followed by the uptake of LDL from blood to liver is accelerated and then the plasma TC decreases. Further, the sustained inhibition of cholesterol synthesis in the liver decreases levels of very low density lipoproteins.

Pharmacodynamics

In a randomized, double-blind, placebo-controlled, 4-way parallel, active-comparator study with moxifloxacin in 174 healthy participants, LIVALO was not associated with clinically meaningful prolongation of the QTc interval or heart rate at daily doses up to 16 mg (4 times the recommended maximum daily dose).

Pharmacokinetics

Absorption

Pitavastatin peak plasma concentrations are achieved about 1 hour after oral administration. Both Cmax and AUC0-inf increased in an approximately dose-proportional manner for single LIVALO doses from 1 to 24 mg once daily. The absolute bioavailability of pitavastatin oral solution is 51%. Administration of LIVALO with a high fat meal (50% fat content) decreases pitavastatin Cmax by 43% but does not significantly reduce pitavastatin AUC. The Cmax and AUC of pitavastatin did not differ following evening or morning drug administration. In healthy volunteers receiving 4 mg pitavastatin, the percent change from baseline for LDL-C following evening dosing was slightly greater than that following morning dosing. Pitavastatin was absorbed in the small intestine but very little in the colon.

Distribution

Pitavastatin is more than 99% protein bound in human plasma, mainly to albumin and alpha 1-acid glycoprotein, and the mean volume of distribution is approximately 148 L. Association of pitavastatin and/or its metabolites with the blood cells is minimal.

Metabolism

Pitavastatin is marginally metabolized by CYP2C9 and to a lesser extent by CYP2C8. The major metabolite in human plasma is the lactone which is formed via an ester-type pitavastatin glucuronide conjugate by uridine 5'-diphosphate (UDP) glucuronosyltransferase (UGT1A3 and UGT2B7).

Excretion

A mean of 15% of radioactivity of orally administered, single 32 mg 14C-labeled pitavastatin dose was excreted in urine, whereas a mean of 79% of the dose was excreted in feces within 7 days. The mean plasma elimination half-life is approximately 12 hours.

Race

In pharmacokinetic studies pitavastatin Cmax and AUC were 21 and 5% lower, respectively in Black or African American healthy volunteers compared with those of Caucasian healthy volunteers. In pharmacokinetic comparison between Caucasian volunteers and Japanese volunteers, there were no significant differences in Cmax and AUC.

Gender

In a pharmacokinetic study which compared healthy male and female volunteers, pitavastatin Cmax and AUC were 60 and 54% higher, respectively in females. This had no effect on the efficacy or safety of LIVALO in women in clinical studies.

Geriatric

In a pharmacokinetic study which compared healthy young and elderly ( ≥ 65 years) volunteers, pitavastatin Cmax and AUC were 10 and 30% higher, respectively, in the elderly. This had no effect on the efficacy or safety of LIVALO in elderly subjects in clinical studies.

Renal Impairment

In patients with moderate renal impairment (glomerular filtration rate of 30 – 59 mL/min/1.73 m2) and end stage renal disease receiving hemodialysis, pitavastatin AUC0-inf is 102 and 86% higher than those of healthy volunteers, respectively, while pitavastatin Cmax is 60 and 40% higher than those of healthy volunteers, respectively. Patients received hemodialysis immediately before pitavastatin dosing and did not undergo hemodialysis during the pharmacokinetic study. Hemodialysis patients have 33 and 36% increases in the mean unbound fraction of pitavastatin as compared to healthy volunteers and patients with moderate renal impairment, respectively.

In another pharmacokinetic study, patients with severe renal impairment (glomerular filtration rate 15 – 29 mL/min/1.73 m2) not receiving hemodialysis were administered a single dose of LIVALO 4 mg. The AUC0-inf and the Cmax were 36 and 18% higher, respectively, compared with those of healthy volunteers. For both patients with severe renal impairment and healthy volunteers, the mean percentage of protein-unbound pitavastatin was approximately 0.6%.

The effect of mild renal impairment on pitavastatin exposure has not been studied.

