Standard High-fat Meal Research Articles

#4328 CHK-336, A FIRST-IN-CLASS ORALLY ADMINISTERED LDH INHIBITOR: SAFETY, PK AND TARGET ENGAGEMENT IN A FIRST-IN-HUMAN PHASE 1 HEALTHY VOLUNTEER STUDY

Abstract Background and Aims CHK-336 is a first-in-class, orally bioavailable, liver-targeted small molecule lactate dehydrogenase (LDH) inhibitor for the treatment of primary hyperoxalurias and other kidney stone disorders caused by oxalate overproduction. The primary objectives of this first-in-human (FIH) study were characterization of the safety and pharmacokinetics (PK) of CHK-336 following single and repeat doses in healthy volunteers (HVs). Exploratory objectives were demonstration of proof of mechanism in HVs based on inhibition of hepatic oxalate production using a stable-label 13C2-glycolate tracer for hepatic LDH target engagement and characterization of the exposure-response relationship. Method This Phase 1, placebo-controlled (6:2 randomization within a cohort), dose escalation study explored single ascending (SAD, 15-500 mg) and multiple ascending (MAD, 30 mg and planned up to 500 mg QD, 14 consecutive days) doses. A total of 104 subjects will be enrolled in this study. A stable-label 13C2-glycolate tracer was administered orally at baseline and following CHK-336 administration to evaluate the inhibition of LDH-mediated production of [13C2]-oxalate by CHK-336, as a measure of hepatic LDH target engagement in HVs. Food-effect was evaluated following a single dose after a standard high fat meal. CHK-336 concentrations were determined in plasma and urine by a validated LC-MS/MS assay. Total oxalate and 13C2-oxalate were determined in urine by validated GC/MS assays. Results CHK-336 was generally well tolerated following single doses from 15 – 500 mg, with no dose-related trends in total adverse events (AEs) or types of AEs. There were no serious AEs, or severe treatment-related AEs (TRAEs). Treatment-emergent AEs were observed in 10 of 56 (17.9%) subjects, 7 (12.5%) of whom experienced TRAEs; all TRAEs were mild or moderate in severity. CHK-336 PK profiles were characterized with a median tmax of 6 hrs following absorption in fasted-state followed by bi-exponential decline and a terminal half-life of 18 ± 8 hrs. Dose-proportional increases in exposure AUC were observed from 15 up to 500 mg. Cmax increase was greater than dose-proportional at ≥60 mg with a concomitant decrease in median tmax from 6hr to 2hr. A high fat meal decreased CHK-336 AUC0-72h by 32% (AUC0-72h) and Cmax by 55%. Renal elimination of unchanged CHK-336 was quantitatively minor (<1% of administered dose). A direct effect inhibitory Imax-IC50 model adequately described the relationship between CHK-336 plasma concentrations and urinary 13C2-oxalate (% of control). Robust target engagement was demonstrated with an exposure-related reduction in urinary 13C2-oxalate from 15 – 60 mg, with maximum inhibition achieved at CHK-336 doses ≥60 mg. Conclusion CHK-336 is a first-in-class, orally administered, liver-targeted LDH inhibitor that was generally well-tolerated following single doses from 15 – 500 mg, with dose proportional increases in AUC exposure. Hepatic oxalate production was robustly reduced by CHK-336, as measured by urinary 13C2-oxalate, thus achieving proof of mechanism in HVs.

The effect of postprandial in vivo and experimental in vitro hyperlipidemia on human peripheral blood monocytes

