Population pharmacokinetics of a novel PCSK9 antisense oligonucleotide.

AIMS: The aim of this study was to characterize the population pharmacokinetics of AZD8233, an antisense oligonucleotide (ASO) that targets the PCSK9 transcript to reduce hepatocyte PCSK9 protein production and plasma levels. AZD8233 utilizes generation 2.5 S-constrained ethyl motif (cET) chemistry and is conjugated to a triantennary N-acetylgalactosamine (GalNAc3) ligand for targeted hepatocyte uptake. METHODS: A non-linear mixed-effect modelling approach utilizing NONMEM software was applied to AZD8233 concentration-time data from 3416 samples in 219 participants from four phase 1-2 studies, one in healthy volunteers (NCT03593785) and three in patients with dyslipidaemia (NCT04155645, NCT04641299 and NCT04823611). RESULTS: The final model described the AZD8233 plasma concentration-time profile from four phase 1-2 studies in healthy volunteers or participants with dyslipidaemia, covering a dose range of 4 to 120 mg. The pharmacokinetics of AZD8233 were adequately described by a two-compartment model with first-order absorption. The supra-proportional increase in maximum plasma concentration (Cmax) across the observed dose range was described by non-linear Michaelis-Menten elimination (maximum elimination rate, 9.9 mg/h [12% relative standard error]; concentration yielding half-maximal elimination rate, 4.8 mg/L [18% relative standard error]). Body weight, sex, estimated glomerular filtration rate and disease status (healthy participant vs. patient with dyslipidaemia) were identified as factors affecting exposure to AZD8233. CONCLUSIONS: Covariate analysis showed body weight to be the main factor affecting exposure to AZD8233, which largely explained the higher Cmax observed in the Asian population relative to non-Asians.

AZD8233 antisense oligonucleotide targeting PCSK9 does not prolong QT interval.

AIMS: AZD8233 is a proprotein convertase subtilisin/kexin type 9 (PCSK9) antisense oligonucleotide under development for treatment of hypercholesterolaemia. A prespecified concentration-QT analysis was performed based on data from a single ascending dose study that was prospectively designed to act as a TQT study substitute. METHODS: Subcutaneous single doses ranging from 4 to 120 mg were evaluated in 73 adult healthy male subjects. Time-matched 12-lead digital ECG and plasma concentrations (n = 15) were measured at baseline and up to 48 hours after dose in each subject. The analysis was performed using a linear mixed effect model, where change from baseline QTc (ΔQTc) was a dependent variable and time-matched AZD8233 concentration was an independent variable. RESULTS: The high clinical exposure scenario was defined as 1.7-fold the expected Cmax following an assumed therapeutic dose of 60 mg, which corresponds to AZD8233 plasma concentration of 1.39 µg/mL. Estimated placebo-corrected and baseline-adjusted QTcF interval (ΔΔQTcF) at this concentration was -2.2 ms (90% CI: -4.11, -0.28). Furthermore, the upper 90% ΔΔQTcF confidence interval was estimated to be below 10 ms at all observed concentrations. CONCLUSION: As the effect on ΔΔQTcF is below the threshold for regulatory concern (10 ms), it can be concluded that AZD8233 does not induce QTcF prolongation at the high clinical exposure scenario.

Omega-3 fatty acid exposure with a low-fat diet in patients with past hypertriglyceridemia-induced acute pancreatitis; an exploratory, randomized, open-label crossover study.

