Pharmacokinetic drug evaluation of ezetimibe +

Expert Opinion on Drug Metabolism & Toxicology

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Pharmacokinetic drug evaluation of ezetimibe + simvastatin for the treatment of hypercholesterolemia Marilisa Bove, Federica Fogacci & Arrigo F. G. Cicero To cite this article: Marilisa Bove, Federica Fogacci & Arrigo F. G. Cicero (2017): Pharmacokinetic drug evaluation of ezetimibe + simvastatin for the treatment of hypercholesterolemia, Expert Opinion on Drug Metabolism & Toxicology, DOI: 10.1080/17425255.2017.1381085 To link to this article: http://dx.doi.org/10.1080/17425255.2017.1381085

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Date: 26 September 2017, At: 00:55

EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY, 2017 https://doi.org/10.1080/17425255.2017.1381085

DRUG EVALUATION

Pharmacokinetic drug evaluation of ezetimibe + simvastatin for the treatment of hypercholesterolemia Marilisa Bove, Federica Fogacci

and Arrigo F. G. Cicero

Downloaded by [87.6.95.103] at 00:55 26 September 2017

Internal and Surgical Medicine Sciences Department, University of Bologna, Bologna, Italy ABSTRACT

ARTICLE HISTORY

Introduction: Cholesterol lowering treatment is mainly based on statins eventually associated to adjunctive drugs of different class such as ezetimibe. In the present review, we analysed the pharmacokinetics, efficacy and safety of ezetimibe + simvastatin drug association. Areas covered: The bio-equivalence of ezetimibe and simvastatin when co-administrated in separate tablets or combined in a single pill is well documented. Ezetimibe is absorbed in small intestine, reaching peak plasma concentrations in 4–12 h, with a plasma half-life of 22 h. Simvastatin, ingested as a prodrug, is hydrolyzed in liver to its active beta-hydroxyacid metabolite, reaching peak plasma concentrations in 2–4 h, with a plasma half-life of approximately 5 h. The available evidence support the clinical efficacy of this drug combination, both in term of LDL-cholesterol reduction and cardiovascular risk decrease. Expert opinion: The synergistic action of these two drugs and the efficacy and safety extensively demonstrated of their association (in particular in the large IMProved Reduction of Outcomes: Vytorin Efficacy International Trial -IMPROVE-IT-) promote its clinical use, especially in subjects with high cardiovascular risk who need to optimize their LDL-Cholesterolemia, but also in patients who cannot tolerate high-dose of more powerful statins.

Received 26 February 2017 Accepted 14 September 2017

1. Introduction Hypercholesterolemia is a major risk factor for cardiovascular disease (CVD), the leading cause of death in the Western world [1]. The international guidelines on CVD prevention agree that the cholesterol-lowering treatment has to be mainly based on the prescription of statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors), eventually associated to adjunctive drugs with different mechanisms of action such as ezetimibe, bile acid sequestrants, and fibrates [2]. The main difference regards the management of high-risk subjects. The US guidelines for CVD prevention recommend the administration of the maximum tolerated dose of statins in order to obtain a reduction of at least 50% of low-density-lipoprotein cholesterol (LDL-C) [3], whereas other national guidelines suggest the achievement of specific target LDL-C values [4], while the European guidelines prompt a mixed approach, privileging specific LDL-C target but accepting a minimal reduction of 50% for high-risk subjects [5]. Ensuring endogenous cholesterol reduction, statin treatment promotes the prevention of cardiovascular and cerebrovascular events in patients with hypercholesterolemia resistant to diet therapy [6]. However, statin intolerance is a relatively common event and is a common cause of treatment interruption or dose reduction [7]. On the other side, even the most powerful statins, when used in monotherapy, are not able to optimize LDL-C levels in the most severe familial forms of hypercholesterolemia and in patients with a very high cardiovascular risk profile; consequently, adding a second or third lipid-lowering drug can be necessary [8,9]. In October 2002, the US FDA approved the use of ezetimibe as a

CONTACT Arrigo F. G. Cicero

[email protected]