Abstract Objective: In this study, we aimed to investigate the effect of transient postprandial in vivo and prolonged experimental in vitro hyperlipidemia on human peripheral blood monocytes. Methods: Peripheral blood was collected from seven healthy subjects after an overnight fast and three hours after a standardized high-fat meal. Both fasting and postprandial samples were stained for surface markers CD14/CD11b and intracellular lipids using BODIPY493/503. Postprandial samples only were used for isolation of peripheral blood mononuclear cells that were further incubated overnight with postprandial hyperlipidemic autologous plasma, then stained as described above. All samples were analyzed on a FACSAria III flow cytometer. Results: Flow cytometric analysis revealed two monocyte populations (CD14+): CD14low and CD14high. In fasting, these populations show similar morphology (FSC/SSC), but different expressions of CD14, CD11b, and BODIPY493/503. At three hours postprandially, a moment of maximum hyperlipidemia, neither population suffered significant changes. After the 24-hour incubation, cell activation was observed in both populations: similar fold change increase in SSC, increase in FSC for CD14high cells only, similar foldchange increase in CD14, slightly higher foldchange increase in CD11b for CD14low monocytes, and significantly higher foldchange increase in lipid content for CD14high monocytes. CD14high monocytes appear to undergo a more intense activation than CD14low monocytes. Conclusions: We conclude that all monocytes react after prolonged in vitro exposure to plasma lipids, each subset having its own activation pattern. All monocyte types may play a role in inflammation and the development of plaques. Monocyte assays are a valuable tool for the investigation of atherosclerosis at the cellular level.

High-Fat or High-Carbohydrate Meal-Does It Affect the Metabolism of Men with Excess Body Weight?

Excessive adipose tissue in the body may lead to adverse health effects, carbohydrate and lipid metabolism disorders, and cardiovascular diseases. The aim of this study was to analyze the effect of a standardized high-fat meal (HF) on changes in energy expenditure and changes in the oxidation of energy substrates as well as the concentration of glucose, insulin, triglycerides and homocysteine in blood serum in relation to a standardized high-carbohydrate (non-fat, HC) meal in men with different nutritional status. In this study, 26 men (aged 19–60) without carbohydrate disorders (study group GS = 13 overweight/obese; control group GC = 13 normal body weight) were examined. It was observed that following a high-fat or high-carbohydrate meal, men with excessive body weight metabolized the main nutrients differently than men with normal body weight, and postprandial insulin secretion was also different (even without any significant differences in glucose concentrations). Overweight/obesity, which is in itself a risk factor for cardiovascular disease, contributes to an increase in the concentration of other risk factors, such as the concentration of homocysteine and triglycerides, which is referred to as cardiometabolic risk. Consumption of a high-fat meal increased the number of potential risk factors for cardiovascular disease (homocysteine and triglycerides) compared to a high-carbohydrate meal.

The Arg82Cys Polymorphism of the Protein Nepmucin Implies a Role in HDL Metabolism.

ContextBlood lipid levels are linked to the risk of cardiovascular disease and regulated by genetic factors. A low-frequency polymorphism Arg82Cys (rs72836561) in the membrane protein nepmucin, encoded by CD300LG, is associated with lower fasting concentration of high-density lipoprotein cholesterol (HDLc) and higher fasting triglycerides. However, whether the variant is linked to postprandial lipids and glycemic status remains elusive.ObjectiveHere, we augment the genetic effect of Arg82Cys on fasting plasma concentrations of HDL subclasses, postprandial lipemia after a standardized high-fat meal, and glycemic status to further untangle its role in HDL metabolism.MethodsWe elucidated fasting associations with HDL subclasses in a population-based cohort study (Oxford BioBank, OBB), including 4522 healthy men and women. We investigated fasting and postprandial consequences on HDL metabolism in recall-by-genotype (RbG) studies (fasting: 20 carrier/20 noncarrier; postprandial: 7 carrier/17 noncarrier), and shed light on the synergistic interaction with glycemic status.ResultsA lower fasting plasma concentration of cholesterol in large HDL particles was found in healthy male carriers of the Cys82 polymorphism compared to noncarriers, both in the OBB (P = .004) and RbG studies (P = .005). In addition, the Cys82 polymorphism was associated with low fasting plasma concentrations of ApoA1 (P = .008) in the OBB cohort. On the contrary, we did not find differences in postprandial lipemia or 2-hour plasma glucose levels.ConclusionTaken together, our results indicate an association between the Arg82Cys variant and a lower concentration of HDL particles and HDLc, especially in larger HDL subclasses, suggesting a link between nepmucin and HDLc metabolism or maturation.

