Livalo (pitavastatin)

The following drug information is obtained from various newswires, published medical journal articles, and medical conference presentations.

Company:

Approval Status:

Approved August 2009

Specific Treatments:

primary hyperlipidemia and mixed dyslipidemia

Therapeutic Areas

General Information

Livalo is a HMG-CoA reductase inhibitor. It differs from other statins in that it has a unique cyclopropyl group on the base structure. This cyclopropyl group contributes to a more effective inhibition of the HMG-CoA reductase enzyme to inhibit cholesterol production, and potentially affords greater low-density lipoprotein cholesterol (LDL-C) clearance and reduction of plasma cholesterol.

Livalo is specifically indicated as an adjunctive therapy to diet to reduce elevated total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), triglycerides (TG), and to increase HDL-C in adult patients with primary hyperlipidemia or mixed dyslipidemia.

Livalo is supplied as a tablet (1, 2 and 4 mg) for oral administration. The recommended initial dose of the drug is 2 mg and the maximum dose is 4 mg. After initiation or upon titration of Livalo, lipid levels should be analyzed after 4 weeks and the dosage adjusted accordingly.
Considerations:
Renal Impairment: Patients with moderate renal impairment and end stage renal disease receiving hemodialysis should receive a starting dose of Livalo 1 mg once daily and a maximum dose of Livalo 2 mg once daily. Those with severe renal impairment should not use Livalo.
Use with Erythromycin: a dose of Livalo 1 mg once daily should not be exceeded.
Use with Rifampin: a dose of Livalo 2 mg once daily should not be exceeded.

Clinical Results

FDA Approval
The FDA approval of Livalo was based on the following trials:

Dose-ranging Study
This multicenter, randomized, double-blind, placebo-controlled, dose-ranging study enrolled 251 subjects with primary hyperlipidemia. The subjects received Livalo 1, 2 or 4 mg or placebo for 12 weeks. Livalo 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.

Active-controlled study with atorvastatin (NK-104-301):
This randomized, multicenter, double-blind, double-dummy, active-controlled, non-inferiority study enrolled 817 subjects with primary hyperlipidemia or mixed dyslipidemia. The subjects 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. 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 were 0% (-3%, 3%) and 1% (-2%, 4%), respectively.

Active-controlled study with simvastatin (NK-104-302)
This randomized, multicenter, double-blind, double-dummy, active-controlled, non-inferiority study enrolled 843 subjects with primary hyperlipidemia or mixed dyslipidemia. The subjects 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. 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 were 4% (1%, 7%) and 1% (-2%, 4%), respectively.

Active-controlled study with pravastatin in elderly (NK-104-306)
This randomized, multicenter, double-blind, double-dummy, parallel group, active-controlled non-inferiority study enrolled 942 elderly patients (older than 65 years) with primary hyperlipidemia or mixed dyslipidemia. The subjects 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. 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 were 9% (6%, 12%), 10% (7%, 13%) and 10% (7%, 13% ), respectively.

Active-controlled study with simvastatin in patients with greater then 2 risk factors for coronary heart disease (NK-104-304)
This randomized, multicenter, double-blind, double-dummy, active-controlled, non-inferiority study enrolled 351 subjects with primary hyperlipidemia or mixed dyslipidemia. Following a 6- to 8-week wash-out/dietary lead-in period, subjects were randomized to a 12-week treatment with either Livalo or simvastatin. Livalo 4 mg was non-inferior to simvastatin 40 mg for percent change from baseline to endpoint in LDL-C. The mean treatment difference was 0% (-2%, 3%).

Active- controlled study with atorvastatin in patients with type II diabetes mellitus (NK-104-305)
This randomized, multicenter, double-blind, double-dummy, parallel group, active-controlled, non-inferiority study enrolled 410 subjects with type II diabetes mellitus and combined dyslipidemia. The subjects 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. The treatment difference 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.

Ongoing Study Commitments

  • Kowa has agreed to conduct a clinical trial to assess the effect of severe renal impairment on pitavastatin pharmacokinetics.
    Final Protocol Submission: October 30, 2009
    Study Completion Date: October 30, 2010
    Final Report Submission: December 31, 2010
  • Kowa has agreed to conduct a drug-drug interaction clinical trial to examine the effect of the combination of lopinavir/ritonavir on pitavastatin Cmax and AUC.
    Final Protocol Submission: October 30, 2009
    Study Completion Date: October 30, 2010
    Final Report Submission: December 31, 2010

Side Effects

Adverse events associated with the use of Livalo may include, but are not limited to, the following:

  • Back Pain
  • Constipation
  • Diarrhea
  • Myalgia
  • Pain in extremity

Mechanism of Action

Livalo is a HMG-CoA reductase inhibitor. It differs from other statins in that it has a unique cyclopropyl group on the base structure. This cyclopropyl group contributes to a more effective inhibition of the HMG-CoA reductase enzyme to inhibit cholesterol production, and potentially affords greater low-density lipoprotein cholesterol (LDL-C) clearance and reduction of plasma cholesterol.

Literature References

Yamakawa T, Takano T, Tanaka S, Kadonosono K, Terauchi Y Influence of pitavastatin on glucose tolerance in patients with type 2 diabetes mellitus. Journal of Atherosclerosis and Thrombosis 2008 Oct;15(5):269-75

Sasaki J, Ikeda Y, Kuribayashi T, Kajiwara K, Biro S, Yamamoto K, Ageta M, Kobori S, Saikawa T, Otonari T, Kono SL A 52-week, randomized, open-label, parallel-group comparison of the tolerability and effects of pitavastatin and atorvastatin on high-density lipoprotein cholesterol levels and glucose metabolism in Japanese patients with elevated levels of low-density lipoprotein cholesterol and glucose intolerance. Clinical Therapeutics 2008 Jun;30(6):1089-101

Kawai T, Tokui M, Funae O, Meguro S, Yamada S, Tabata M, Shimada A Efficacy of pitavastatin, a new HMG-CoA reductase inhibitor, on lipid and glucose metabolism in patients with type 2 diabetes. Diabetes Care 2005 Dec;28(12):2980-1

Park S, Kang HJ, Rim SJ, Ha JW, Oh BH, Chung N, Cho SY A randomized, open-label study to evaluate the efficacy and safety of pitavastatin compared with simvastatin in Korean patients with hypercholesterolemia. Clinical Therapeutics 2005 Jul;27(7):1074-82

Saito Y, Yamada N, Teramoto T, Itakura H, Hata Y, Nakaya N, Mabuchi H, Tushima M, Sasaki J, Goto Y, Ogawa N Clinical efficacy of pitavastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, in patients with hyperlipidemia. Dose-finding study using the double-blind, three-group parallel comparison. Arzneimittel-Forschung 2002;52(4):251-5

Saito Y, Yamada N, Teramoto T, Itakura H, Hata Y, Nakaya N, Mabuchi H, Tushima M, Sasaki J, Ogawa N, Goto Y A randomized, double-blind trial comparing the efficacy and safety of pitavastatin versus pravastatin in patients with primary hypercholesterolemia. Atherosclerosis 2002 Jun;162(2):373-9

Additional Information

For additional information regarding Livalo or primary hyperlipidemia and mixed dyslipidemia, please visit the Livalo web page.