© 2017 Informa UK Limited, trading as Taylor & Francis Group

KEYWORDS

Ezetimibe/simvastatin administration; pharmacokinetics; efficacy; safety

specific inhibitor of intestinal cholesterol absorption. Then, the ezetimibe/simvastatin combination in a single tablet with a fixed dose of ezetimibe (10 mg) and variable doses of simvastatin (10/ 20/40 mg) was approved to treat the primitive and secondary forms of hypercholesterolemia. The use of this combination therapy has been in the last decade a great opportunity in clinical practice to reach the LDL target values in a large number [10], especially in subjects at high cardiovascular risk [11,12] or resistant to statin monotherapy, and in some patients with important doserelated statin-associated side effects [13]. A recent meta-analysis or randomized clinical trials suggest that the treatment with ezetimibe/simvastatin is associated to a significant reduction of CVD [14]. The recent development of human monoclonal antibodies against the proprotein convertase subtilisin/kexin type 9 (PCSK9) remains an effective option to maximize the LDL-C reduction in patients at very high risk, but its use is limited by the high cost of therapy [15], so that the ezetimibe–statin association remains a gold standard of treatment for a large part of high-risk hypercholesterolemic patients. The aim of this review is to resume the pharmacokinetic characteristics of this drug combination and their clinical implication.

2. Chemistry and dosages 1-(4-Fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4 (S)-(4-hydroxyphenyl)-2-azetidinone (C24H21F2NO3) is the chemical formula of ezetimibe (Figure 1), whose recommended dose is 10 mg/day [16]. The chemical structure of simvastatin is shown in Figure 2, and its chemical formula is 2,2-dimethyl-,1,2,3,7,8,8a-

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Table 1. Pharmacokinetic characteristics of ezetimibe and simvastatin: their association does not modify the individual drug parameters (bioavailability, half-life, excretion). Pharmacokinetic parameters of ezetimibe and simvastatin Ezetimibe Solubility

Figure 1. Chemical structure of ezetimibe.

Absorption (%) Bioavailability (%) Proteins bind (%) Prodrug Metabolic pathway Active metabolites Half-life (h) Transporters involved in liver Unmodified urinary excretion (%)

Ethanol, methanol, and acetone soluble 90 Not measurable >90 Yes Glucuronide conjugation Yes 22 ATP-binding cassette transporters Not significant

Simvastatin Fat soluble 60–80 95 Yes CYP3A4 Yes 2–5 OATP1B1 Not significant


CYP3A4: cytochrome P450 3A4.

Figure 2. Chemical structure of simvastatin.

hexahydro-3,7-[1α,3α,7β,8β(2S*,4S*),-8aβ]] (C25H38O5), a butanoic acid available in different doses 10/20/40 mg/day (Box 1)[17].

3. Pharmacokinetics Ezetimibe, after oral administration, is rapidly absorbed in the intestine and metabolized by glucuronidation reaction in liver, reaching peak plasma concentrations in 4–12 h, with a plasma half-life of 22 h. In bloodstream, we find the 10–20% of ezetimibe and the 80–90% of glucuronide active metabolite, both forms being highly bound to plasma proteins. Ezetimibe and ezetimibe–glucuronide, through the enterohepatic circulation that involves different ATB-binding cassette transporters, reach the intestinal epithelial cell brush border which inhibit cholesterol and phytosterols absorption. Most of the drug ingested (80%) is excreted in the feces, a small share of ezetimibe–glucuronide is excreted in the urine [18] (Table 1). Simvastatin is ingested in the form of inactive lactone prodrug, rapidly absorbed in gastrointestinal tract and hydrolyzed in liver to its active beta-hydroxy acid metabolite, reaching peak plasma concentrations in 2–4 h with a plasma halflife of approximately 5 h. The 95% of circulating drug is bound to carrier proteins. Several enzymes are involved in the metabolism and elimination of simvastatin, in particular cytochrome P450 (CYP) 3A4 and 1B1 (SLCO1B1) are responsible of its oxidation process and intrahepatic transport. It is mainly eliminated in the feces by biliary excretion, a small percentage by renal one [19] (Table 1). The bioequivalence of the coadministration of separate tablets of ezetimibe and simvastatin and the combination of ezetimibe/simvastatin in a single tablet in the same doses has been deeply investigated and demonstrated [20]. Migoya and colleagues [20] showed the bioequivalence between the ezetimibe/simvastatin in unique formulation pill

and the coadministration of ezetimibe and simvastatin as separate tablets; they considered as main pharmacokinetic parameter the area under the plasma concentration–time curve from 0 to the last quantifiable time point (AUC0–last) and as secondary end point the maximum observed plasma concentration (Cmax) for ezetimibe and simvastatin acid. In their research, any statistically significant difference between geometric mean of AUC0–last and Cmax was observed for ezetimibe and simvastatin both in the first part of the study (ezetimibe/simvastatin 10/10 mg/mg vs. ezetimibe 10 mg + simvastatin 10 mg) and in the second one (ezetimibe/simvastatin 10/80 mg/mg vs. ezetimibe 10 mg + simvastatin 80 mg) [16].