BACKGROUND: Omega-3 fatty acids (OM3-FAs) are recommended with a low-fat diet for severe hypertriglyceridemia (SHTG), to reduce triglycerides and acute pancreatitis (AP) risk. A low-fat diet may reduce pancreatic lipase secretion, which is required to absorb OM3-ethyl esters (OM3-EEs), but not OM3-carboxylic acids (OM3-CAs). METHODS: In this exploratory, randomized, open-label, crossover study, 15 patients with SHTG and previous AP were instructed to take OM3-CA (2 g or 4 g) and OM3-EE 4 g once daily for 4 weeks, while adhering to a low-fat diet. On day 28 of each treatment phase, a single dose was administered in the clinic with a liquid low-fat meal, to assess 24-h plasma exposure. Geometric least-squares mean ratios were used for between-treatment comparisons of baseline (day 0)-adjusted area under the plasma concentration versus time curves (AUC0-24) and maximum plasma concentrations (Cmax) for eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). RESULTS: Before initiating OM3-FA treatment, mean baseline fasting plasma EPA + DHA concentrations (nmol/mL) were 723 for OM3-CA 2 g, 465 for OM3-CA 4 g and 522 for OM3-EE 4 g. At week 4, mean pre-dose fasting plasma EPA + DHA concentrations increased by similar amounts (+ 735 - + 768 nmol/mL) for each treatment. During the 24-h exposure assessment (day 28), mean plasma EPA + DHA increased from pre-dose to the maximum achieved concentration by + 32.7%, + 45.8% and + 3.1% with single doses of OM3-CA 2 g, OM3-CA 4 g and OM3-EE 4 g, respectively. Baseline-adjusted AUC0-24 was 60% higher for OM3-CA 4 g than for OM3-EE 4 g and baseline-adjusted Cmax was 94% higher (both non-significant). CONCLUSIONS: Greater 24-h exposure of OM3-CA versus OM3-EE was observed for some parameters when administered with a low-fat meal at the clinic on day 28. However, increases in pre-dose fasting plasma EPA + DHA over the preceding 4-week dosing period were similar between treatments, leading overall to non-significant differences in baseline (day 0)-adjusted AUC0-24 and Cmax EPA + DHA values. It is not clear why the greater 24-h exposure of OM3-CA versus OM3-EE observed with a low-fat meal did not translate into significantly higher pre-dose fasting levels of DHA + EPA with longer-term use. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02189252, Registered 23 June 2014.

Comparative quantitative systems pharmacology modeling of anti-PCSK9 therapeutic modalities in hypercholesterolemia.

Since the discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9) as an attractive target in the treatment of hypercholesterolemia, multiple anti-PCSK9 therapeutic modalities have been pursued in drug development. The objective of this research is to set the stage for the quantitative benchmarking of two anti-PCSK9 pharmacological modality classes, monoclonal antibodies (mAbs) and small interfering RNA (siRNA). To this end, we developed an integrative mathematical model of lipoprotein homeostasis describing the dynamic interplay between PCSK9, LDL-cholesterol (LDL-C), VLDL-cholesterol, HDL-cholesterol (HDL-C), apoB, lipoprotein a [Lp(a)], and triglycerides (TGs). We demonstrate that LDL-C decreased proportionally to PCSK9 reduction for both mAb and siRNA modalities. At marketed doses, however, treatment with mAbs resulted in an additional ∼20% LDL-C reduction compared with siRNA. We further used the model as an evaluation tool and determined that no quantitative differences were observed in HDL-C, Lp(a), TG, or apoB responses, suggesting that the disruption of PCSK9 synthesis would provide no additional effects on lipoprotein-related biomarkers in the patient segment investigated. Predictive model simulations further indicate that siRNA therapies may reach reductions in LDL-C levels comparable to those achieved with mAbs if the current threshold of 80% PCSK9 inhibition via siRNA could be overcome.

Importance of pancreatic exocrine dysfunction in patients with type 2 diabetes: A randomized crossover study.

