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02.09.2009 – 08:35

Kowa Company, Ltd.

Pitavastatin Demonstrates no Significant Drug-to-Drug Interaction When Administered With CYP3A4 Inhibitors

Barcelona, Spain (ots/PRNewswire)

- Data Shows Potential Tolerability Advantage for Pitavastatin
Compared With Other Statins
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
    - 90% confidence intervals (CI) were calculated for geometric mean ratios
      of maximum drug concentration (Cmax) 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 Cmax and AUC0-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.
    - The co-administration of itraconazole slightly reduced mean Cmax,
      AUC0-t and AUC0-inf but did not influence any other parameter for
      pitavastatin or PL. The 90% CI of the ratio of the means of AUC0-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 Cmax and AUC0-t for
      pitavastatin (0.69 and 0.71 respectively) and Cmax 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
    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 SpA. Pitavastatin
will be available in three dosage strengths (1, 2 and 4 mg).
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
For more information about Kowa, please visit
(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:
dicine/1424/SPC/Lipitor+10mg%2c+20mg%2c+40mg%2c+80mg+Tablets/  (last
accessed 25.08.09)
(Due to the length of this URL, it may be necessary to copy and
paste this hyperlink into your Internet browser's URL address field.
Remove the space if one exists.)
(4) Phatak H et al Atherosclerosis 2009;202:225-33
(5) Ferrieres J et al Arch Cardiovasc Dis 2008;101:557-63
(6) Garcia 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


CONTACT: Laura Anderson, +44(0)207-861-3033,