Source: FDA, National Drug Code (US) Revision Year: 2019
Pitavastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, a rate-limiting step in the biosynthetic pathway for cholesterol. 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. Sustained inhibition of cholesterol synthesis in the liver also decreases levels of very low density lipoproteins.
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 dose of 4 mg daily).
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 mg to 24 mg once daily. The absolute bioavailability of pitavastatin oral solution is 51%. 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.
Administration of LIVALO with a high fat meal (50% fat content) decreases pitavastatin Cmax by 43% but does not significantly reduce pitavastatin AUC.
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.
The principal route of pitavastatin metabolism is glucuronidation via liver uridine 5'-diphosphate glucuronosyltransferase (UGT) with subsequent formation of pitavastatin lactone. There is only minimal metabolism by the cytochrome P450 system. 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 UGTs (UGT1A3 and UGT2B7).
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.
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.
In a pharmacokinetic study, which compared healthy male and female volunteers, pitavastatin Cmax and AUC were 60 and 54% higher, respectively in females.
In a pharmacokinetic study which compared healthy young and geriatric (≥65 years) volunteers, pitavastatin Cmax and AUC were 10 and 30% higher, respectively, in the geriatric patients [see Use in Specific Populations (8.5)].
A 12-week study in pediatric patients 8 to 16 years of age treated with pitavastatin 1 mg, 2 mg and 4 mg administered once daily, showed a dose-dependent increase in pitavastatin plasma concentrations at trough (for 2 mg and 4 mg doses) and 1 hour post dose. A dose-dependent increase in pitavastatin lactone plasma concentrations was observed at trough and 1 hour post dose.
In adult patients with moderate renal impairment (estimated 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 [see Use in Specific Populations (8.6)].
In another pharmacokinetic study, adult patients with severe renal impairment (estimated 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% [see Use in Specific Populations (8.6)].
The effect of mild renal impairment on pitavastatin exposure has not been studied.
The disposition of pitavastatin was compared in healthy volunteers and patients with various degrees of hepatic impairment. Pitavastatin Cmax and AUCinf in patients with moderate hepatic impairment (Child-Pugh B disease) was 2.7-fold and 3.8-fold higher, respectively as compared to healthy volunteers. In patients with mild hepatic impairment (Child-Pugh A disease), pitavastatin Cmax and AUCinf were 30% and 60% higher as compared to healthy volunteers. Mean pitavastatin half-life for moderate hepatic impairment, mild hepatic impairment, and healthy volunteers were 15, 10, and 8 hours, respectively [see Contraindications (4), Warnings and Precautions (5.3)].
The steady-state pharmacodynamics (international normalized ratio [INR] and prothrombin time [PT]) and pharmacokinetics of warfarin in healthy volunteers were unaffected by the coadministration of LIVALO 4 mg daily.
Table 3 presents the effect of coadministered drugs on pitavastatin systemic exposure:
Table 3. Effect of Coadministered Drugs on Pitavastatin Systemic Exposure:
| Coadministered drug | Dosage 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 20-24 + 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 11-15 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 coadministration 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 (2.4),Drug Interactions (7)]
BID = twice daily; QD = once daily; LA = Long Acting
Table 4 presents the effect of pitavastatin coadministration on systemic exposure of other drugs:
Table 4. Effect of Pitavastatin Coadministration on Systemic Exposure to Other Drugs:
| Coadministered drug | Dosage 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 20-24 + lopinavir/ritonavir 400 mg/100 mg BID on Days 9-24 | ↓ 9% | ↓ 7% | |
| Ritonavir | Pitavastatin 4 mg QD on Days 1-5 and 20-24 + 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 11-15 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
In a 92-week carcinogenicity study in mice given pitavastatin, at the maximum tolerated dose of 75 mg/kg/day with systemic maximum exposures (AUC) 26 times the clinical maximum exposure at 4 mg daily, there was an absence of drug-related tumors.
In a 92-week carcinogenicity study in rats given pitavastatin at 1, 5, 25 mg/kg/day by oral gavage there was a significant increase in the incidence of thyroid follicular cell tumors at 25 mg/kg/day, which represents 295 times human systemic exposures based on AUC at the 4 mg daily maximum human dose.
In a 26-week transgenic mouse (Tg rasH2) carcinogenicity study where animals were given pitavastatin at 30, 75, and 150 mg/kg/day by oral gavage, no clinically significant tumors were observed.
Pitavastatin was not mutagenic in the Ames test with Salmonella typhimurium and Escherichia coli with and without metabolic activation, the micronucleus test following a single administration in mice and multiple administrations in rats, the unscheduled DNA synthesis test in rats, and a Comet assay in mice. In the chromosomal aberration test, clastogenicity was observed at the highest doses tested, which also elicited high levels of cytotoxicity.
Pitavastatin had no adverse effects on male and female rat fertility at oral doses of 10 and 30 mg/kg/day, respectively, at systemic exposures 56- and 354-times clinical exposure at 4 mg daily based on AUC.