Comparison of a Standardized High-Fat Meal versus a High-Fat Meal Scaled to Body Mass for Measuring Postprandial Triglycerides: A Randomized Crossover Study.

Post-meal triglycerides are an independent cardiovascular disease (CVD) risk factor, but the ideal high-fat meal formulation has yet to be standardized and is one challenge prohibiting widespread clinical adoption of postprandial triglyceride assessment. Two general approaches often used are giving individuals a high-fat meal scaled to body weight or a standardized high-fat meal containing a set fat bolus. A recent expert panel statement has endorsed the latter, specifying 75 g of fat as an appropriate fat dosage. Despite this recommendation, no study to date has tested whether there is a difference in postprandial triglycerides or if risk classification is affected based on these different approaches. We recruited 16 generally healthy individuals with roughly equal distribution among body mass index (BMI)class (n = 5–6/per BMI category) and sex (n = 2–3 M/F) within each BMI class. Each participant underwent two abbreviated fat tolerance tests separated by ~1 week: one with a scaled to body weight high-fat meal (9 kcal/kg; 70% fat) and a standardized meal containing 75 g of fat (70% fat). Fasting, 4 h, and absolute change in triglycerides across the entire sample and within each BMI category were similar regardless of high-fat meal. Only one participant with obesity had discordant postprandial responses between the fat tolerance tests (i.e., different CVD risk classification). These findings suggest that, within a certain range of fat intake, generally healthy individuals will have a similar postprandial triglyceride response. Considering the greater convenience of utilizing standardized high-fat meals, our data suggest that a standardized high-fat meal may be acceptable for large-scale studies and clinical implementation.

Genomics of Postprandial Lipidomics in the Genetics of Lipid-Lowering Drugs and Diet Network Study.

Postprandial lipemia (PPL) is an important risk factor for cardiovascular disease. Inter-individual variation in the dietary response to a meal is known to be influenced by genetic factors, yet genes that dictate variation in postprandial lipids are not completely characterized. Genetic studies of the plasma lipidome can help to better understand postprandial metabolism by isolating lipid molecular species which are more closely related to the genome. We measured the plasma lipidome at fasting and 6 h after a standardized high-fat meal in 668 participants from the Genetics of Lipid-Lowering Drugs and Diet Network study (GOLDN) using ultra-performance liquid chromatography coupled to (quadrupole) time-of-flight mass spectrometry. A total of 413 unique lipids were identified. Heritable and responsive lipid species were examined for association with single-nucleotide polymorphisms (SNPs) genotyped on the Affymetrix 6.0 array. The most statistically significant SNP findings were replicated in the Amish Heredity and Phenotype Intervention (HAPI) Heart Study. We further followed up findings from GOLDN with a regional analysis of cytosine-phosphate-guanine (CpGs) sites measured on the Illumina HumanMethylation450 array. A total of 132 lipids were both responsive to the meal challenge and heritable in the GOLDN study. After correction for multiple testing of 132 lipids (α = 5 × 10−8/132 = 4 × 10−10), no SNP was statistically significantly associated with any lipid response. Four SNPs in the region of a known lipid locus (fatty acid desaturase 1 and 2/FADS1 and FADS2) on chromosome 11 had p < 8.0 × 10−7 for arachidonic acid FA(20:4). Those SNPs replicated in HAPI Heart with p < 3.3 × 10−3. CpGs around the FADS1/2 region were associated with arachidonic acid and the relationship of one SNP was partially mediated by a CpG (p = 0.005). Both SNPs and CpGs from the fatty acid desaturase region on chromosome 11 contribute jointly and independently to the diet response to a high-fat meal.

Impact of a High-Fat Meal and Sprinkled Administration on the Bioavailability and Pharmacokinetics of Viloxazine Extended-Release Capsules (QelbreeTM) in Healthy Adult Subjects.

