New Data Showed Minimal Potential for Drug Interaction Between Cholesterol Drug LIVALO® and a Common Antiretroviral Therapy

MONTGOMERY, Ala. and INDIANAPOLIS, July 18, 2011 /PRNewswire/ -- Kowa Pharmaceuticals America, Inc. and Eli Lilly and Company (NYSE: LLY) today released new study results that investigated the potential interaction of cholesterol drug LIVALO (pitavastatin) 4 mg in healthy volunteers taking the protease inhibitor (PI) combination lopinavir/ritonavir, a fixed dose combination drug for the treatment of HIV infection.(1)  Protease inhibitors are commonly used antiretroviral HIV medications.(2)  The study, presented at the 6th International AIDS Society (IAS) Conference on HIV Pathogenesis, Treatment and Prevention in Rome, Italy, found that when co-administered, the individual drug blood levels for LIVALO or each of the PIs was minimally affected.  Based on these data from this FDA-mandated phase IV study, the United States Food and Drug Administration recently approved a labeling change to delete the lopinavir/ritonavir limitation of use from the U.S. LIVALO labeling.

(Logo:  http://photos.prnewswire.com/prnh/20100621/NY23523LOGO)

"HIV is a chronic illness today, as opposed to 30 years ago, and patients with HIV are faced with additional challenges concerning dyslipidemia, accentuated by both the disease process as well as antiretroviral therapies. Additionally, these patients are frequently on multiple medications and the management of dyslipidemia can be even more of a challenge. We are pleased with the results of this study and the absence of a significant drug interaction when LIVALO is co-administered with this combination of protease inhibitors," said Craig Sponseller, MD, Vice President of Medical Affairs, Kowa Pharmaceuticals America, Inc.  

The study was designed to assess the pharmacokinetic (PK) interaction, or effect on overall exposure in the body, of the combination lopinavir/ritonavir on the PK of LIVALO, and secondarily any potential PK effect of LIVALO on lopinavir and ritonavir.(3)  LIVALO (4 mg) and lopinavir/ritonavir (800 mg/200 mg) were co-administered in 24 healthy, adult volunteers over a 24 day period.  At study end, peak exposure of pitavastatin at steady state, as measured by C(max), was not affected by co-administration of lopinavir/ritonavir. Total exposure of pitavastatin at steady state, as measured by AUC(0-T), was weakly affected by co-administration of lopinavir/ritonavir (decrease of approximately 20%). C(max) and AUC(0-T) of lopinavir and ritonavir at steady state were marginally affected by co-administration of pitavastatin. These effects were not considered to be clinically significant.(4)

A second objective of the study was to investigate any potential effect on the safety of LIVALO by the addition of lopinavir/ritonavir. No significant safety issues were observed. Eighteen of 24 patients reported at least one treatment emergent adverse event (TEAE), with the highest percentage coming from subjects receiving lopinavir/ritonavir only. All TEAEs were mild in severity, except for four subjects who had TEAEs after lopinavir/ritonavir only that were moderate in severity.  One subject was discontinued from the study because of an adverse event (AE) of diarrhea during treatment with lopinavir/ritonavir only. There were no severe AEs, SAEs, or deaths.(5)

"This study is important to caregivers and patients alike, as LIVALO showed minimal drug-drug interactions with a common antiretroviral therapy HIV patients need to fight the disease. For a patient population that is taking multiple medications, this is exciting news," said Dr. Judith Aberg, Director of Virology, Bellevue Hospital Center and Director, Division of Infectious Diseases and Immunology, NYU School of Medicine.  

Elevated cholesterol, particularly the "bad" cholesterol, low density lipoprotein cholesterol (LDL-C), triglycerides (TG), or both, is a common complication associated with HIV infection as well as the use of antiretroviral therapies.(6,7)  The frequency of hyperlipidemia, elevation of fats in the blood, in HIV-infected patients taking protease inhibitors, including lopinavir/ritonavir, is up to 66 percent of the patient population.(8)

Cholesterol-lowering drugs, particularly statins, are often used in patients with HIV; therefore it is important for physicians to understand the potential drug-drug interactions with antiretroviral therapies.

About LIVALO

LIVALO is a HMG-CoA reductase inhibitor indicated for patients with primary hyperlipidemia and mixed dyslipidemia 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 high-density lipoprotein cholesterol (HDL-C).  LIVALO is predominantly metabolized via glucuronidation and is only minimally metabolized by CYP system, which may help reduce its potential for CYP-mediated drug-drug interactions.

In addition to being launched in the U.S. June 2010, LIVALO is also approved in Japan (2003), South Korea (2005), Thailand (2007), China (2008), European Union (2010), Taiwan (2011) and Lebanon (2011).

About Primary Hyperlipidemia and Mixed Dyslipidemia

Primary Hyperlipidemia is defined as an elevation of cholesterol, particularly "bad" cholesterol (LDL-C), triglycerides (TG), or both. Mixed dyslipidemia is usually characterized by an elevation of LDL-C, TG, and a decrease in the "good" cholesterol (HDL-C) in the blood.

Despite the availability of treatments in the U.S. there is still a need for more options to help treat elevated cholesterol. According to the American Heart Association, approximately one out of every three American adults has an LDL-C level of 130 mg/dL or higher, which is a major health risk. In addition, less than half of patients who qualify for any kind of lipid-modifying treatment are receiving it, and only about one-third of patients who are on treatment are achieving their LDL-C goals.

What is LIVALO?

LIVALO is a prescription medicine that, along with diet, has been approved for the treatment of high cholesterol.