Pitavastatin treatment in rabbits resulted in mortality in males and females given 1 mg/kg/day (30-times clinical systemic exposure at 4 mg daily based on AUC) and higher during a fertility study. Although the cause of death was not determined, rabbits had gross signs of renal toxicity (kidneys whitened) indicative of possible ischemia. Lower doses (15-times human systemic exposure) did not show significant toxicity in adult males and females. However, decreased implantations, increased resorptions, and decreased viability of fetuses were observed.
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).
LIVALO was compared with Atorvastatin Calcium Tablets (referred to as atorvastatin) in a randomized, multicenter, double-blind, double-dummy, active-controlled, non-inferiority study of 817 adult 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. Lipid Response by Dose of LIVALO and Atorvastatin in Adult Patients with Primary Hyperlipidemia or Mixed Dyslipidemia in Study 301 (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 |
LIVALO was compared with Simvastatin Tablets (referred to as simvastatin) in a randomized, multicenter, double-blind, double-dummy, active-controlled, non-inferiority study of 843 adult 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. Lipid Response by Dose of LIVALO and Simvastatin in Adult Patients with Primary Hyperlipidemia or Mixed Dyslipidemia in Study 302 (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 | 319 | -44 | -35 | -32 | -17 | 6 | -41 |
| Simvastatin 20 mg daily | 107 | -35 | -27 | -25 | -16 | 6 | -32 |
| Simvastatin 40 mg daily | 110 | -43 | -34 | -31 | -16 | 7 | -39 |
LIVALO was compared with Pravastatin Sodium Tablets (referred to as pravastatin) in a randomized, multicenter, double-blind, double-dummy, parallel group, active-controlled non-inferiority study of 942 geriatric patients (≥65 years) 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 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. Lipid Response by Dose of LIVALO and Pravastatin in Geriatric Patients with Primary Hyperlipidemia or Mixed Dyslipidemia in Study 306 (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 |
LIVALO was compared with Simvastatin Tablets (referred to as simvastatin) in a randomized, multicenter, double-blind, double-dummy, active-controlled, non-inferiority study of 351 adult 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. Lipid Response by Dose of LIVALO and Simvastatin in Adult Patients with Primary Hyperlipidemia or Mixed Dyslipidemia with ≥2 Risk Factors for Coronary Heart Disease in Study 304 (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 |
LIVALO was compared with Atorvastatin Calcium Tablets (referred to as atorvastatin) in a randomized, multicenter, double-blind, double-dummy, parallel group, active-controlled, non-inferiority study of 410 adult patients with type 2 diabetes mellitus and mixed 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. The study failed to demonstrate that LIVALO was not significantly different than atorvastatin in lowering LDL-C in patients with type 2 diabetes mellitus and mixed dyslipidemia.
Table 9. Lipid Response by Dose of LIVALO and Atorvastatin in Adult Patients with Type 2 Diabetes Mellitus and Mixed Dyslipidemia in Study 305 (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 |
The treatment differences in efficacy in LDL-C change from baseline between LIVALO and active controls (i.e., atorvastatin, simvastatin, or pravastatin) in the in the active-controlled studies described above are summarized in Figure 1.
Figure 1. Treatment Difference in Adjusted Mean Percent Change in LDL-C between LIVALO and the Comparator (Atorvastatin, Simvastatin, or Pravastatin):
In a double-blind, placebo-controlled, 12-week trial, 82 pediatric patients (36 boys and 46 girls), 8 to 16 years of age with genetically confirmed HeFH, fasting low-density lipoprotein cholesterol (LDL-C) ≥190 mg/dL or LDL-C ≥160 mg/dL with an additional cardiovascular risk factor (male gender, a family history of premature CV disease, presence of low HDL (<45 mg/dL) or high TG (>150 mg/dL), presence of high lipoprotein (a) (>75 nmol/L), presence of type 2 diabetes mellitus or presence of hypertension) were randomized to LIVALO 1 mg, 2 mg, and 4 mg. Mean LDL-C at baseline was 235 mg/dL (range 160.5 mg/dL to 441mg/dL). Approximately 39% of patients were Tanner Stage 1 at baseline.
LIVALO significantly reduced plasma LDL-C, non-HDL-C, TC, and Apo-B compared to placebo. The reductions in LDL-C, Apo-B, TC, and non-HDL-C were dose dependent. There was no statistically significant improvement in HDL-C or TG at any LIVALO dose. See the lipid results in Table 10.
Table 10. Lipid Response in Pediatric Patients with HeFH (Mean % Change from Baseline at Week 12):
| Treatment | N | LDL-C | Apo-B | TC | TG*# | HDL-C* | non-HDL-C |
|---|---|---|---|---|---|---|---|
| Placebo | 19 | -1 | -3 | -1 | -3 | -1 | -1 |
| LIVALO 1 mg daily | 20 | -21 | -20 | -16 | -14 | 7 | -21 |
| LIVALO 2 mg daily | 24 | -30 | -25 | -25 | -15 | -3 | -29 |
| LIVALO 4 mg daily | 19 | -38 | -28 | -30 | 5 | -2 | -36 |
* Difference from placebo not statistically significant
# Median Percent Change from Baseline at Week 12
The long-term efficacy of LIVALO initiated in childhood to reduce morbidity and mortality in adulthood has not been established.
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