BACKGROUND: Levels of faecal elastase-1 (FE-1), a marker of exocrine pancreatic function, are lower in patients with type 2 diabetes than without diabetes. We aimed to investigate the association between FE-1 and nutritional status, gastrointestinal symptoms, and lipid absorption. METHODS: This randomized, open-label, crossover study included 315 patients with type 2 diabetes aged 18-70 years treated with oral antidiabetics, with HbA1c 6.5-9.0% and BMI 18-40 kg/m2. Assessments included levels of FE-1 and blood biomarkers of nutrition, and Bristol Stool Scale and Gastrointestinal Symptom Rating Scale (GSRS) scores. Plasma exposure of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) after oral administration of free omega-3 carboxylic acids or ethyl esters with breakfast was investigated in patients with low, intermediate, and normal FE-1 levels. RESULTS: The prevalence of low and intermediate FE-1 levels was 5.2% and 4.9%, respectively. Bristol Stool Scale scores and mean values of GSRS Diarrhoea and Indigestion domain symptoms were similar across groups, but patients with low FE-1 were heavier and reported lower stool frequency. FE-1 levels correlated positively with plasma levels of amylase, lipase, 25-hydroxy vitamin D, and albumin. Mean EPA + DHA exposure was similarly higher after intake of free vs. esterified omega-3 fatty acids in all FE-1 groups. CONCLUSIONS: The prevalence of low FE-1 (<100 µg/g) as a measure of pancreatic exocrine insufficiency was infrequent in type 2 diabetes. Except for low plasma concentrations of EPA and 25-hydroxy vitamin D, type 2 diabetes patients with low FE-1 had no other signs of malabsorption or gastrointestinal disorders. Plasma levels of EPA and DHA after the intake of esterified versus free EPA and DHA did not correlate with FE-1 levels. TRIAL REGISTRATION: ClinicalTrials.gov NCT02370537.

Pharmacokinetics and Acid-suppressive Effects of Esomeprazole in Infants 1-24 Months Old With Symptoms of Gastroesophageal Reflux Disease.

OBJECTIVES: To evaluate the pharmacokinetics and acid-suppressive effects of esomeprazole in infants with gastroesophageal reflux disease (GERD). PATIENTS AND METHODS: In this single-blind, randomized, parallel-group study, 50 infants 1 to 24 months old with symptoms of GERD, and ≥ 5% of time with intraesophageal pH <4 during 24-hour dual pH monitoring, received oral esomeprazole 0.25 mg/kg (n = 26) or 1 mg/kg (n = 24) once daily for 1 week. Intraesophageal and intragastric pH were recorded at 1 week, and blood samples were taken for pharmacokinetic analysis. RESULTS: At baseline, mean percentages of time with intragastric pH >4 and intraesophageal pH <4 were 30.5% and 11.6%, respectively, in the esomeprazole 0.25 mg/kg group and 28.6% and 12.5% in the esomeprazole 1 mg/kg group. After 1 week of treatment, times with intragastric pH >4 were 47.9% and 69.3% in the esomeprazole 0.25 mg/kg and 1 mg/kg groups, respectively (P < 0.001 vs baseline), and times with intraesophageal pH <4 were 8.4% (P < 0.05 vs baseline) and 5.5% (P < 0.001 vs. baseline), respectively. The mean number of acid reflux episodes of >5 minutes duration decreased from 6 at baseline to 3 and 2 with esomeprazole 0.25 mg/kg and 1 mg/kg, respectively. The geometric mean AUC0-t of esomeprazole were 0.24 and 1.79 µmol · h/L for the 0.25 mg/kg and 1 mg/kg dosages of esomeprazole, respectively. Both esomeprazole dosages were well tolerated. CONCLUSIONS: Oral treatment with esomeprazole 0.25 mg/kg and 1 mg/kg was well tolerated and provided dose-related acid suppression, dose-related exposure to esomeprazole, and decreased esophageal acid exposure in infants 1-24 months old with GERD.

Pharmacokinetics and Acid-suppressive Effects of Esomeprazole in Infants 1-24 Months Old With Symptoms of Gastroesophageal Reflux Disease.