Background and ObjectivesViloxazine extended-release (viloxazine ER) capsules (QelbreeTM) is a novel nonstimulant recently approved as a treatment for attention-deficit/hyperactivity disorder in children and adolescents. Here, we determined whether the pharmacokinetics of viloxazine are impacted by consuming the capsule contents sprinkled on applesauce rather than an intact capsule, and the effect of a high-fat meal on the pharmacokinetics of viloxazine ER.MethodsThis was a randomized, open-label, crossover, three-treatment, three-period study in healthy adults using orally administered single-dose viloxazine ER 200 mg capsules. Subjects consumed: (1) an intact capsule after a 10-h fast (control condition); (2) the capsule contents sprinkled on one tablespoon of applesauce; and (3) an intact capsule with a standard high-fat meal. Blood samples were collected for 48 h post-dosing. Relative bioavailability analyses were performed to assess the impact of each test condition against the control condition (intact capsule, fasting). The absence of an impact was indicated if the 90% confidence interval (CI) for the least-squares geometric mean ratio (LSGMR) of maximal concentration (Cmax), the area under the concentration–time curve from time 0 to the last measurable concentration time (AUClast), and the area under the concentration–time curve from time 0 to infinity (AUCinf) were within the predetermined no-difference limits of 80–125%.ResultsOut of 27 enrolled subjects, 25 were included in the pharmacokinetic analysis. The LSGMR (90% CI) for viloxazine ER sprinkled vs. intact were 90.10% (83.35–97.40) for Cmax, 93.71% (89.09–98.57) for AUClast, and 95.37% (89.80–101.28) for AUCinf. The LSGMR (90% CI) for viloxazine ER consumed in the fed state vs. fasting state were 90.86% (84.05–98.21) for Cmax, 89.68% (85.26–94.33) for AUClast, and 92.35% (86.96–98.07) for AUCinf. The 90% CIs of the LSGMRs were within the predetermined no-difference limits of 80–125%. Viloxazine ER was well tolerated, with most adverse events reported as mild.ConclusionsThese data suggest that viloxazine ER can be consumed sprinkled on applesauce or as intact capsules with or without meals without significantly changing its pharmacokinetics.

Postprandial dyslipidemia after a standardized high-fat meal in BMI-matched healthy individuals, and in subjects with prediabetes or type 2 diabetes

A relationship between postprandial hyperlipidemia and glucose homeostasis/cardiovascular diseases has been suggested. We investigated postprandial plasma lipid patterns after a standardized high-fat meal and their association with glucose homeostasis and subclinical atherosclerosis. Using matching by BMI, 32 healthy individuals with normal glucose tolerance (NGT), 21 subjects with impaired glucose tolerance (IGT), and 20 subjects with drug-naïve type 2 diabetes (T2D) were enrolled. Plasma concentrations of triglycerides (TGs), apolipoprotein-B (ApoB), ApoB48, ApoB100, glucose, and insulin at baseline and 1, 2, 3, 4, 5, 6, and 8h after a standardized meal (1041.03kcal with 70.99g of fat) were measured. Body composition, abdominal visceral fat area, and resting energy expenditure (REE) were measured using dual energy X-ray absorptiometry, computed tomography, and indirect calorimetry, respectively. The intima-media thickness (IMT) of the carotid artery and the ankle-brachial index (ABI) were used to detect subclinical atherosclerosis. Baseline data and area under the curve (AUC) of plasma concentrations of TGs, ApoB, and ApoB48 in the IGT and T2D groups were higher than in the NGT group. The peak TG concentrations after the meal was observed at 5h in subjects with IGT and T2D, while healthy subjects showed the highest concentrations at 4h. In multivariable analysis, high abdominal visceral fat area and low HDL-cholesterol concentrations were independently associated with the AUCTG and AUCApoB after adjusting for confounders including baseline TG and the REE. High LDL-cholesterol and high HbA1c concentrations were also associated with the AUCApoB. Furthermore, high AUCTG and AUCApoB values were independent factors for an increased carotid IMT and a low ABI after adjusting for relevant variables. Abdominal visceral obesity and low HDL-cholesterol concentrations were associated with increased post load excursions of TGs and ApoB in this series. These elevated concentrations of TGs and ApoB were linked with subclinical atherosclerosis.

