Pitavastatin demonstrates no significant drug-to-drug interaction when administered with CYP3A4 inhibitors

Data shows potential tolerability advantage for pitavastatin compared with other statins

Milan, 21 September 2009 – New data presented at the European Society of Cardiology congress (ESC) demonstrated that the co-administration of the cytochrome inhibitor itraconazole has no clinically relevant effect on the pharmacokinetics of pitavastatin, in healthy volunteers.

Many of the existing statins such as atorvastatin and simvastatin are metabolised by cytochromes, particularly CYP3A4, and inhibitors of this pathway such as itraconazole and grapefruit juice can increase plasma concentrations of the statins.  Taking one of these statins with a CYP3A4 inhibitor can increase the risk of a patient being hospitalised with severe muscle problems six-fold.²  Administration of atorvastatin with itraconazole can increase atorvastatin plasma concentrations 2.5-3.3 times normal and even certain foods, like grapefruit juice can increase plasma concentrations by 80%.³

Previous studies with pitavastatin show that grapefruit juice does not have a significant effect on plasma concentrations (concentrations increased by <20%).¹  This study supports previous findings and showed that itraconazole, an antifungal agent that strongly inhibits CYP3A4, did not increase plasma concentrations of pitavastatin or its main metabolite pitavastatin lactone, thus potentially reducing the incidence of adverse events.

The primary objective of the study was to determine any potential pharmacokinetic interaction of itraconazole 200 mg on the pharmacokinetics of pitavastatin 4 mg. The secondary objective was to assess the safety of pitavastatin 4 mg with the addition of itraconazole. In this open-label study, 18 healthy males (18-55 years) received pitavastatin 4 mg (QD) on days 1 and 8, and itraconazole 200 mg (QD) on days 5 to 9.

Analysis of variance (ANOVA) was carried out and confirmed a lack of clinically relevant interactions between itraconazole and pitavastatin. Single-dose pitavastatin was tolerated both as monotherapy and when combined with itraconazole, and no subjects withdrew from the study.  Furthermore, pitavastatin was not associated with attributable moderate or severe adverse events or clinically relevant changes in laboratory, vital or physical signs or ECG.
 
“This study suggests that pitavastatin’s metabolic route may offer a favorable tolerability profile when administered with drugs that inhibit CYP3A4, compared to some other statins,” said Dr Neil Hounslow, Vice President of scientific affairs, Kowa Research Europe. “Combined with pitavastatin’s safety and efficacy profile, a lower risk of DDIs would provide a long-term treatment option for patients with dyslipidaemia.”

While statins are the mainstay of dyslipidaemia management, many patients do not reach clinically optimal lipid targets.^4-7 Many patients taking statins metabolised by CYP3A4 inhibitors require concurrent medications which can result in drug-to-drug interactions (DDIs), and subsequent drug non-compliance.^8,9 This data suggests that pitavastatin is well tolerated statin which has the potential for fewer adverse events and greater long-term treatment compliance.

Notes to editors

Methodology:
• 90% confidence intervals (CI) were calculated for geometric mean ratios of maximum drug concentration (C_max) and area under the plasma concentration-time curve from time 0 to the last measurable concentration (AUC0–t) and between day 1 and day 8 for pitavastatin and its inactive lactone metabolite (PL).
• Analysis of C_max and AUC_0–t was carried out by analysis of variance (ANOVA), with the acceptance range to conclude a lack of DDIs at 0.80 to 1.25.

Results:
• The co-administration of itraconazole slightly reduced mean C_max, AUC_0-t and AUC_0–inf but did not influence any other parameter for pitavastatin or PL. The 90% CI of the ratio of the means of AUC_0-t for PL on days 1 and 8 was inside the predefined range (0.86).
• The lower 90% CIs of the ratios of the means of C_max and AUC_0-t for pitavastatin (0.69 and 0.71 respectively) and C_max for PL (0.76) on days 1 and 8 were marginally outside the predefined range at the low end, suggesting that any interaction is unlikely to be clinically relevant.

Safety evaluations assessed:
• Adverse events, clinical laboratory tests (serum chemistry, heamatology and urinalysis), vital signs, 12-lead electrocardiograms (ECGs) and physical examinations.