OBJECTIVES: To evaluate the pharmacokinetics and acid-suppressive effects of esomeprazole in infants with gastroesophageal reflux disease (GERD). PATIENTS AND METHODS: In this single-blind, randomized, parallel-group study, 50 infants 1 to 24 months old with symptoms of GERD, and ≥ 5% of time with intraesophageal pH <4 during 24-hour dual pH monitoring, received oral esomeprazole 0.25 mg/kg (n = 26) or 1 mg/kg (n = 24) once daily for 1 week. Intraesophageal and intragastric pH were recorded at 1 week, and blood samples were taken for pharmacokinetic analysis. RESULTS: At baseline, mean percentages of time with intragastric pH > 4 and intraesophageal pH < 4 were 30.5% and 11.6%, respectively, in the esomeprazole 0.25 mg/kg group and 28.6% and 12.5% in the esomeprazole 1 mg/kg group. After 1 week of treatment, times with intragastric pH >4 were 47.9% and 69.3% in the esomeprazole 0.25 mg/kg and 1 mg/kg groups, respectively (P < 0.001 vs baseline), and times with intraesophageal pH < 4 were 8.4% (P < 0.05 vs baseline) and 5.5% (P < 0.001 vs. baseline), respectively. The mean number of acid reflux episodes of > 5 minutes duration decreased from 6 at baseline to 3 and 2 with esomeprazole 0.25 mg/kg and 1 mg/kg, respectively. The geometric mean AUC0-t of esomeprazole were 0.24 and 1.79 µmol · h/L for the 0.25 mg/kg and 1 mg/kg dosages of esomeprazole, respectively. Both esomeprazole dosages were well tolerated. CONCLUSIONS: Oral treatment with esomeprazole 0.25 mg/kg and 1 mg/kg was well tolerated and provided dose-related acid suppression, dose-related exposure to esomeprazole, and decreased esophageal acid exposure in infants 1-24 months old with GERD.

A case-study of model-informed drug development of a novel PCSK9 anti sense oligonucleotide. Part 1: First time in man to phase II.

Here, we show model-informed drug development (MIDD) of a novel antisense oligonucleotide, targeting PCSK9 for treatment of hypocholesteremia. The case study exemplifies use of MIDD to analyze emerging data from an ongoing first-in-human study, utility of the US Food and Drug Administration MIDD pilot program to accelerate timelines, innovative use of competitor data to set biomarker targets, and use of MIDD to optimize sample size and dose selection, as well as to accelerate and de-risk a phase IIb study. The focus of the case-study is on the cross-functional collaboration and other key MIDD enablers that are critical to maximize the value of MIDD, rather than the technical application of MIDD.

An oral antisense oligonucleotide for PCSK9 inhibition.

Inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) reduce low-density lipoprotein (LDL) cholesterol and are used for treatment of dyslipidemia. Current PCSK9 inhibitors are administered via subcutaneous injection. We present a highly potent, chemically modified PCSK9 antisense oligonucleotide (ASO) with potential for oral delivery. Past attempts at oral delivery using earlier-generation ASO chemistries and transient permeation enhancers provided encouraging data, suggesting that improving potency of the ASO could make oral delivery a reality. The constrained ethyl chemistry and liver targeting enabled by N-acetylgalactosamine conjugation make this ASO highly potent. A single subcutaneous dose of 90 mg reduced PCSK9 by >90% in humans with elevated LDL cholesterol and a monthly subcutaneous dose of around 25 mg is predicted to reduce PCSK9 by 80% at steady state. To investigate the feasibility of oral administration, the ASO was coformulated in a tablet with sodium caprate as permeation enhancer. Repeated oral daily dosing in dogs resulted in a bioavailability of 7% in the liver (target organ), about fivefold greater than the plasma bioavailability. Target engagement after oral administration was confirmed by intrajejunal administration of a rat-specific surrogate ASO in solution with the enhancer to rats and by plasma PCSK9 and LDL cholesterol lowering in cynomolgus monkey after tablet administration. On the basis of an assumption of 5% liver bioavailability after oral administration in humans, a daily dose of 15 mg is predicted to reduce circulating PCSK9 by 80% at steady state, supporting the development of the compound for oral administration to treat dyslipidemia.

Predicting intestinal precipitation--a case example for a basic BCS class II drug.