Abstract CT109: A phase I/Ib study evaluating GDC-0077 plus fulvestrant in patients with PIK3CA-mutant, hormone receptor-positive/HER2-negative breast cancer

Abstract Background: PIK3CA encodes the PI3K p110α subunit, and dysregulating mutations are widely seen in breast cancer (BC) and other solid tumors. GDC-0077 (G) is a potent p110α-selective inhibitor that degrades mutant p110α and demonstrates antitumor activity in PIK3CA-mutant BC xenograft models, either as a single agent, or combined with anti-estrogen therapy. From an ongoing, open-label, phase I/Ib dose-escalation study of G alone and combined with endocrine + targeted therapies (NCT03006172), we present data of G + fulvestrant (F) in postmenopausal patients (pts) with PIK3CA-mutant, hormone receptor-positive/HER2-negative BC, including a food-effect assessment on the pharmacokinetics (PK) of G. Methods: Safety (NCI-CTCAE v4), PK, and preliminary antitumor activity (clinical benefit rate [CBR]: RECIST v1.1 stable disease for ≥24 weeks, partial response [PR], or complete response) of 9 mg oral once-daily G + 500 mg intramuscular F on Day 1 (and Day 15 of Cycle 1) of 28-day cycles were assessed until intolerable toxicity/disease progression. The effect of a standard high-fat meal on the PK of G was evaluated after a single dose and at steady state. Relevant signaling and pharmacodynamic (PD) biomarkers were assessed using circulating tumor (ct) DNA samples. Results: At clinical cutoff (Jul 19, 2019), 20 pts were enrolled in the food-effect portion of the G + F arm. Fifteen (75%) had received ≥2 prior lines of therapy for metastatic BC. Median G treatment duration was 5.9 months (range 1.7-17.8); cumulative dose intensity, 98%. Adverse events (AEs) led to dose reduction in 3 pts (15%). The most common treatment-related (TR) AEs (≥4 pts, 20%) were hyperglycemia (11, 55%), diarrhea (10, 50%), stomatitis (grouped term; 9, 45%), nausea (8, 40%), decreased appetite (7, 35%), dysgeusia, fatigue, and muscle spasms (4 each, 20%). Grade ≥3 TRAEs were hyperglycemia, nausea, lymphopenia, hyperamylasemia, and hyperlipasemia (1 each, 5%). The PK of G in combination with F was similar to single-agent PK. Comparable G exposures (Cmax and AUC0-24) were observed following administration in fasted or fed states. Seventeen pts (85%) discontinued treatment, all due to radiographic/clinical disease progression. Overall, 5/14 pts with measurable disease had a PR (36%; 2 received prior F; 4, prior CDK4/6i), of whom 2 pts (14%) had a confirmed PR. CBR was 60% (12/20 pts). Most pts showed decreased ctDNA PIK3CA-mutant allele frequency during treatment. Conclusion: G + F demonstrated a manageable safety profile, similar PK to G alone, preliminary antitumor activity, and PD modulation of PIK3CA-mutant allele frequency in ctDNA. The presence of food did not significantly impact the rate or extent of G absorption following single or multiple doses. Additional pts are being enrolled in the G + F arm to further inform the safety and efficacy of this combination. Citation Format: Kevin Kalinsky, Dejan Juric, Philippe L. Bedard, Mafalda Oliveira, Andres Cervantes, Erika Hamilton, Ian E. Krop, Nick Turner, Peter Schmid, Andrea Varga, Antoine Italiano, Zachary Veitch, Cristina Saura, Valentina Gambardella, Sravanthi Cheeti, Naoki Kotani, Guiyuan Lei, Katherine E. Hutchinson, Stephanie Royer-Joo, Anjali Vaze, Jennifer L. Schutzman, Komal Jhaveri. A phase I/Ib study evaluating GDC-0077 plus fulvestrant in patients with PIK3CA-mutant, hormone receptor-positive/HER2-negative breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT109.