Hepatic Impairment

The disposition of pitavastatin was compared in healthy volunteers and patients with various degrees of hepatic impairment. The ratio of pitavastatin Cmax between patients with moderate hepatic impairment (Child-Pugh B disease) and healthy volunteers was 2.7. The ratio of pitavastatin AUCinf between patients with moderate hepatic impairment and healthy volunteers was 3.8. The ratio of pitavastatin Cmax between patients with mild hepatic impairment (Child-Pugh A disease) and healthy volunteers was 1.3. The ratio of pitavastatin AUCinf between patients with mild hepatic impairment and healthy volunteers was 1.6. Mean pitavastatin t½ for moderate hepatic impairment, mild hepatic impairment, and healthy were 15, 10, and 8 hours, respectively.

Drug-Drug Interactions

The principal route of pitavastatin metabolism is glucuronidation via liver UGTs with subsequent formation of pitavastatin lactone. There is only minimal metabolism by the cytochrome P450 system.

Warfarin

The steady-state pharmacodynamics (international normalized ratio [INR] and prothrombin time [PT]) and pharmacokinetics of warfarin in healthy volunteers were unaffected by the co-administration of LIVALO 4 mg daily. However, patients receiving warfarin should have their PT time or INR monitored when pitavastatin is added to their therapy.

Table 2: Effect of Co-Administered Drugs on Pitavastatin Systemic Exposure

Co-administered drug Dose regimen Change in AUC* Change in Cmax*
Cyclosporine Pitavastatin 2 mg QD for 6 days + cyclosporine 2 mg/kg on Day 6 ↑ 4.6 fold† ↑ 6.6 fold †
Erythromycin Pitavastatin 4 mg single dose on Day 4 + erythromycin 500 mg 4 times daily for 6 days ↑ 2.8 fold † ↑3.6 fold †
Rifampin Pitavastatin 4 mg QD + rifampin 600 mg QD for 5 days ↑29% ↑2.0 fold
Atazanavir Pitavastatin 4 mg QD + atazanavir 300 mg daily for 5 days ↑31% ↑60%
Darunavir/ Ritonavir Pitavastatin 4mg QD on Days 1-5 and 12-16 + darunavir/ritonavir 800mg/100 mg QD on Days 6-16 ↓ 26% ↓ 4%
Lopinavir/ Ritonavir Pitavastatin 4 mg QD on Days 1-5 and 2024 + lopinavir/ritonavir 400 mg/100 mg BID on Days 9 – 24 ↓ 20% ↓4 %
Gemfibrozil Pitavastatin 4 mg QD + gemfibrozil 600 mg BID for 7 days ↑ 45% ↑31%
Fenofibrate Pitavastatin 4 mg QD + fenofibrate 160 mg QD for 7 days ↑18% ↑ 11%
Ezetimibe Pitavastatin 2 mg QD + ezetimibe 10 mg for 7 days ↓ 2% ↓0.2%
Enalapril Pitavastatin 4 mg QD + enalapril 20 mg daily for 5 days ↑6% ↓ 7%
Digoxin Pitavastatin 4 mg QD + digoxin 0.25 mg for 7 days ↑ 4% ↓ 9%
Diltiazem LA Pitavastatin 4 mg QD on Days 1-5 and 1115 and diltiazem LA 240 mg on Days 6-15 ↑10% ↑15%
Grapefruit Juice Pitavastatin 2 mg single dose on Day 3 + grapefruit juice for 4 days ↑15% ↓ 12%
Itraconazole Pitavastatin 4 mg single dose on Day 4 + itraconazole 200 mg daily for 5 days ↓ 23% ↓ 22%
*Data presented as x-fold change represent the ratio between co-administration and pitavastatin alone (i.e., 1-fold = no change). Data presented as % change represent % difference relative to pitavastatin alone (i.e., 0% = no change).
† Considered clinically significant [see DOSAGE AND ADMINISTRATION and DRUG INTERACTIONS]
BID = twice daily; QD = once daily; LA = Long Acting

Table 3: Effect of Pitavastatin Co-Administration on Systemic Exposure to Other Drugs