About pitavastatin
Pitavastatin (a statin) is a fully synthetic and highly potent inhibitor of HMG-CoA reductase used for primary hypercholesterolaemia and combined dyslipidaemia. Pitavastatin has a unique cyclopropyl group on the base structure common to the statin class.  Since its 2003 launch in Japan, pitavastatin has accumulated millions of patient-years of exposure. Many of these patients have comorbidities and are taking multiple medications. Kowa received FDA approval of pitavastatin  for the primary treatment of hypercholesterolemia and combined dyslipidemia in August 2009, and is expected to launch in the U.S. during Q1 of 2010. Additionally, Kowa filed in Europe in August 2008 using the decentralised authorisation procedure. In Europe, pitavastatin will be marketed by Recordati. Pitavastatin will be available in three dosage strengths (1, 2 and 4 mg).

About Recordati
Recordati, established in 1926, is a European pharmaceutical group, listed on the Italian Stock Exchange (Reuters RECI.MI, Bloomberg REC IM, ISIN IT 0003828271),with a total staff of over 2,950, dedicated to the research, development, manufacturing and marketing of pharmaceuticals. It has headquarters in Milan, Italy, operations in the main European countries, and a growing presence in the new markets of Central and Eastern Europe.  A European field force of over 1,450 medical representatives promotes a wide range of innovative pharmaceuticals, both proprietary and under license, in a number of therapeutic areas including a specialized business dedicated to treatments for rare diseases. Recordati’s current and growing coverage of the European pharmaceutical market makes it a partner of choice for new product licenses from companies which do not have European marketing organizations.  Recordati is committed to the research and development of new drug entities within the cardiovascular and urogenital therapeutic areas and of treatments for rare diseases.  Consolidated revenue for 2008 was € 689.6 million, operating income was € 144.7 million and net income was € 100.4 million.

For further information:

Recordati website: www.recordati.com

About Kowa
Since its establishment in 1894, Kowa has grown into a multinational Japanese company actively engaged in various manufacturing and trading activities in the fields of pharmaceutical, life science and information technology, textiles, machinery and various consumer products. Kowa focuses its efforts on the acquisition, development, licensing and marketing of pharmaceutical products. During its long history, Kowa has consistently strived to meet the changing needs of the global market, and with its continuing entrepreneurial initiative, is determined to meet the needs of future generations. It is this commitment to consistency and initiative in an ever-changing world that Kowa vows to carry forward through each generation.

For more information about Kowa, please visit www.kowa.com.
CONTACT:
Laura Anderson
+44 (0)207 861 3033
l.anderson@bellpottingerhealth.com

References
1. Ando H, et al Br J Clin Pharmacol 2005;60(5): 494–497
2. Cziraky MJ et  al Am J Cardiol   2006;97:61C-68C
3. Atorvastatin SPC avaliable at: http://emc.medicines.org.uk/medicine/1424/SPC/Lipitor+10mg%2c+20mg%2c+40mg%2c+80mg+Tablets/ (last accessed 25.08.09)
4. Phatak H et al Atherosclerosis 2009;202:225-33
5. Ferrières J et al Arch Cardiovasc Dis 2008;101:557-63
6. García Ruiz FJ et al Pharmacoeconomics 2004;22 Suppl 3:1-12
7. Hermans MP et al Acta Cardiol 2009;64:177-85
8. Devold HM et al Br J Clin Pharmacol 2009;67:234-41
9. Cziraky MJ et al Am J Cardiol 2006;97:61C-68C

Statements contained in this release, other than historical facts, are "forward-looking statements" (as such term is defined in the Private Securities Litigation Reform Act of 1995). These statements are based on currently available information, on current best estimates, and on assumptions believed to be reasonable. This information, these estimates and assumptions may prove to be incomplete or erroneous, and involve numerous risks and uncertainties, beyond the Company’s control. Hence, actual results may differ materially from those expressed or implied by such forward-looking statements. All mentions and descriptions of Recordati products are intended solely as information on the general nature of the company’s activities and are not intended to indicate the advisability of administering any product in any particular instance.