SUN-022 Metformin-Fish Oil Adjunct Therapy Improves apoB-Remnant Lipoprotein and Triglyceride Levels in Women with Polycystic Ovary Syndrome

Background: Polycystic ovary syndrome (PCOS) is highly associated with the metabolic syndrome (MetS): obesity, insulin resistance and atherogenic dyslipidemia. Women with PCOS-MetS are at higher risk of developing ischemic cardiovascular disease (CVD) and Type-2 Diabetes. First-line intervention in PCOS-MetS includes targeting diet and lifestyle, and metformin is commonly prescribed to treat insulin resistance, however these interventions have shown limited effectiveness to improve dyslipidemia. At present there are limited safe and efficious options to target atherogenic dyslipidemia in young women with PCOS. Fish oil (FO) and Icosapentyl ethyl supplementation have been shown to reduce fasting TG, apoB and to improve ischemic CVD outcomes. The efficacy of FO or as an adjunct therapy to metformin to improve ApoB-remnant lipemia in PCOS-MetS is unknown. The aim of this pilot study was to determine the effect of metformin, FO and FO-metformin combination treatment on fasting and non-fasting plasma TG and apoB-remnant lipoprotein metabolism in patients with PCOS-MetS. Methods: Participants diagnosed with PCOS aged 18-30yrs received dietary counselling and were randomly assigned to receive FO (n=8), metformin (n=7) or FO-metformin (n=12) treatment for 12 wks. Plasma lipids (TG and cholesterol), ApoB48 and ApoB100 lipoprotein metabolism were assessed in the fasting and non-fasting state using a standardized high-fat meal test. Results: At baseline, the fasting plasma TG, ApoB48 and ApoB100 was 238.0 ± 21.0 mg/dL, 9.00 ± 1.12 ug/ml and 290 ± 18.00 mg/dL. FO and FO-metformin decreased fasting plasma TG by 10% and 30% compared to the metformin treatment group (7%). Fasting ApoB48 was reduced 45%, 16% and 19% in FO-metformin, FO and metformin treatment groups, respectively. Non-fasting plasma TG and apoB48 lipoprotein area under the curve were reduced by 30% in the FO-metformin treatment group. Conclusion: These pilot findings demonstrate FO-metformin adjunct therapy may have greater efficacy to improve atherogenic apoB-dyslipidemia compared to metformin or FO alone in high-risk patients with PCOS-MetS. A larger clinical trial is warranted to determine the long term effects of FO-metformin intervention on apoB-dyslipidemia and atherosclerotic cardiovascular disease indices.

Acute Exenatide Therapy Attenuates Postprandial Vasodilation in Humans with Prediabetes: A Randomized Controlled Trial.

Background: The state of prediabetes comprises atherosclerotic changes leading to decreased vascular function in humans. This study examined the effects on incretin mimetics on vascular physiology in the prediabetic postprandial state. Methods: Fifteen obese adults with prediabetes participated in a randomized, crossover, double-blinded trial comparing the postprandial effects of exenatide, saxagliptin, and placebo on peripheral vasodilation. All studies utilized a standardized high-fat meal. Resting and peak forearm blood flow (FBF) were measured via strain gauge venous occlusion plethysmography, and makers of vascular dysfunction were measured in plasma. Results: Exenatide attenuated resting FBF at 3 hr (P = 0.003) and 6 hr (P = 0.056) postmeal, compared to placebo. Nonsignificant reductions in resting FBF were observed between saxagliptin and placebo at the same time points. No group differences were observed for peak FBF, plasma nitrotyrosine, and plasma 8-iso-prostaglandin F2alpha. A transient increase in plasma triglyceride was abated in the exenatide group, when compared to saxagliptin and placebo groups. Only exenatide group showed no significant upsurge in plasma insulin. Plasma-free fatty acids significantly declined in all three groups, although less markedly for exenatide. Postmeal glucose increased at 2 hr with placebo and saxagliptin, but simultaneously decreased with exenatide. Conclusions: Acute treatment with exenatide blunted the postprandial vasodilatory effect of a high-fat meal in prediabetes. Exenatide's acute effects derived primarily from multiple endothelium-independent processes. Trial Registration Number: NCT02104739.