PURPOSE: To investigate the prediction accuracy of in vitro and in vitro/in silico methods for in vivo intestinal precipitation of basic BCS class II drugs in humans. METHODS: Precipitation rate of a model drug substance, AZD0865 (pKa = 6.1; log K(D) = 4.2), was investigated in vitro using simulated intestinal media, and calculations of the crystallization rates were made with a theoretical model. Human intestinal precipitation was estimated by analysis of pharmacokinetic data from clinical studies at different doses. RESULTS: All in vitro models predicted rapid drug precipitation, where the intestinal concentration of dissolved AZD0865 at the highest dose tested was expected to decrease to half after less than 20 min. However, there was no indication of precipitation in vivo in humans as there was a dose proportional increase in drug plasma exposure. The theoretical model predicted no significant precipitation within the range of expected in vivo intestinal concentrations. CONCLUSIONS: This study indicated that simple in vitro methods of in vivo precipitation of orally administered bases overpredict the intestinal crystalline precipitation in vivo in humans. Hydrodynamic conditions were identified as one important factor that needs to be better addressed in future in vivo predictive methods.

Pharmacokinetics of Single and Multiple Doses of Omega-3 Carboxylic Acids in Healthy Chinese Subjects: A Phase I, Open-Label Study.

In patients with coronary heart disease undergoing primary prevention, hypertriglyceridemia is a residual risk for cardiovascular events. Omega-3 carboxylic acid (OM3-CA), a mixture of the free fatty acid forms of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), may be beneficial in reducing triglyceride levels. As part of the clinical development program of OM3-CA in China, this phase I study evaluated the pharmacokinetics, safety, and tolerability profile of OM3-CA in healthy subjects. The pharmacokinetic results of this study were also compared with those of available data for Western populations. Fourteen healthy Chinese subjects (aged 18-45 years) received once-daily oral OM3-CA 4 g for 14 consecutive days. Pharmacokinetic parameters were assessed from both baseline-uncorrected and baseline-corrected plasma concentrations vs time profile of EPA, DHA, and EPA plus DHA. Following single and multiple oral doses of OM3-CA, the absorption of EPA, DHA, and EPA plus DHA was steady with median tmax occurring at 5.5-6 hours after both single and multiple dosing. Close to steady-state concentrations in plasma were reached after 14 days of continuous once-daily dosing, and accumulation was confirmed for EPA, DHA, and EPA plus DHA. Of the 14 subjects treated with OM3-CA, 6 (42.9%) reported at least 1 adverse event (diarrhea) during the study, which was determined as mild and treatment emergent. No serious adverse events were reported. In summary, the pharmacokinetic profile of oral OM3-CA 4 g after single and multiple dosing in healthy Chinese subjects is consistent with that observed in other ethnic populations.

Evolving data analysis of an Oral Lipid Tolerance Test toward the standard for the Oral Glucose Tolerance Test: Cross species modeling effects of AZD7687 on plasma triacylglycerol.

We have developed a novel mechanistic pharmacokinetic-pharmacodynamic (PK/PD) model to describe the time course of plasma triglyceride (TAG) after Oral Lipid Tolerance Test (OLTT) and the effects of AZD7687, an inhibitor of diacylglycerol acyltransferase 1 (DGAT1), in humans, rats, and mice. Pharmacokinetic and plasma TAG data were obtained both in animals and in two phase I OLTT studies. In the PK/PD model, the introduction of exogenous TAG is represented by a first order process. The endogenous production and removal of TAG from plasma are described with a turnover model. AZD7687 inhibits the contribution of exogenous TAG into circulation. One or two compartment models with first order absorption was used to describe the PK of AZD7687 for the different species. Nonlinear mixed effect modeling was used to fit the model to the data. The effects of AZD7687 on the plasma TAG time course during an OLTT as well as interindividual variability were well described by the model in all three species. Meal fat content or data from single vs repeated dosing did not affect model parameter estimates. Body mass index was found to be a significant covariate on the plasma TAG baseline. The system parameters of the model will facilitate analysis for other compounds and provide tools to bring the standard of OLTT data analysis closer to the analyses of Oral Glucose Tolerance Test data maximizing knowledge gain.