Co-administered drug Dose regimen Change in AUC* Change in Cmax *
Atazanavir Pitavastatin 4 mg QD + atazanavir 300 mg daily for 5 days ↑ 6% ↑ 13%
Darunavir Pitavastatin 4mg QD on Days 1-5 and 12-16 + darunavir/ritonavir 800mg/100 mg QD on Days 6-16 ↑3% ↑ 6%
Lopinavir Pitavastatin 4 mg QD on Days 1-5 and 2024 + lopinavir/ritonavir 400 mg/100 mg BID on Days 9 – 24 ↓ 9% ↓7%
Ritonavir Pitavastatin 4 mg QD on Days 1-5 and 2024 + lopinavir/ritonavir 400 mg/100 mg BID on Days 9 – 24 ↓11% ↓ 11%
Ritonavir Pitavastatin 4mg QD on Days 1-5 and 12-16 + darunavir/ritonavir 800mg/100 mg QD on Days 6-16 ↑8% ↑2%
Enalapril Pitavastatin 4 mg QD + enalapril 20 mg daily for 5 days Enalapril ↑12% ↑12%
Enalaprilat ↓ 1% ↓1%
Warfarin Individualized maintenance dose of warfarin (2 -7 mg) for 8 days + pitavastatin 4 mg QD for 9 days R-warfarin ↑ 7% ↑ 3%
S-warfarin ↑6% ↑3%
Ezetimibe Pitavastatin 2 mg QD + ezetimibe 10 mg for 7 days ↑9% ↑2%
Digoxin Pitavastatin 4 mg QD + digoxin 0.25 mg for 7 days ↓ 3% ↓ 4%
Diltiazem LA Pitavastatin 4 mg QD on Days 1-5 and 1115 and diltiazem LA 240 mg on Days 6-15 ↓2% ↓7%
Rifampin Pitavastatin 4 mg QD + rifampin 600 mg QD for 5 days ↓15% ↓ 18%
Data presented as % change represent % difference relative to the investigated drug alone (i.e., 0% = no change).
BID = twice daily; QD = once daily; LA = Long Acting

Animal Toxicology and/or Pharmacology

Central Nervous System Toxicity

CNS vascular lesions, characterized by perivascular hemorrhages, edema, and mononuclear cell infiltration of perivascular spaces, have been observed in dogs treated with several other members of this drug class. A chemically similar drug in this class produced dose-dependent optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in dogs, at a dose that produced plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose. Wallerian degeneration has not been observed with pitavastatin. Cataracts and lens opacities were seen in dogs treated for 52 weeks at a dose level of 1 mg/kg/day (9 times clinical exposure at the maximum human dose of 4 mg/day based on AUC comparisons.

Clinical Studies

Primary Hyperlipidemia or Mixed Dyslipidemia

Dose-ranging study

A multicenter, randomized, double-blind, placebo-controlled, dose-ranging study was performed to evaluate the efficacy of LIVALO compared with placebo in 251 patients with primary hyperlipidemia (Table 4). LIVALO given as a single daily dose for 12 weeks significantly reduced plasma LDL-C, TC, TG, and Apo-B compared to placebo and was associated with variable increases in HDL-C across the dose range.

Table 4: Dose-Response in Patients with Primary Hypercholesterolemia (Adjusted Mean % Change from Baseline at Week 12)

Treatment N LDL-C Apo-B TC TG HDL-C
Placebo 53 -3 -2 -2 1 0
LIVALO 1mg 52 -32 -25 -23 -15 8
LIVALO 2mg 49 -36 -30 -26 -19 7
LIVALO 4mg 51# -43 -35 -31 -18 5
# The number of subjects for Apo-B was 49

Active-controlled study with atorvastatin (NK-104-301)

LIVALO was compared with the HMG-CoA reductase inhibitor atorvastatin in a randomized, multicenter, double-blind, double-dummy, active-controlled, non-inferiority Phase 3 study of 817 patients with primary hyperlipidemia or mixed dyslipidemia. Patients entered a 6-to 8-week wash-out/dietary lead-in period and then were randomized to a 12-week treatment with either LIVALO or atorvastatin (Table 5). Non-inferiority of pitavastatin to a given dose of atorvastatin was considered to be demonstrated if the lower bound of the 95% CI for the mean treatment difference was greater than -6% for the mean percent change in LDL-C.

