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      Pharmacokinetic interaction between fimasartan and atorvastatin in healthy male volunteers

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          Abstract

          Introduction

          Major cardiovascular risk factors, including hypertension and dyslipidemia, are often comorbidities, frequently leading to concurrent prescription of angiotensin receptor blockers and 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins). The study’s objective was to evaluate the effect of coadministration of fimasartan and atorvastatin on their pharmacokinetics (PKs).

          Subjects and methods

          In a randomized, open-label, three-period, six-sequence, crossover, multiple-dose study, 36 healthy subjects received 120 mg fimasartan, 40 mg atorvastatin, or both (based on their assigned sequence) once daily for 7 days in each period, with a 7-day washout between periods. Blood samples for the PK analysis of fimasartan, atorvastatin, and the 2-hydroxy atorvastatin metabolite were collected up to 48 h after the last dose.

          Results

          The coadministration of fimasartan and atorvastatin was well tolerated and led to an increase in the peak concentration and area under the concentration–time curve at steady state of fimasartan by 2.18-fold (95% confidence interval [CI], 1.79–2.65) and 1.35-fold (95% CI, 1.26–1.43) and those of atorvastatin increased by 1.82-fold (95% CI, 1.51–2.18) and 1.12-fold (95% CI, 1.04–1.22), respectively.

          Conclusion

          Coadministration increased the systemic exposures of fimasartan and atorvastatin, but the clinical significance of this finding needs to be evaluated with respect to exposure responses and clinical outcomes.

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          Most cited references 30

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          Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance.

          Lipid-lowering drugs, especially 3-hydroxy-3-methylglutaryl-coenzyme A inhibitors (statins), are widely used in the treatment and prevention of atherosclerotic disease. The benefits of statins are well documented. However, lipid-lowering drugs may cause myopathy, even rhabdomyolysis, the risk of which is increased by certain interactions. Simvastatin, lovastatin, and atorvastatin are metabolized by cytochrome P450 (CYP) 3A4 (simvastatin acid is also metabolized by CYP2C8); their plasma concentrations and risk of myotoxicity are greatly increased by strong inhibitors of CYP3A4 (eg, itraconazole and ritonavir). Weak or moderately potent CYP3A4 inhibitors (eg, verapamil and diltiazem) can be used cautiously with small doses of CYP3A4-dependent statins. Cerivastatin is metabolized by CYP2C8 and CYP3A4, and fluvastatin is metabolized by CYP2C9. The exposure to fluvastatin is increased by less than 2-fold by inhibitors of CYP2C9. Pravastatin, rosuvastatin, and pitavastatin are excreted mainly unchanged, and their plasma concentrations are not significantly increased by pure CYP3A4 inhibitors. Cyclosporine (INN, ciclosporin) inhibits CYP3A4, P-glycoprotein (multidrug resistance protein 1), organic anion transporting polypeptide 1B1 (OATP1B1), and some other hepatic uptake transporters. Gemfibrozil and its glucuronide inhibit CYP2C8 and OATP1B1. These effects of cyclosporine and gemfibrozil explain the increased plasma statin concentrations and, together with pharmacodynamic factors, the increased risk of myotoxicity when coadministered with statins. Inhibitors of OATP1B1 may decrease the benefit/risk ratio of statins by interfering with their entry into hepatocytes, the site of action. Lipid-lowering drugs can be involved also in other interactions, including those between enzyme inducers and CYP3A4 substrate statins, as well as those between gemfibrozil and CYP2C8 substrate antidiabetics. Knowledge of the pharmacokinetic and pharmacodynamic properties of lipid-lowering drugs and their interaction mechanisms helps to avoid adverse interactions, without compromising therapeutic benefits.
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            Clinical pharmacokinetics of atorvastatin.

            Hypercholesterolaemia is a risk factor for the development of atherosclerotic disease. Atorvastatin lowers plasma low-density lipoprotein (LDL) cholesterol levels by inhibition of HMG-CoA reductase. The mean dose-response relationship has been shown to be log-linear for atorvastatin, but plasma concentrations of atorvastatin acid and its metabolites do not correlate with LDL-cholesterol reduction at a given dose. The clinical dosage range for atorvastatin is 10-80 mg/day, and it is given in the acid form. Atorvastatin acid is highly soluble and permeable, and the drug is completely absorbed after oral administration. However, atorvastatin acid is subject to extensive first-pass metabolism in the gut wall as well as in the liver, as oral bioavailability is 14%. The volume of distribution of atorvastatin acid is 381L, and plasma protein binding exceeds 98%. Atorvastatin acid is extensively metabolised in both the gut and liver by oxidation, lactonisation and glucuronidation, and the metabolites are eliminated by biliary secretion and direct secretion from blood to the intestine. In vitro, atorvastatin acid is a substrate for P-glycoprotein, organic anion-transporting polypeptide (OATP) C and H+-monocarboxylic acid cotransporter. The total plasma clearance of atorvastatin acid is 625 mL/min and the half-life is about 7 hours. The renal route is of minor importance (<1%) for the elimination of atorvastatin acid. In vivo, cytochrome P450 (CYP) 3A4 is responsible for the formation of two active metabolites from the acid and the lactone forms of atorvastatin. Atorvastatin acid and its metabolites undergo glucuronidation mediated by uridinediphosphoglucuronyltransferases 1A1 and 1A3. Atorvastatin can be given either in the morning or in the evening. Food decreases the absorption rate of atorvastatin acid after oral administration, as indicated by decreased peak concentration and increased time to peak concentration. Women appear to have a slightly lower plasma exposure to atorvastatin for a given dose. Atorvastatin is subject to metabolism by CYP3A4 and cellular membrane transport by OATP C and P-glycoprotein, and drug-drug interactions with potent inhibitors of these systems, such as itraconazole, nelfinavir, ritonavir, cyclosporin, fibrates, erythromycin and grapefruit juice, have been demonstrated. An interaction with gemfibrozil seems to be mediated by inhibition of glucuronidation. A few case studies have reported rhabdomyolysis when the pharmacokinetics of atorvastatin have been affected by interacting drugs. Atorvastatin increases the bioavailability of digoxin, most probably by inhibition of P-glycoprotein, but does not affect the pharmacokinetics of ritonavir, nelfinavir or terfenadine.
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              ACCF/AHA 2011 expert consensus document on hypertension in the elderly: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents.

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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2018
                24 July 2018
                : 12
                : 2301-2309
                Affiliations
                Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea, ksyu@ 123456snu.ac.kr
                Author notes
                Correspondence: Kyung-Sang Yu, Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Republic of Korea, Tel +82 2 2072 1920, Fax +82 2 742 9252, Email ksyu@ 123456snu.ac.kr
                Article
                dddt-12-2301
                10.2147/DDDT.S165171
                6063220
                © 2018 Choi et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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                Original Research

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