Pitavastatin – PMX 205

Pitavastatin − pharmacological proﬁle from early phase studies

Alberico L. Catapano*
Professor of Pharmacology and Director, Centre for the Study of Atherosclerosis, Department of Pharmacological Sciences, University of Milan, and IRCSS Multimedica, Sesto S. Giovanni, Milan, Italy

Abstract

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.

Keywords: Pitavastatin; Statins; Dyslipidaemia; Hypercholesterolaemia; Drug–drug interactions

1. Introduction

Pitavastatin calcium (NK-104) was designed as a novel 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) re- ductase inhibitor (statin) with a synthetic cyclopropyl side group (Fig. 1). This unique structure contributes to a number of pharmacological beneﬁts compared to other statins, including inhibition of cholesterol synthesis at lower doses than the commonly-used statins, minimal metabolism leading to increased bioavailability and an extended duration of action, and a unique metabolic proﬁle that reduces the risk of drug–food and drug–drug interactions (DDIs) [1−4].

2. Mechanism of action

Statins are structurally similar to HMG-CoA and generally bind to HMG-CoA reductase with a several thousand-fold greater afﬁnity than the natural substrate [5]. This inhibits mevalonate production from HMG-CoA and reduces the level of intracellular cholesterol, thereby stimulating low- density lipoprotein- (LDL-) receptor activity and increasing the uptake of non-high-density lipoprotein (non-HDL) particles from the systemic circulation.

In vitro studies show that pitavastatin binds to HMG- CoA reductase with a 1.6- and 3.5-fold greater afﬁnity than simvastatin or pravastatin, respectively [4], and that it in- hibits HMG-CoA reductase in a competitive, concentration- dependent manner that is 2.4 times more potent than simvastatin and 6.8 times more potent than pravastatin [3]. Moreover, studies in HepG2 cells using radio-labelled LDL show that pitavastatin enhances LDL-receptor binding and LDL-internalisation in a dose-dependent manner, with a 2.7-fold increase in binding at 10−6 M (P < 0.01 vs. no pitavastatin) and a 2.4-fold increase in internalisation at 10−6 M (P < 0.01) [6]. Similarly, a further study showed that pitavastatin was associated with increased LDL-receptor mRNA expression in HepG2 cells – an effect that was signiﬁcantly more potent than that produced by either atorvastatin or simvastatin (P < 0.01 for both) [4]. Overall, these results are consistent with those from clinical trials, which demonstrate that pitavastatin effectively reduces LDL-C levels at lower doses than other statins [7−16]. In addition to reducing the level of cholesterol synthesis and increasing LDL uptake from the circulation, in vitro studies in HepG2 cells show that pitavastatin promotes the degradation of newly synthesised apolipoprotein B (apoB) [17], reduces very low-density lipoprotein-C (VLDL-C) and apoB secretion [18], and increases lipoprotein lipase activity by 30% more than other statins [19]. Moreover, pitavastatin appears to have a consistent beneﬁcial effect on HDL-C levels [20]. An ELISA-based study in HepG2 cells, for example, showed that pitavastatin 3 mM dose- dependently induced expression of apoAI – the major pro- tein component of HDL-C – to a greater extent than either simvastatin 10 mM or atorvastatin 30 mM [20]. This effect was inhibited by the addition of mevanolate, indicating an HMG-CoA reductase inhibition-dependent mechanism. Furthermore, pitavastatin increased ATP-binding cassette transporter ABCA1 (cholesterol efﬂux regulatory protein) mRNA expression, thereby promoting apoA1 and apoE lipidation and protecting apoA1 from catabolism, and suppressed Rho and Rho kinase activity, thereby increasing apoA1 levels via a third pathway. Since low levels of HDL-C are associated with a higher risk of coronary heart disease, even in patients with ‘normal’ (<1.8 mmol/L; <70 mg/dL) LDL-C [21−23], pitavastatin has the potential to reduce CV risk by increasing HDL-C levels as well as by reducing total cholesterol (TC), LDL-C, apoB, and triglyceride (TG) concentrations. 3. Pharmacokinetic proﬁle of pitavastatin The pharmacokinetic proﬁles of statins vary considerably between drugs. For example, systemic bioavailability ranges from 5% with simvastatin and lovastatin to >60% with pitavastatin (Table 1), depending on the extent of ﬁrst-pass metabolism and variations in the activity of intestinal and hepatic transport proteins [2]. Pitavastatin’s oral absorption is, at 80%, second only to ﬂuvastatin and protein binding varies from >95% for pitavastatin, simvastatin, atorvastatin and lovastatin, to 50% for pravastatin [24,25]. However, the most important differences between pitavastatin and other statins are due to metabolism. Whereas lovastatin, simvastatin and atorvastatin are metabolised predominantly by cytochrome P450 (CYP)3A4 and ﬂuvastatin and rosuvas- tatin are metabolised by CYP2C9, pitavastatin’s cyclopropyl group diverts the drug away from metabolism by CYP3A4 and allows only a small amount of clinically insigniﬁcant metabolism by CYP2C9 (Fig. 2) [25−29]. As a result, most of the bioavailable fraction of an oral dose of pitavastatin is excreted unchanged in the bile and is then ready for entero- hepatic circulation by reabsorption in the small bowel. Less than 5% of a dose of pitavastatin is excreted in the urine.