Safety, Tolerability, and Pharmacokinetics of Single and Multiple Oral Doses of an Omega-3-Carboxylic Acid Formulation in Healthy Male Japanese Subjects: A Phase 1 Single-Blind, Randomized, Placebo-Controlled Trial.

OM3-CA (omega-3-carboxylic acids) is a complex mixture of omega-3 carboxylic acids, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which is approved in the United States for the treatment of hypertriglyceridemia. As part of its clinical development in Japan, we performed a phase 1 study to investigate the safety, tolerability, and pharmacokinetics after single and multiple doses of OM3-CA in healthy male Japanese subjects. Eighteen Japanese subjects were allocated to receive 2 or 4 g/day OM3-CA, or placebo (n = 6 per group). In addition, 6 white subjects received 4 g/day OM3-CA. The primary objective was to determine the safety and tolerability of OM3-CA. Plasma concentrations of EPA and DHA were adjusted for baseline values for pharmacokinetic analysis. Overall, OM3-CA was well tolerated in healthy Japanese subjects. Two Japanese subjects in each group and 5 white subjects experienced adverse events (AEs). Alanine aminotransferase increase was the most common AE in Japanese subjects, also seen with placebo, and diarrhea was the most common AE in white subjects. The maximum plasma concentrations of EPA and DHA were observed 5-6 hours postdose. The pharmacokinetic profiles of EPA and DHA after administration of OM3-CA were comparable between Japanese and white subjects.

Pharmacokinetics and acid-suppressive effects of esomeprazole in infants 1-24 months old with symptoms of gastroesophageal reflux disease.

OBJECTIVES: To evaluate the pharmacokinetics and acid-suppressive effects of esomeprazole in infants with gastroesophageal reflux disease (GERD). PATIENTS AND METHODS: In this single-blind, randomized, parallel-group study, 50 infants 1 to 24 months old with symptoms of GERD, and >or=5% of time with intraesophageal pH <4 during 24-hour dual pH monitoring, received oral esomeprazole 0.25 mg/kg (n = 26) or 1 mg/kg (n = 24) once daily for 1 week. Intraesophageal and intragastric pH were recorded at 1 week, and blood samples were taken for pharmacokinetic analysis. RESULTS: At baseline, mean percentages of time with intragastric pH >4 and intraesophageal pH <4 were 30.5% and 11.6%, respectively, in the esomeprazole 0.25 mg/kg group and 28.6% and 12.5% in the esomeprazole 1 mg/kg group. After 1 week of treatment, times with intragastric pH >4 were 47.9% and 69.3% in the esomeprazole 0.25 mg/kg and 1 mg/kg groups, respectively (P < 0.001 vs baseline), and times with intraesophageal pH <4 were 8.4% (P < 0.05 vs baseline) and 5.5% (P < 0.001 vs. baseline), respectively. The mean number of acid reflux episodes of >5 minutes duration decreased from 6 at baseline to 3 and 2 with esomeprazole 0.25 mg/kg and 1 mg/kg, respectively. The geometric mean AUC0-t of esomeprazole were 0.24 and 1.79 micromol x h/L for the 0.25 mg/kg and 1 mg/kg dosages of esomeprazole, respectively. Both esomeprazole dosages were well tolerated. CONCLUSIONS: Oral treatment with esomeprazole 0.25 mg/kg and 1 mg/kg was well tolerated and provided dose-related acid suppression, dose-related exposure to esomeprazole, and decreased esophageal acid exposure in infants 1-24 months old with GERD.

Assessment of pharmacokinetic interaction between omega-3 carboxylic acids and the statins rosuvastatin and simvastatin: Results of 2 phase I studies in healthy volunteers.