Bioavailability of aspirin in fasted and fed states of a novel pharmaceutical lipid aspirin complex formulation

Dyspeptic symptoms are common with aspirin and clinicians frequently recommend that it be taken with food to reduce these side effects. However, food can interfere with absorption, especially with enteric-coated aspirin formulations. We evaluated whether food interferes with the bioavailability of a new, pharmaceutical lipid-aspirin complex (PL-ASA) liquid-filled capsule formulation. In this randomized, open label, crossover study, 20 healthy volunteers fasted for ≥ 10 h and then randomized as either “fasted”, receiving 650 mg of PL-ASA, or as “fed”, with a standard high-fat meal and 650 mg of PL-ASA 30 min later. After a washout of 7 days, participants crossed over to the other arm. The primary outcome was comparison of PK parameters of the stable aspirin metabolite salicylic acid (SA) between fasted and fed states. Mean age of participants was 36.8 years and 55% were male. The ratios for the fed to fasted states of the primary SA PK parameters of AUC0−t and AUC0−∞ were 88.7% and 88.8% respectively, with 90% confidence intervals between 80 and 125%, which is consistent with FDA bioequivalence guidance. Mean peak SA concentration was about 22% lower and occurred about 1.5 h later in the fed state. Food had a modest effect on peak SA levels and the time required to reach them after PL-ASA administration, but did not impact the extent of exposure (AUC) compared with intake in a fasted state. These data demonstrate that PL-ASA may be co-administered with food without significant impact on aspirin bioavailability.Clinical Trial Registration:http://www.clinicaltrials.gov Unique Identifier: NCT01244100

Abstract TP432: Bioavailability of Aspirin in Fasted and Fed States of a Novel Formulation of a Pharmaceutical Lipid-Aspirin Complex

Introduction: Lifelong aspirin therapy is recommended after a TIA or stroke, but dyspeptic symptoms frequently lead to non-adherence. Clinicians often recommend that daily doses be taken with food to reduce these side effects. However, food can interfere with absorption, especially with enteric coated aspirin tablets. Hypothesis: We evaluated whether food interferes with bioavailability of a new, pharmaceutical lipid-aspirin complex (PL-ASA) liquid-filled capsule formulation. Methods: This was a randomized, open label, crossover study in 20 healthy volunteers. Participants fasted for ≥10 hours prior to randomization; if assigned to “fasting” they then received the single 650 mg dose of PL-ASA. If they were randomized to “fed”, they first ate a standard high-fat meal and were dosed 30 minutes later. After a washout period of 10 days each participant crossed over to the other arm and was again dosed with a 650 mg dose of PL-ASA. The primary outcome was the comparison of PK parameters of the primary metabolite salicylic acid (SA) between fasting and fed states. Results: Mean age of participants was 36.8 years and 55% were male. The primary SA PK parameters of AUC 0-t and AUC 0- infinity in the fed state were within 88.7% and 88.8% of concentrations in the fasting state consistent with bio-equivalence (FDA guidance &gt;80%). Mean peak SA concentration was about 25% lower and occurred about 1.5 hours later in the fed state (Figure). Conclusions: Food had a modest effect on the time required to reach peak SA concentration and on the actual peak SA levels after PL-ASA administration, but did not impact the extent of exposure (area under the curve) compared with intake in a fasting state. These data demonstrate that PL-ASA may be co-administered with food without significant variability in absorption, a recognized limitation of coated aspirin formulations.