Fig. 2. Pitavastatin and pitavastatin lactone: Distribution, metabolism and mechanisms of potential drug–drug interactions (modiﬁed from [30]). The drugs listed are substrates for the pathways indicated and therefore have the potential to interact with pitavastatin. OATP, organic anion transporting polypeptide; MDR1, multidrug resistance associated protein 1; NTCP, sodium taurocholate cotransporting polypeptide; BCRP, breast cancer resistance protein.

Most statins are administered orally as an active acidic form that is biotransformed by glucuronosyltransferase (UGT) to a very unstable compound. This compound is then quickly converted to a lactone metabolite, which is rapidly metabolised by CYP450 isoenzymes [25,27,30]. In human hepatic microsomes the metabolic clearance of the lactone metabolites of atorvastatin, simvastatin, and rosuvastatin is between 64- and 73-fold higher than the biotransformation of the acid forms of these statins. The metabolic clearance of the acid and lactone forms of atorvastatin and simvas- tatin, for example, are 26 and 1892 ml/min/mg protein, re- spectively, and 28 and 1959 ml/min/mg protein. In contrast, both pitavastatin acid and lactone show little metabolism in human hepatic microsomes (metabolic clearance 3 and 5 ml/min/mg protein, respectively) [27]. Thus, pitavastatin has a unique metabolic proﬁle compared to other statins that contributes to an increased bioavailability, a longer duration of action and a lower probability of drug–food or drug–drug interactions.

4. Safety and tolerability

The safety, tolerability and pharmacokinetics of pitavastatin and pitavastatin lactone have been investigated in a number of different patient groups with similar results [31]. In healthy Caucasian subjects (N = 71), pitavastatin 1−64 mg or placebo was administered under fasted conditions on Day 1, followed by a 7-day washout period and then once daily dosing under fed conditions for 2 weeks. After multiple
dosing, pitavastatin was rapidly absorbed with a median Tmax of 1.0−1.8 hours. The Cmax and AUC for pitavastatin and pitavastatin lactone increased in an approximately dose- proportional manner for both single and multiple once-daily administrations and there was no relevant drug accumula- tion (mean AUC0−24 Day 21 : AUC0−24 Day 8 ratios ranged from 1.0 to 1.5). The mean t1/ 2 was 8−9 hours after a single-dose administration and 9−12 hours after multiple dosing, suggesting there was no relevant accumulation after repeated, once-daily doses. A steady-state was reached after approximately 4 days. In this study, pitavastatin 1−64 mg was well tolerated with no serious adverse events (AEs) and no signiﬁcant changes in safety or laboratory parameters, including alanine transaminase, aspartate transaminase, and creatinine kinase.

5. Pitavastatin has a low potential for DDIs

To attain their recommended LDL-C targets, patients with dyslipidaemia and high CV risk often require combinations of lipid-lowering agents that include statins, ezetimibe, niacin, and/or bile acid sequestrants. Furthermore, since dyslipidaemia frequently coexists with conditions such as hypertension, diabetes, and renal disease, additional agents for the treatment of chronic conditions are often used alongside these drugs. Combinations of certain drugs can increase the plasma concentration of statins [32] and increase the risk of statin-related AEs, including myopa- thy and rhabdomyolysis [33]. Whereas most statins are rapidly metabolised by CYP isoenzymes – in particular CYP3A4 – pitavastatin acid undergoes only a small amount of metabolism by CYP2C9 and UGT and none at all by CYP3A4 (Fig. 2) [26,27]. Consequently, pitavastatin at the recommended doses for clinical use is likely to have a better DDI proﬁle than other statins.