3.1. Effect of ingested food The extent of ezetimibe absorption is not affected by any type of food eaten, but high-fat foods cause an increase (38%) of the maximum observed plasma concentration (Cmax) [18]. The pharmacokinetic profile of simvastatin is not affected by meals when it is administered before the ingestion of low fat food [21].

3.2. Effect of age, gender, and race In literature, any significant effect of age, gender and race on the pharmacokinetics of ezetimibe and statins has been reported [21]. However, recent pharmacogenomic studies have identified variants of more than 40 candidate genes that are able to modify the pharmacokinetics of statins, and in particular parameters such as AUC0–last and half-life [22]. In particular, some gene variants could increase the risk of statin-related myopathy by increasing the statin plasma level (for instance, variants of genes codifying for the transporters OATP1B1, OATP1B3, OATP2B1, ABCB1, and ABCG2 or for the cytochrome enzymes 3A4, 3A5, 2C8, 1A2, and 2), the statin internalization in cells (for instance variants of the genes codifying for OATP2B1 and MRP1, 4, 5), or increasing the sensitivity of muscle to the negative effect of statins (for instance, variants of the genes PYGM, GAA, CPT2, COQ10A, COQ10B, DMD – dystrophin-, MYOT – myotilin-, LMNA – lamin-, CAV3 – caveolin-, RYR – ryanodine receptors-, ATP1A1, ATP1A2, ATP1B1 -NaKATPase) [22].

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3.3. Effect of liver dysfunction The ezetimibe treatment (10 mg) does not require a dose adjustment in subjects with a mild liver impairment, but it should be discontinued in subjects with a moderate or severe hepatic insufficiency (Child–Pugh score >9) because of an increased exposure to the drug [18]. Significant effects on the pharmacokinetics of statins in patients with mild hepatic impairment are not reported in literature; an increased statin peak concentration and steady state were noted in severe hepatic insufficiency [23].


3.4. Effect of kidney dysfunction The ezetimibe treatment (10 mg) is also well tolerated in subjects with severe renal failure, for whom it is not necessary any dosage adjustment [18]. Renal insufficiency does not affect the pharmacokinetics of simvastatin; in the United Kingdom Heart and Renal Protection (UK-HARP-1) study, the authors showed the safety of simvastatin 20 mg therapy in 448 subjects with chronic kidney disease (CKD) [24]. However, in patients with glomerular filtration rate (GFR) lower than 30 ml/min, it is suggested to use low doses of simvastatin (10 mg), even if its use is not strictly contraindicated [21]. Moreover, the UK-HARP-2 study demonstrated the safety and tolerability of the combined treatment (simvastatin 20 mg + ezetimibe 10 mg) in 203 subjects divided into three categories: 152 pre-dialysis patients with a serum creatinine value ≥1.7 mg/dL, 51 hemodialysis patients, 33 peritoneal dialysis patients; the value of GFR was estimated only for patients not requiring dialysis (GFR mean ± SD was 28.0 ± 12.4 ml/min/ 1.73 m2) [25]. The safety of the simvastatin–ezetimibe association in CKD patients was definitively assessed in the large Study on Heart and Renal Protection (SHARP), including 9270 patients with CKD (3023 on dialysis and 6247 not) with no known history of myocardial infarction or coronary revascularization [26]: compared with simvastatin alone, there was no evidence of excess risks of myopathies, hepatitis, gallstones, cancer nor death from any nonvascular cause.