BACKGROUND: Omega-3 carboxylic acids (OM3-CA) can lower triglyceride levels. OM3-CA is often prescribed concomitantly with a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin). OBJECTIVE: The aim of the article was to assess the potential for pharmacokinetic interaction between OM3-CA and the statins rosuvastatin and simvastatin. METHODS: Data from 2 phase I studies (ECLIPSE III and OM-EPA-007 [NCT01486433]) were analyzed. In ECLIPSE III, 59 participants received OM3-CA 4 g once daily for 13 days, with rosuvastatin 40 mg (single dose) co-administered with the 11th dose. In OM-EPA-007, 52 participants received simvastatin 40 mg plus acetylsalicylic acid 81 mg daily for 14 days, with or without OM3-CA. Lack of a drug-drug interaction was declared if the 90% confidence interval (CI) of the geometric least-squares mean ratio of pharmacokinetic parameters was in the range 80% to 125%. RESULTS: For rosuvastatin, values for the geometric mean ratio (90% CI) with:without OM3-CA were 86.38% (80.68-92.48), 90.50% (85.99-95.25), and 89.01% (84.30-93.98), respectively, for maximum plasma concentration (Cmax), area under the concentration-time curve up to last measurable concentration (AUC0-t) and extrapolated to infinity (AUC0-inf). Co-administration with a single dose of rosuvastatin did not affect the multiple-dose pharmacokinetics of constituent OM3-CA fatty acids eicosapentaenoic acid and docosahexaenoic acid. For simvastatin, values for steady state geometric mean ratio (90% CI) with:without OM3-CA were 91.61% (82.82-101.33) and 87.47% (80.19-95.41), respectively, for Cmax and AUC0-t. No deaths or serious adverse events occurred in either trial. CONCLUSION: OM3-CA can be administered with either rosuvastatin or simvastatin without affecting the pharmacokinetics of these statins.

No Effect of Omega-3 Carboxylic Acids on Pharmacokinetics/Pharmacodynamics of Warfarin or on Platelet Function When Co-administered with Acetylsalicylic Acid: Results of Two Phase I Studies in Healthy Volunteers.

BACKGROUND: Omega-3 carboxylic acids (OM3-CA) can lower triglyceride levels. OBJECTIVE: Our objective was to assess the effects of OM3-CA on warfarin pharmacokinetics and pharmacodynamics and on acetylsalicylic acid (ASA)-dependent and independent platelet activation when co-administered with ASA in two phase I studies. METHODS: In ECLIPSE II (NCT01431690), 26 participants received warfarin 25 mg on days 1 and 22 and OM3-CA 4 g once daily from day 8 to day 28. In OM-EPA-007 (NCT01486433), 52 participants received simvastatin 40 mg plus ASA 81 mg once daily for 14 days, with or without OM3-CA 4 g. Lack of a drug-drug interaction was indicated when 90% confidence intervals (CIs) fell entirely within the range 80-125% for least-squares mean (LSM) ratios of area under the concentration-time curve (AUC), maximum observed plasma concentration (C max), international normalized ratio (INR) AUC to 168 h and maximum INR. RESULTS: In ECLIPSE II, 90% CIs for LSM ratios of with:without OM3-CA fell within 80-125% for AUC and C max of S- and R-warfarin enantiomers. The 90% CIs for LSM ratios of with:without OM3-CA fell within 80-125% for INR AUC to 168 h after dosing and for maximum INR of warfarin. In OM-EPA-007, no significant effect of OM3-CA was observed on ASA-dependent or ASA-independent platelet activation. No deaths or serious adverse events occurred in either study. CONCLUSION: OM3-CA did not affect the pharmacokinetics or pharmacodynamics of warfarin or the pharmacodynamic effects of ASA. OM3-CA did not affect platelet function when co-administered with ASA.

Systemic Bioavailability and Dose Proportionality of Omega-3 Administered in Free Fatty Acid Form Compared With Ethyl Ester Form: Results of a Phase 1 Study in Healthy Volunteers.