Lipid results are shown in Table 5. For the percent change from baseline to endpoint in LDL-C, LIVALO was non-inferior to atorvastatin for the two pairwise comparisons: LIVALO 2 mg vs. atorvastatin 10 mg and LIVALO 4 mg vs. atorvastatin 20 mg. Mean treatment differences (95% CI) were 0% (-3%, 3%) and 1% (-2%, 4%), respectively.

Table 5: Response by Dose of LIVALO and Atorvastatin in Patients with Primary Hyperlipidemia or Mixed Dyslipidemia (Mean % Change from Baseline at Week 12)

Treatment N LDL-C Apo-B TC TG HDL-C non-HDL-C
LIVALO 2 mg daily 315 -38 -30 -28 -14 4 -35
LIVALO 4 mg daily 298 -45 -35 -32 -19 5 -41
Atorvastatin 10 mg daily 102 -38 -29 -28 -18 3 -35
Atorvastatin 20 mg daily 102 -44 -36 -33 -22 2 -41
Atorvastatin
40 mg daily
-Not Studied-
Atorvastatin
80 mg daily
-Not Studied-

Active-controlled study with simvastatin (NK-104-302)

LIVALO was compared with the HMG-CoA reductase inhibitor simvastatin in a randomized, multicenter, double-blind, double-dummy, active-controlled, non-inferiority Phase 3 study of 843 patients with primary hyperlipidemia or mixed dyslipidemia. Patients entered a 6-to 8-week wash-out/dietary lead-in period and then were randomized to a 12 week treatment with either LIVALO or simvastatin (Table 6). Non-inferiority of pitavastatin to a given dose of simvastatin was considered to be demonstrated if the lower bound of the 95% CI for the mean treatment difference was greater than -6% for the mean percent change in LDL-C.

Lipid results are shown in Table 6. For the percent change from baseline to endpoint in LDL-C, LIVALO was non-inferior to simvastatin for the two pairwise comparisons: LIVALO 2 mg vs. simvastatin 20 mg and LIVALO 4 mg vs. simvastatin 40 mg. Mean treatment differences (95% CI) were 4% (1%, 7%) and 1% (-2%, 4%), respectively.

Table 6: Response by Dose of LIVALO and Simvastatin in Patients with Primary Hyperlipidemia or Mixed Dyslipidemia (Mean % Change from Baseline at Week 12)

Treatment N LDL-C Apo-B TC TG HDL-C non-HDL-C
LIVALO 2 mg daily 307 -39 -30 -28 -16 6 -36
LIVALO 4 mg daily Simvastatin 319 -44 -35 -32 -17 6 -41
20 mg daily Simvastatin 107 -35 -27 -25 -16 6 -32
40 mg daily 110 -43 -34 -31 -16 7 -39
Simvastatin 80 mg -Not Studied-

Active-controlled study with pravastatin in elderly (NK-104-306)

LIVALO was compared with the HMG-CoA reductase inhibitor pravastatin in a randomized, multicenter, double-blind, double-dummy, parallel group, active-controlled non-inferiority Phase 3 study of 942 elderly patients ( ≥ 65 years) with primary hyperlipidemia or mixed dyslipidemia. Patients entered a 6-to 8-week washout/dietary lead-in period, and then were randomized to a once daily dose of LIVALO or pravastatin for 12 weeks (Table 7). Non-inferiority of LIVALO to a given dose of pravastatin was assumed if the lower bound of the 95% CI for the treatment difference was greater than -6% for the mean percent change in LDL-C.

Lipid results are shown in Table 7. LIVALO significantly reduced LDL-C compared to pravastatin as demonstrated by the following pairwise dose comparisons: LIVALO 1 mg vs. pravastatin 10 mg, LIVALO 2 mg vs. pravastatin 20 mg and LIVALO 4 mg vs. pravastatin 40 mg. Mean treatment differences (95% CI) were 9% (6%, 12%), 10% (7%, 13%) and 10% (7%, 13% ), respectively.

