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Effect of concomitant icosapent ethyl (eicosapentaenoic acid ethyl ester) on the pharmacokinetics of atorvastatin.

ABSTRACT: Icosapent ethyl is a high-purity prescription form of eicosapentaenoic acid ethyl ester approved as an adjunct to diet to reduce triglyceride levels in adult patients with triglyceride levels ?500 mg/dL (?5.65 mmol/L). The objective of this open-label, drug-drug interaction study was to examine the effects of icosapent ethyl on the steady-state pharmacokinetics of atorvastatin, a commonly prescribed medication in patients with dyslipidaemia.Thirty healthy subjects received atorvastatin 80 mg/day on days 1-7, icosapent ethyl 4 g/day on days 8-28, and co-administration on days 29-35. Primary end-points were natural log-transformed maximum plasma concentration (C(max)) and area under the concentration-versus-time curve from 0 to 24 h (AUC(0-24)) for atorvastatin, 2-hydroxyatorvastatin, and 4-hydroxyatorvastatin with and without icosapent ethyl.Of the 30 subjects enrolled, 26 completed the study. The 90% confidence intervals for C(max) and AUC(0-24) least-squares geometric mean ratios were within the 0.80-1.25 bounds. Concomitant administration of icosapent ethyl and atorvastatin was safe and well tolerated and icosapent ethyl did not significantly change the steady state C(max) and AUC(0-24) of atorvastatin, 2-hydroxyatorvastatin, or 4-hydroxyatorvastatin.At steady-state concentrations, icosapent ethyl did not have an effect on the pharmacokinetics of atorvastatin. Co-administration of icosapent ethyl and atorvastatin was safe and well tolerated in healthy adult subjects.

SUBMITTER: Braeckman RA

PROVIDER: S-EPMC4281350 | biostudies-other | 2015 Jan

REPOSITORIES: biostudies-other

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Effect of concomitant icosapent ethyl (eicosapentaenoic acid ethyl ester) on the pharmacokinetics of atorvastatin.

Braeckman Rene A RA Stirtan William G WG Soni Paresh N PN

Clinical drug investigation 20150101 1

<h4>Background and objective</h4>Icosapent ethyl is a high-purity prescription form of eicosapentaenoic acid ethyl ester approved as an adjunct to diet to reduce triglyceride levels in adult patients with triglyceride levels ≥500 mg/dL (≥5.65 mmol/L). The objective of this open-label, drug-drug interaction study was to examine the effects of icosapent ethyl on the steady-state pharmacokinetics of atorvastatin, a commonly prescribed medication in patients with dyslipidaemia.<h4>Methods</h4>Thirty ...[more]

PMID: 25471740

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Project description:BackgroundIcosapent ethyl (IPE) is a high-purity prescription form of eicosapentaenoic acid ethyl ester approved by the US Food and Drug Administration as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe (≥500 mg/dL) hypertriglyceridemia. In addition to TG-lowering effects, IPE also reduces non-high-density lipoprotein cholesterol and apolipoprotein B levels without significantly increasing low-density lipoprotein cholesterol (LDL-C) in patients with very high TG levels ≥500 mg/dL (MARINE study) and in patients with well-controlled LDL-C and residually high TG levels 200-500 mg/dL (ANCHOR study). This analysis examined the effect of IPE on inflammatory markers in patients from MARINE and ANCHOR.MethodsMARINE (N = 229) and ANCHOR (N = 702) were Phase III, double-blind studies that randomized hypertriglyceridemic patients to IPE 4 g/day, 2 g/day, or placebo. This analysis assessed the median placebo-adjusted percentage change from baseline in markers representing various stages of atherosclerotic inflammation such as intercellular adhesion molecule-1 (ICAM-1), oxidized low-density lipoprotein (Ox-LDL), lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), interleukin-6 (IL-6), and high-sensitivity C-reactive protein (hsCRP).ResultsCompared to placebo, IPE 4 g/day significantly decreased Ox-LDL (13 %, p < 0.0001, ANCHOR), Lp-PLA(2) (14 %, p < 0.001, MARINE; 19 %, p < 0.0001, ANCHOR), and hsCRP levels (36 %, p < 0.01, MARINE; 22 %, p < 0.001, ANCHOR), but did not significantly change ICAM-1 and IL-6 levels. In the MARINE study, IPE 2 g/day did not significantly change ICAM-1, Ox-LDL, Lp-PLA(2), IL-6, or hsCRP levels. Also, compared to placebo in the ANCHOR study, IPE 2 g/day significantly decreased Lp-PLA(2) levels (8 %, p < 0.0001), but did not significantly change levels of other assessed inflammatory markers.ConclusionCompared to placebo, in hypertriglyceridemic patients, IPE 4 g/day significantly decreased Ox-LDL, Lp-PLA(2), and hsCRP levels.

