Pitavastatin - pharmacological profile from early phase studies.

Pitavastatin has been designed as a synthetic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor with a novel cyclopropyl moiety that results in several differences compared to other statins. These include effective inhibition of cholesterol synthesis and increased lipoprotein lipase expression at lower doses than other statins, and significant high-density lipoprotein-cholesterol and apolipoprotein A1-elevating activity that persists with time. The safety, tolerability and pharmacokinetics of pitavastatin and its major metabolite, pitavastatin lactone, have been investigated in a variety of patient groups with similar results, which suggests dosage adjustments are not required for gender, age or race. In healthy subjects, pitavastatin is well tolerated at the approved doses with no serious adverse events. The bioavailability of pitavastatin is, at 60%, higher than that of any other statin and the majority of the bioavailable fraction of an oral dose is excreted unchanged in the bile. The entero-hepatic circulation of unchanged drug contributes to the prolonged duration of action and allows once-daily, any-time dosing. Pitavastatin is only slightly metabolised by cytochrome P450 (CYP) 2C9 and not at all by CYP3A4. Neither pitavastatin nor its lactone form, have inhibitory effects on CYP, and CYP3A4 inhibitors have no effect on pitavastatin concentrations. Moreover, P-glycoprotein-mediated transport does not play a major role in the drug's disposition and pitavastatin does not inhibit P-glycoprotein activity. Pitavastatin is transported into the liver by several hepatic transporters but OATP1B1 inhibitors have relatively little effect on plasma concentrations compared with other statins. In general, interactions, except with multi-transporter inhibitors like ciclosporin, are not clinically significant. Consequently, pitavastatin has minimal drug-food and drug-drug interactions making it a treatment option in the large group of dyslipidaemic people that require multidrug therapy.