BACKGROUND: Omega-3 carboxylic acids (OM3-CA) contains eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in free fatty acid form. Per gram, OM3-CA includes approximately half as much EPA as icosapent ethyl (IPE), an ethyl ester formulation of EPA. OBJECTIVE: The study aim was to assess systemic EPA and EPA + DHA exposures and plasma lipid parameters following multiple OM3-CA or IPE doses under low-fat dietary conditions, and dose proportionality after OM3-CA administration. METHODS: In this phase 1, two-cohort, open-label study (N = 114), participants following the Therapeutic Lifestyle Changes diet received either OM3-CA 2 g once daily for 10 days then OM3-CA 4 g once daily for 10 days, or IPE 2 g twice daily for 20 days. Exposure was considered similar if the 90% confidence intervals (CIs) of geometric least-squares mean (LSM) ratios for key pharmacokinetic parameters were within 80-125%. RESULTS: Baseline-adjusted steady-state EPA exposure was similar after dosing with OM3-CA 4 g/day versus IPE 4 g/day (LSM ratio, area under the concentration-time curve from time 0 to 24 h: 93.9%; 90% CI 85.6, 103.0). Combined molar-equivalent EPA + DHA exposure was 30.6% higher following OM3-CA 4 g/day than IPE 4 g/day. EPA and DHA exposure increased approximately proportionally with OM3-CA dose (2-4 g/day). Changes from baseline in lipid parameters were similar in the two cohorts. CONCLUSION: EPA exposure from OM3-CA and IPE was similar under low-fat dietary conditions, despite OM3-CA containing only approximately half as much EPA as IPE. EPA and DHA exposure from OM3-CA increased proportionally with dose.

Effects of Food on the Pharmacokinetics of Omega-3-Carboxylic Acids in Healthy Japanese Male Subjects: A Phase I, Randomized, Open-label, Three-period, Crossover Trial.

AIMS: Omega-3-carboxylic acids (OM3-CA) contain omega-3 free fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), as carboxylic acids. Food intake is known to affect the bioavailability of ethyl ester fatty acid formulations. We conducted a phase I study to investigate the effects of the timing of OM3-CA administration relative to food intake on the pharmacokinetics of EPA and DHA. METHODS: In this randomized, open-label, three-period crossover study, Japanese healthy male subjects were administered 4×1 g OM3-CA capsules with continued fasting, before a meal, or after a meal. All subjects fasted for ≥10 h prior to drug/meal administration. The primary objective was to examine the effect of meal timing on the pharmacokinetics of EPA and DHA after OM3-CA administration. The secondary objectives were to examine the safety and tolerability of OM3-CA. RESULTS: A total of 42 Japanese subjects was enrolled in the study. The baseline-adjusted maximum concentration and area under the concentration-time curve from 0 to 72 h for EPA, DHA, and EPA +DHA were lower in the fasting and before meal conditions than in the after meal condition. The maximum total EPA, total DHA, and total EPA+DHA concentrations were reached later when administered in fasting conditions than in fed conditions, indicating slower absorption in fasting conditions. Diarrhea was reported by five, six, and no subjects in the fasting, before meal, and after meal conditions, respectively. CONCLUSIONS: The timing of OM3-CA administration relative to food intake influences the systemic bioavailability of EPA and DHA in healthy Japanese male subjects. TRIAL REGISTRATION: NCT02372344.

Modeling gene associations for virulence classification of verocytotoxin-producing E. coli (VTEC) from patients and beef.

An evaluation of 22 EHEC genes was carried out for virulence classification of VTEC. The data consisted of 116 patient isolates and 42 beef isolates. The symptoms among patients ranged from mild (diarrhea) to severe (bloody diarrhea and HUS). A cluster of genes-efa1, eae, ecf4, paa, and ureC-were more frequent in patient isolates than beef isolates. They also contributed to the classification of high virulence isolates compared with low virulence isolates. These genes may together constitute a general virulence factor, being also associated with well-known virulence serogroups: O157, O26, O103, O111, O145, O121, and O118. In a regression model of patient versus beef isolates, the combined presence of efa1 and paa proved a particularly efficient indicator of patient isolates (OR: 32.9). In contrast, a single gene, vtx22 (subtype vtx2 of vtx2) was a relatively efficient predictor of high virulence among patient isolates (OR: 41.6), but not of virulence in general. Significant interaction effects observed between genes need to be addressed and clarified in future studies.