In general, substrates for CYP2C9 and UGT, such as warfarin [34], fenoﬁbrate, and rifampicin do not interact signiﬁcantly with pitavastatin [24]. Although fenoﬁbrate increases pitavastatin’s steady state AUC0−24 by 18%, concurrent administration is well-tolerated and the interac- tion is not clinically signiﬁcant [35]. Furthermore, whereas the co-administration of CYP3A4 inhibitors with other statins causes signiﬁcant clinical effects, co-administration with pitavastatin does not. Concurrent administration of atorvastatin with grapefruit juice (a CYP3A4 inhibitor), for example, increases the mean AUC0−24 by 83% for atorvastatin and by only 13% for pitavastatin [36].

Pitavastatin is transported from the circulation into the liver by organic anion-transporting polypeptides (OATPs) and from the liver to the bile duct by Breast Cancer Resistance Protein (BCRP), and for the lactone, Multi- drug Resistance Associated Protein 1 (MDR1) (Fig. 2) [28,29,37]. Whereas interactions between MDR and sim- vastatin/atorvastatin are thought to be responsible for the increased risk of rhabdomyolysis in people taking these statins with digoxin [38,39], drugs that either inhibit or compete with MDR do not interact signiﬁcantly with pitavastatin [24]. In contrast, pitavastatin has limited inter- actions with a number of OATP1B1 inhibitors. Gemﬁbrozil, for example, inhibits OATP1B1 and increases the AUC of pitavastatin 1.4-fold [40]. However, given the interactions between gemﬁbrozil and lovastatin (3.8-fold increase in AUC), simvastatin (1.9-fold), pravastatin (2.2-fold) and rosuvastatin (1.9-fold) [41], pitavastatin appears to be less dependent on OATP1B1 transportation than other statins. This observation is also reﬂected by the interaction between ciclosporin and statins. Co-administration of pitavastatin and ciclosporin, for example, increased the mean AUC0−24 of pitavastatin by 4.6-fold compared to 8.7- and 7-fold for atorvastatin and rosuvastatin, respectively [40]. Whilst the pharmacokinetic interaction between ciclosporin and pitavastatin is less marked than with other statins, there is not enough clinical data to demonstrate safety and the co- administration of ciclosporin with pitavastatin is currently contraindicated. Nevertheless, most studies demonstrate that pitavastatin has a lower potential for DDIs than the most commonly used statins, making it an excellent choice for dyslipidaemic patients that require polypharmacy.

6. Conclusions

Early phase studies suggest that pitavastatin’s unique cyclo- propyl side-group offers a number of pharmacokinetic bene- ﬁts compared to other statins [1−4]. These include a greater inhibition of HMG-CoA reductase [3] and cholesterol syn- thesis [4], increased LDL-receptor activity, and increased HDL-C production in HepG2 cells [20]. These observations, together with pitavastatin’s minimal metabolism and high bioavailability, explain why pitavastatin achieves signiﬁcant LDL-C reductions and HDL-C increases at doses lower than many other statins. Unlike other statins, pitavastatin’s cyclopropyl group diverts the drug away from metabolism by CYP isoenzymes and, although pitavastatin undergoes a small amount of clinically insigniﬁcant metabolism by CYP2C9, it is not metabolised by CYP3A4 and therefore has a reduced risk of DDIs. This metabolic stability is likely to have signiﬁcant beneﬁts in the vast numbers of dyslipidaemic patients that require additional medications for concomitant conditions, such as hypertension, diabetes, and acute coronary syndromes. Thus, early phase studies suggest that pitavastatin has potential as a useful addition to the statin family.

Conﬂict of interest statement

Prof. Catapano has received speaker fees from AstraZeneca, Merck, Schering-Plough, Pﬁzer, sanoﬁ-aventis, and Kowa.

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