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

WOKINGHAM, England, July 18, 2011 /PRNewswire/ --

- Study Demonstrated no Significant Impact on Blood Levels When LIVAZO (pitavastatin) was Taken With HIV Protease Inhibitor Combination lopinavir/ritonavir in Healthy Volunteers

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, known as LIVAZO in the EU) 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 6^th 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 LIVAZO or each of the PIs was minimally affected. Based on the data from this FDA mandated phase IV study, the United States Food and Drug Administration recently approved a labelling change to delete the lopinavir/ritonavir limitation of use from the US LIVALO labelling.

"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 PIs" 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 LIVAZO, and secondarily any potential PK effect of LIVAZO on lopinavir and ritonavir.^[3] LIVAZO (4mg) and lopinavir/ritonavir (800mg/200mg) 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-tau was weakly affected by co-administration of lopinavir/ritonavir (decrease of approximately 20%). C_max and AUC_0-tau 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 LIVAZO 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 AE of diarrhoea 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 LIVAZO

LIVAZO 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 cholestrerol (LDL-C), apolipoprotein B (Apo B), triglycerides (TG), and to increase high-density lipoprotein cholesterol (HDL-C) LIVAZO 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, LIVAZO is also approved in Japan (2003), South Korea (2005), Thailand (2007), China (2008), European Union (2010), Taiwan (2011) and Lebanon (2011.)

About Kowa

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 was founded in 1947, and is focused on cardiovascular therapeutics, with sales of the company's flagship product, LIVALO, totalling $520 million (14.3% market share) in Japan during 2010 and expected to exceed $700 million in the near future.

Kowa Research Europe Ltd. (KRE), established in 1999 in the United Kingdom, is responsible for European clinical trials for Kowa's strategic global pharmaceutical development.

Kowa Pharmaceutical Europe (KPE) Co. Ltd, established in 2000, is a specialty pharmaceutical company located in Wokingham, UK, focused primarily on cardiometabolic therapeutics. Working in harmony with KRE, these European pharmaceutical divisions of Japanese Kowa Company, Ltd. are committed to ground-breaking research, development and marketing to ensure quality products are made available to people around the world, enabling them to enjoy a better standard of health and a more comfortable life.

Visit our New Website: http://www.kowapharmaceuticals.eu/

References

^[1] Sponseller, C. Effects of Steady State Lopinavir/Ritonavir on the Pharmacokinetics of Pitavastatin in Healthy Adult Volunteers. 6^th 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. 6^th 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. 6^th 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. 6^th 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. 6^th 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, CintiSK, Carver PL et al. HIV protease inhibitors: advances in therapy and adverse reactions, including metabolic complications. Pharmacotherapy. 1999; 19:281-98.

^[9] Guengerich FP. Chem Res Toxicol. 2008;21(1):70-83; Jayakanthan M et al. Analysis of CYP3A4-HIV-1 protease drugs interactions by computational methods for Highly Active Antiretroviral Therapy in HIV/AIDS Mol Graph Model. 2010 Jan;28(5):455-63.