LIVALO has not been studied to evaluate its effect on reducing heart-related disease or death.

LIVALO Important Safety Information

Who should NOT take LIVALO?

LIVALO is not right for everyone, including:

• Those who have had an allergic reaction to LIVALO
• Anyone with liver disease
• Patients with severe kidney disease not on hemodialysis
• Women who are nursing, pregnant, or who may become pregnant
• Anyone currently taking cyclosporine

What should I talk to my doctor about?

• If you take LIVALO, tell your doctor right away if you experience any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by fever or a general feeling of discomfort. This could be a sign of a rare but serious side effect.  
• Your doctor should do blood tests to monitor your liver function before starting LIVALO, and then at 12 weeks following the start of LIVALO, after any increase in dose, and periodically (e.g., every 6 months) thereafter.
• Please talk to your doctor about your alcohol use.
• Tell your doctor about all the medications you take including nonprescription medicines, vitamins, or herbal supplements.

What are the most common side effects of LIVALO?

The most common side effects of LIVALO in clinical studies were:

• Back pain
• Constipation
• Diarrhea
• Muscle pain
• Pain in the legs or arms

This is not a complete list of side effects.  

For more information about LIVALO, and to access the Full Prescribing Information go to www.LIVALORX.com.  

(1) Sponseller, C. Effects of Steady State Lopinavir/Ritonavir on the Pharmacokinetics of Pitavastatin in Healthy Adult Volunteers.  6th International AIDS Society (IAS) Conference on HIV Pathogenesis, Treatment and Prevention.  Rome, Italy.  July 17-20, 2011.

(2) Sponseller, C. Effects of Steady State Lopinavir/Ritonavir on the Pharmacokinetics of Pitavastatin in Healthy Adult Volunteers.  6th International AIDS Society (IAS) Conference on HIV Pathogenesis, Treatment and Prevention.  Rome, Italy.  July 17-20, 2011.

(3) Sponseller, C. Effects of Steady State Lopinavir/Ritonavir on the Pharmacokinetics of Pitavastatin in Healthy Adult Volunteers.  6th International AIDS Society (IAS) Conference on HIV Pathogenesis, Treatment and Prevention.  Rome, Italy.  July 17-20, 2011.

(4) Sponseller, C. Effects of Steady State Lopinavir/Ritonavir on the Pharmacokinetics of Pitavastatin in Healthy Adult Volunteers.  6th  International AIDS Society (IAS) Conference on HIV Pathogenesis, Treatment and Prevention.  Rome, Italy.  July 17-20, 2011.

(5) Sponseller, C. Effects of Steady State Lopinavir/Ritonavir on the Pharmacokinetics of Pitavastatin in Healthy Adult Volunteers.  6th International AIDS Society (IAS) Conference on HIV Pathogenesis, Treatment and Prevention.  Rome, Italy.  July 17-20, 2011.

(6) Calza L, Manfredi R, Pocaterra D, Chiodo F. Risk of premature atherosclerosis and ischemic heart disease associated with HIV infection and antiretroviral therapy. J Infect 2008; 57:16-32.

(7) Echevarria KL, Hardin TC, Smith JA. Hyperlipidemia associated with protease inhibitor therapy. Ann Pharmacother. 1999; 33:859-63.

(8) Kaul DR, Cinti SK, Carver PL et al. HIV protease inhibitors: advances in therapy and adverse reactions, including metabolic complications. Pharmacotherapy. 1999; 19:281-98.

About Kowa Company, Ltd. and Kowa Pharmaceuticals America, Inc.

Kowa Company, Ltd. (KCL) is a privately held multinational company headquartered in Nagoya, Japan. Established in 1894, KCL is actively engaged in various manufacturing and commercial activities in the fields of pharmaceutical, life science, information technology, textiles, machinery and various consumer products. KCL's pharmaceutical division is focused on cardiovascular therapeutics, with sales of the company's flagship product LIVALO, totaling $530 million (14.6% market share) in Japan in the 2010 fiscal year, and was launched in the United States in June 2010.

Kowa Pharmaceuticals America, Inc. (KPA) is a pharmaceutical company specializing primarily in the area of cardiometabolic diseases. The company, started in 2001 as ProEthic Pharmaceuticals, Inc., was acquired by KCL in September of 2008. A privately held company, KPA directs its efforts towards the acquisition, licensing and marketing of pharmaceutical products.  

exchange rate used $1=85JPY

About Lilly

Lilly, a leading innovation-driven corporation, is developing a growing portfolio of pharmaceutical products by applying the latest research from its own worldwide laboratories and from collaborations with eminent scientific organizations. Headquartered in Indianapolis, Ind., Lilly provides answers – through medicines and information – for some of the world's most urgent medical needs. Additional information about Lilly is available at www.lilly.com.   P-LLY

This news release contains forward-looking statements. These statements are subject to known and unknown risks and uncertainties that may cause actual future experience and results to differ materially from the statements made. Factors that might cause such a difference include, among others, Lilly and Kowa abilities to successfully commercialize and market LIVALO, competition from other pharmaceutical companies (including generic versions of other statin products), potential regulatory developments affecting the product, and other factors described in Lilly's most recent filings with the Securities and Exchange Commission. For additional information about the factors that affect the company's business, please see Lilly's latest Form 10-K, filed February 2009, and Form 10-Q filed October 2009. Lilly undertakes no duty to update forward-looking statements.

LIVALO is a registered trademark of the Kowa group of companies.

PS72893 LIV-MT-124

SOURCE Kowa Pharmaceuticals America, Inc.