4. Pharmacodynamics Ezetimibe is an effective inhibitor of intestinal cholesterol and phytosterols absorption but not of triglycerides (TGs) and fatsoluble vitamins. It selectively blocks the Niemann–Pick C1Like 1 (NPC1L1) protein in the jejune brush border, that allows the dietary and biliary sterols absorption, with an upregulation of LDL-receptors and an increased hepatic uptake of LDL [27]. Genetic variants of NPC1L1 proteins seem to affect the LDL-C plasma level [28], but their effects on ezetimibe efficacy are not yet clear [29,30] and need further investigation. Simvastatin, derived from the methylation process of lovastatin, is a potent and reversible inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, the main microsomal enzyme involved in hepatic cholesterol biosynthesis. Its action results in a reduced production of mevalonic acid, the precursor of cholesterol, and in a consequent upregulation of the LDL-receptors expression by the liver, with a significant reduction of LDL-C serum levels and cardiovascular risk [31]. The mechanism of action

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of the two aforementioned lipid-lowering drugs is substantially different but complementary; in fact, a simultaneous intake leads to an enhanced drug efficacy [32–34]. Some gene polymorphisms seem to strongly influence the lipid-lowering efficacy of simvastatin, sometimes dramatically reduce its effect. Among the genes more strictly involved in the variability of simvastatin efficacy seems to be RHOA [35], ESR1 [36], and HNRNPA1 [37].

5. Clinical efficacy Several studies suggest the clinical efficacy of this combination therapy; in fact, the administration of ezetimibe (10 mg), already effective in monotherapy [38,39], added to ongoing statin therapy leads to a further lowering of LDL-C serum concentrations (−20% to 25%) [32]. Moreover, the addition of ezetimibe (10 mg) to lipid-lowering simvastatin treatment (20 mg) causes a decrease of LDL-C greater than that achieved doubling the simvastatin dose (40 mg); the administration of ezetimibe 10 mg + simvastatin 10 mg reduces LDL-C serum levels (−44%) such as the simvastatin 80 mg monotherapy [40]. These results are partly expected because it is wellknown that statins may upregulate intestinal cholesterol absorption and ezetimibe may enhance hepatic cholesterol synthesis [16,21]. Therefore, it is important to inhibit both pathways (i.e. intestinal and hepatic) concomitantly by the coadministration of ezetimibe + simvastatin. As reported in IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT), a randomized, double-blind, active-control, multicenter, clinical trial of 18,000 subjects stabilized after an acute coronary syndrome and be followed for at least of 2.5 years; the combination treatment ezetimibe 10 mg/simvastatin 40 mg vs. simvastatin 40 mg monotherapy leads to a significant improvement of the cardiovascular outcomes (primary end point: cardiovascular death, myocardial infarction, stroke, unstable angina leading to hospitalization, coronary revascularization ≥30 days post-randomization), with a more marked lowering of LDL-C values 53.7 mg/dl vs. 69.5 mg/dl [41]: the reduction in total events was driven by decreases in total nonfatal myocardial infarction (risk ratio [RR]: 0.87; 95% confidence interval [CI]: 0.79–0.96; p = 0.004) and total nonfatal stroke (RR: 0.77; 95% CI: 0.65– 0.93; p = 0.005). This was the first trial to show further significant CVD risk reduction in very high-risk patients (after an acute coronary syndrome) at relative low baseline LDL-C levels already on a statin and this CVD benefit was produced by a non-statin regimen. [41] The very low level of LDL-C achieved during the trials supports the hypothesis that a more rigorous reduction in LDL-C level is associated with a further CV risk reduction without a parallel increase in the risk of adverse events. Of particular interest is also that the protective effect of ezetimibe–simvastatin association seems to be particularly relevant in subjects with lower estimated GFR (eGFR). In fact, compared with individuals receiving monotherapy, individuals receiving combination therapy with a baseline eGFR of 60 ml/ min/1.73 m2 experienced a 12% risk reduction (hazard ratio [HR]: 0.88; 95% CI: 0.82–0.95); those with a baseline eGFR of 45 ml/min/1.73 m2 had a 13% risk reduction (HR: 0.87; 95% CI: 0.78–0.98) [42].

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Table 2. Drugs potentially interacting with simvastatin. CYP3A4 substrates

MDR/P-glycoprotein

Inhibitors Inducers Azole antifungals, Phenytoin, erythromycin, phenobarbital, clarithromycin, tricyclic rifampin, antidepressants, dexamethasone, nefazodone, venlafaxine, cyclophosphamide, fluvoxamine, fluoxetine, carbamazepine, sertraline, cyclosporin A, omeprazole, St. tacrolimus, amiodarone, John’s wort danazol, diltiazem, verapamil, protease inhibitors, midazolam, corticosteroids, tamoxifen Ritonavir, cyclosporin, Rifampicin, St. John’s verapamil, erythromycin, wort ketoconazole, itraconazole, quinidine

CYP3A4: cytochrome P450 3A4; MDR: multidrug resistance.