Project description:Background & aimsThe role of fatty acid ethyl esters (FAEEs) during human alcoholic pancreatitis is unknown. We compared FAEEs levels with their nonesterified fatty acids (NEFAs) precursors during alcohol intoxication and clinical alcoholic pancreatitis. The pathophysiology underlying FAEEs increase and their role as diagnostic biomarkers for alcoholic pancreatitis was investigated.MethodsA prospective blinded study compared FAEEs, NEFAs, and ethanol blood levels on hospitalization for alcoholic pancreatitis (n = 31), alcohol intoxication (n = 25), and in normal controls (n = 43). Serum FAEEs were measured at admission for nonalcoholic pancreatitis (n = 75). Mechanistic cell and animal studies were done.ResultsMedian FAEEs were similarly elevated during alcohol intoxication (205 nmol/L; 95% confidence interval [CI], 71.8-515 nmol/L, P < .001) and alcoholic pancreatitis (103.1 nmol/L; 95% CI, 53-689 nmol/L, P < .001) vs controls (1.7 nmol/L; 95% CI, 0.02-4.3 nmol/L) or nonalcoholic pancreatitis (8 nmol/L; 95% CI, 1.1-11.5 nmol/L). Alcoholic pancreatitis increased serum NEFAs (1024 ± 710 μmol/L vs 307 ± 185 μmol/L in controls, P < .05). FAEEs comprised 0.1% to 2% of the parent NEFA concentrations. FAEES correlated strongly with NEFAs independent of ethanol levels in alcoholic pancreatitis but not during alcohol intoxication. On receiver operating characteristic curve analysis for diagnosing alcoholic pancreatitis, the area under the curve for serum FAEEs was 0.87 (95% CI, 0.78-0.95, P < .001). In mice and cells, alcohol administration transiently increased all FAEEs. Oleic acid ethyl ester was the only FAEE with a sustained increase up to 24 hours after intraperitoneal oleic acid plus ethanol administration.ConclusionsThe sustained, alcohol-independent, large (20- to 50-fold) increase in circulating FAEEs during alcoholic pancreatitis results from their visceral release and mirrors the 2- to 4-fold increase in parent NEFA. The large areas under the curve of FAEEs on receiver operating characteristic curve analysis supports their role as alcoholic pancreatitis biomarkers.

Project description:Abstract Study Objective. To assess the effects of the cytochrome P450 (CYP) 3A genotype, CYP3A5, on atorvastatin pharmacokinetics and its interaction with clarithromycin. Design. Prospective, two-phase, randomized-sequence, open-label pharmacokinetic study. Setting. Clinical research center at a teaching hospital. Subjects. Twenty-three healthy volunteers who were screened for genotype: 10 subjects carried the CYP3A5*1 allele (expressors) and 13 subjects did not (nonexpressors). Intervention. In one phase, subjects received a single oral dose of atorvastatin 20 mg. In the other phase, subjects received clarithromycin 500 mg twice/day for 5 days; on day 4 after the morning dose, subjects also received a single oral dose of atorvastatin 20 mg. All subjects participated in both phases of the study, which were separated by at least 14 days. Measurements and Main Results. Pharmacokinetic parameters of both forms of atorvastatin-atorvastatin acid and atorvastatin lactone-were compared between CYP3A5 expressors and nonexpressors, both in the absence and presence of clarithromycin, a strong CYP3A inhibitor. The acid form is pharmacologically active, and the lactone form has been associated with the atorvastatin's muscle-related adverse effects. Atorvastatin acid exposure did not differ significantly between CYP3A5 genotype groups. When subjects had not received clarithromycin pretreatment, the area under the concentration-time curve from time zero extrapolated to infinity (AUC(0-∞)) of atorvastatin lactone was 36% higher in nonexpressors than in expressors (median 47.6 ng•hr/ml [interquartile range (IQR) 37.8-64.3 ng•hr/ml] vs 34.9 ng•hr/ml [IQR 21.6-42.2 ng•hr/ml], p=0.038). After clarithromycin pretreatment, changes in the pharmacokinetic parameters of atorvastatin acid and lactone were not significantly different between the nonexpressors versus the expressors; however, the increase in the AUC(0-∞) of atorvastatin lactone was 37% greater in expressors than in nonexpressors (geometric mean ± SD 3.59 ± 0.57 vs 2.62 ± 0.35, p=0.049). Conclusion. Our data suggest that the CYP3A5 genotype has minimal effects on the pharmacokinetic parameters of atorvastatin and its interaction with clarithromycin; these effects are unlikely to be clinically significant.

Dataset Information

Effect of concomitant icosapent ethyl (eicosapentaenoic acid ethyl ester) on the pharmacokinetics of atorvastatin.

Publications

Effect of concomitant icosapent ethyl (eicosapentaenoic acid ethyl ester) on the pharmacokinetics of atorvastatin.

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