Table 7: Response by Dose of LIVALO and Pravastatin in Patients with Primary Hyperlipidemia or Mixed Dyslipidemia (Mean % Change from Baseline at Week 12)

Treatment N LDL-C Apo-B TC TG HDL-C non-HDL-C
LIVALO 1 mg daily 207 -31 -25 -22 -13 1 -29
LIVALO 2 mg daily 224 -39 -31 -27 -15 2 -36
LIVALO 4 mg daily 210 -44 -37 -31 -22 4 -41
Pravastatin 10 mg daily 103 -22 -17 -15 -5 0 -20
Pravastatin 20 mg daily 96 -29 -22 -21 -11 -1 -27
Pravastatin 40 mg daily 102 -34 -28 -24 -15 1 -32
Pravastatin
80 mg daily
Not Studied

Active-controlled study with simvastatin in patients with ≥ 2 risk factors for coronary heart disease (NK-104-304)

LIVALO was compared with the HMG-CoA reductase inhibitor simvastatin in a randomized, multicenter, double-blind, double-dummy, active-controlled, non-inferiority Phase 3 study of 351 patients with primary hyperlipidemia or mixed dyslipidemia with ≥ 2 risk factors for coronary heart disease. After a 6-to 8-week wash-out/dietary lead-in period, patients were randomized to a 12-week treatment with either LIVALO or simvastatin (Table 8). Non-inferiority of LIVALO to simvastatin was considered to be demonstrated if the lower bound of the 95% CI for the mean treatment difference was greater than -6% for the mean percent change in LDL-C.

Lipid results are shown in Table 8. LIVALO 4 mg was non-inferior to simvastatin 40 mg for percent change from baseline to endpoint in LDL-C. The mean treatment difference (95% CI) was 0% (-2%, 3%).

Table 8: Response by Dose of LIVALO and Simvastatin in Patients with Primary Hyperlipidemia or Mixed Dyslipidemia with ≥ 2 Risk Factors for Coronary Heart Disease (Mean % Change from Baseline at Week 12)

Treatment N LDL-C Apo-B TC TG HDL-C non-HDL-C
LIVALO 4 mg daily 233 -44 -34 -31 -20 7 -40
Simvastatin 40 mg daily 118 -44 -34 -31 -15 5 -39
Simvastatin
80 mg daily
Not Studied

Active-controlled study with atorvastatin in patients with type II diabetes mellitus (NK-104-305)

LIVALO was compared with the HMG-CoA reductase inhibitor atorvastatin in a randomized, multicenter, double-blind, double-dummy, parallel group, active-controlled, non-inferiority Phase 3 study of 410 subjects with type II diabetes mellitus and combined dyslipidemia. Patients entered a 6-to 8-week washout/dietary lead-in period and were randomized to a once daily dose of LIVALO or atorvastatin for 12 weeks. Non-inferiority of LIVALO was considered to be demonstrated if the lower bound of the 95% CI for the mean treatment difference was greater than -6% for the mean percent change in LDL-C.

Lipid results are shown in Table 9. The treatment difference (95% CI) for LDL-C percent change from baseline was -2% (-6.2%, 1.5%). The two treatment groups were not statistically different on LDL-C. However, the lower limit of the CI was -6.2%, slightly exceeding the -6% non-inferiority limit so that the non-inferiority objective was not achieved.

Table 9: Response by Dose of LIVALO and Atorvastatin in Patients with Type II Diabetes Mellitus and Combined Dyslipidemia (Mean % Change from Baseline at Week 12)

Treatment N LDL-C Apo-B TC TG HDL-C non-HDL-C
LIVALO 4 mg daily 274 -41 -32 -28 -20 7 -36
Atorvastatin 20 mg daily 136 -43 -34 -32 -27 8 -40
Atorvastatin 40 mg daily Not Studied
Atorvastatin 80 mg daily Not Studied

The treatment differences in efficacy in LDL-C change from baseline between LIVALO and active controls in the Phase 3 studies are summarized in Figure 1.

Figure 1 : Treatment Difference in Adjusted Mean Percent Charge in LDL-C

Treatment Difference in Adjusted Mean Percent Charge in LDL-C - Illustration

Last reviewed on RxList: 3/13/2012
This monograph has been modified to include the generic and brand name in many instances.

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