6. Safety The use of simvastatin resulted over the years in cases of related intolerance as muscle disorders (myalgia, myositis, rhabdomyolysis), and increased levels of transaminases, similarly to all other statins did [43]. Most of the statin-related adverse effects are dose dependent and several studies support genetic susceptibility as a decisive prerequisite for their clinical expression [44]. In a large randomized clinical trial, the author founded that simvastatin 80 mg compared to simvastatin 40 mg administration causes an increase of alanine transaminase 3 times upper limit of normal in 0–9% of cases vs. 0–4% of cases, an increase of creatinine kinase 10 times upper limit of normal or myopathy in 0–4% of cases vs. 0–0.04%, a rhabdomyolysis incidence in 0–1% of cases vs. 0% [45]. These results confirm what is reported in simvastatin product information: a miopathy incidence of 0–53% for simvastatin 80 mg daily compared with 0–0.8% for 40 mg daily. The use of simvastatin 80 mg is not recommended for active liver disease, GFR G polymorphism in NPC1L1 gene influences the efficacy of ezetimibe monotherapy on apolipoprotein A1 in hyperlipidemic patients. Pharmazie. 2014;69 (6):424–429. 30. Zambrano T, Saavedra N, Lanas F, et al. Efficacy of ezetimibe is not related to NPC1L1 gene polymorphisms in a pilot study of Chilean hypercholesterolemic subjects. Mol Diagn Ther. 2015;19(1):45–52. 31. Heart Protection Study Collaborative Group, Bulbulia R, Bowman L, et al. Effects on 11-year mortality and morbidity of lowering LDL cholesterol with simvastatin for about 5 years in 20.536 high-risk individuals: a randomised controlled trial. Lancet. 2011;378(9808):2013–2020. 32. Mikhailidis DP, Sibbring GC, Ballantyne CM, et al. Meta-analysis of the cholesterol-lowering effect of ezetimibe added to ongoing statin therapy. Curr Med Res Opin. 2007;23:2009–2026. 33. Borthwick F, Mangat R, Warnakula S, et al. Simvastatin treatment upregulates intestinal lipid secretion pathways in a rodent model of the metabolic syndrome. Atherosclerosis. 2014;232(1):141–148. 34. Choi YH, Kim Y, Hyeon CW, et al. Influence of previous statin therapy on cholesterol-lowering effect of ezetimibe. Korean Circ J. 2014;44(4):227–232. 35. Medina MW, Theusch E, Naidoo D, et al. RHOA is a modulator of the cholesterol-lowering effects of statin. PLoS Genet. 2012;8(11):e1003058. 36. Smiderle L, Fiegenbaum M, Hutz MH, et al. ESR1 polymorphisms and statin therapy: a sex-specific approach. Pharmacogenomics J. 2016 Nov;16(6):507–513. 37. Yu CY, Theusch E, Lo K, et al. HNRNPA1 regulates HMGCR alternative splicing and modulates cellular cholesterol metabolism. Hum Mol Genet. 2014;23(2):319–332. 38. Gazi IF, Daskalopoulou SS, Nair DR, et al. Effect of ezetimibe in patients who cannot tolerate statins or cannot get to the low density lipoprotein cholesterol target despite taking a statin. Curr Med Res Opin. 2007;23(9):2183–2192. 39. Pandor A, Ara RM, Tumur I, et al. Ezetimibe monotherapy for cholesterol lowering in 2,722 people: systematic review and meta-analysis of randomized controlled trials. J Intern Med. 2009;265:568–580. 40. Davidson MH, McGarry T, Bettis R, et al. Ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia. J Am Coll Cardiol. 2002;40:2125–2134. 41. Murphy SA, Cannon CP, Blazing MA, et al. Reduction in total cardiovascular events with ezetimibe/simvastatin post-acute coronary syndrome: the IMPROVE-IT trial. J Am Coll Cardiol. 2016;67 (4):353–361.

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