5 (1.0–6.0) 1.5

(0.7–8.0) t 1/2 (h) 1.5 (0.7) 1.4 (0.7) K el (L/h) 0.56 (0.22) 0.62 (0.26) AUC 0–24 area under the JQEZ5 order plasma concentration-time curve from time 0 to 24 h, C max maximum observed concentration, K el apparent terminal elimination rate constant, PK pharmacokinetic, t 1/2 apparent terminal elimination half-life, T max time of maximum observed concentration aMean (standard deviation) displayed for all PK parameters except T max, which is displayed as median (minimum–maximum) Table 2 Statistical analysis of drug–drug interaction following omeprazole 40 mg/day without or with oral icosapent ethyl 4 g/day (pharmacokinetic analysis population, n = 28) PK Parameter (unit) Statistica Treatment Omeprazole 40 mg Icosapent Ethyl 4 g + Omeprazole 40 mg AUC0–24 (ng·h/mL) LSGM 2,973 2,484 Ratio 0.84 90 % CI 75.99–91.87 C max (ng/mL) LSGM 1,051 1,059 Ratio 1.01 90 % CI 87.36–116.3 AUC 0–24 area under the plasma concentration-time curve from time 0 to 24 h, CI confidence MAPK inhibitor interval, C max maximum observed concentration, LSGM least squares geometric means, PK pharmacokinetic aLSGM derived from mixed models; LSGM ratios are provided for icosapent ethyl plus omeprazole/omeprazole alone 3.3 Safety There were no clinically significant findings from laboratory test results or following physical examination and vital sign assessments.

All reported AEs were mild or moderate in severity and there were no discontinuations because of

an AE. 4 Discussion This drug–drug interaction study examined the effects of IPE on the EVP4593 PK of omeprazole. The ratio of least squares means for AUC0–24 and C max (without or with IPE) and the resulting 90 % almost CIs indicated that a regimen of IPE 4 g/day did not inhibit omeprazole PK. Administration of omeprazole alone or co-administered with IPE was well tolerated in healthy subjects. IPE is a prescription form of EPA ethyl ester and has been studied for potential CYP-mediated drug–drug interactions in healthy adults. In addition to the effects described herein for omeprazole (CYP2C19 substrate), the administration of IPE 4 g/day did not display a significant effect on the AUC or C max of atorvastatin (CYP3A4 substrate), rosiglitazone (CYP2C8 substrate), or warfarin (CYP2C9 substrate) [4]. Patients with hypertriglyceridemia often have comorbidities including obesity, metabolic syndrome, and diabetes mellitus [1, 2]. Obesity and metabolic syndrome are associated with erosive esophagitis [14–17], with obesity being a very strong independent risk factor for GERD symptoms [14]. Consequently, many candidates for IPE TG-lowering therapy may be taking a concomitant medication for GERD or erosive esophagitis, such as omeprazole. Other proton pump inhibitors, including lansoprazole and esomeprazole, may also be involved in CYP2C19-mediated metabolism [18].