Postprandial Lipemic Responses to Various Sources of Dietary Fat in Healthy Adults (P08-101-19)

ObjectivesPostprandial lipemia (PPL), or a large increase in triglycerides (TG) post-meal, has been identified as an independent risk factor for cardiovascular disease (CVD) and may be a stronger predictor of CVD risk than fasting TG. However, the effects of various sources of dietary fat on PPL are not well understood. Therefore, the objective of this project is to examine the postprandial TG response to commonly consumed sources of dietary fat. MethodsParticipants engaged in 4 randomized meal trials separated by at least 1 week. For each meal trial, following a 10-hour overnight fast, an intravenous catheter was inserted into a forearm vein from which a fasting blood draw was taken. Thereafter, participants consumed a standard high-fat meal (HFM; 13 kcal/kg; 61% fat, 32% CHO) with the fat source derived from either butter (B), virgin unrefined coconut oil (CoO), extra virgin olive oil (OO), or canola oil (CaO). Serial blood draws were collected hourly for 6-hours post-meal to quantify postprandial TG responses. ResultsSeven healthy participants have completed the protocol (4 M/3F; age 23.8 ± 1.3 years; BMI: 25.5 ± 7.2 kg/m2). Fasting TG was not different (P = 0.26) across trials (B: 76.1 ± 41.6 mg/dL; CoO: 69.6 ± 27.1 mg/dL; OO: 75.3 ± 45.7 mg/dL; CaO: 85.1 ± 34.7 mg/dL). Two-way ANOVA revealed a significant time effect (P < 0.0001) but no time x meal interaction (P = 0.51) or overall meal effect (P = 0.10). Meal trials did not differ (P = 0.14) with regard to TG total area under the curve (AUC; B: 772.5 ± 449.5 mg/dL × 6 hr; CoO: 605.6 ± 268.2 mg/dL × 6 hr; OO: 726.3 ± 485.3 mg/dL × 6 hr; CaO: 715.1 ± 355.4 mg/dL × 6 hr). However, TG incremental AUC was significantly different (P = 0.03) across meal trials (B: 315.6 ± 229.1 mg/dL × 6 hr; CoO: 188.1 ± 151.7 mg/dL × 6 hr; OO: 274.7 ± 246.3 mg/dL × 6 hr; CaO: 204.2 ± 206.7 mg/dL × 6 hr), although no post hoc pairwise comparisons were significantly different (B vs CoO: P = 0.06; B vs OO: P = 0.76; B vs CaO: P = 0.06; CoO vs OO: P = 0.45; CoO vs CaO: P = 0.98; OO vs CaO: P = 0.19). ConclusionsIn this continuing experiment, postprandial TG responses to HFMs comprised of different dietary fat sources are largely similar to this point, although a difference in incremental AUC was observed. Upon completion, this study will advance our understanding of the effects of commonly consumed dietary fats on PPL, an indicator of CVD risk. Funding SourcesInstitutional internal funding.

Safety, Tolerability and Pharmacokinetics of Yimitasvir Phosphate Capsule, a Novel Oral Hepatitis C Virus NS5A Inhibitor, in Healthy Chinese Volunteers.

Yimitasvir is a novel oral hepatitis C virus non-structural protein 5A (NS5A) inhibitor. The aims of this first-in-human study were to evaluate the safety, tolerability and pharmacokinetics of single and multiple doses of yimitasvir in healthy adult Chinese volunteers and to assess the effect of food on yimitasvir pharmacokinetics. Randomized, double-blind, placebo-controlled, single-ascending-dose (30, 100, 200 and 400mg) and multiple-ascending-dose (100 and 200mg once daily for 7days) studies were performed in 32 and 24 subjects, respectively, in male and female adults. Additionally, the effect of food on yimitasvir pharmacokinetics was assessed with a crossover study in 15 male subjects. Yimitasvir was absorbed slowly after oral administration with a median time to maximum plasma concentration (Tmax) of 3.5-4.0h. Increases in the maximum plasma concentration (Cmax) and area under the concentration-time curve from 0 to the last measurable time point (AUC0-t) were proportional to the dose of yimitasvir over a dose range of 30-100mg, while increases were less than dose proportional over a dose range of 200-400mg in part 1, indicating that absorption at the 200-mg dose was nearly saturated. The geometric mean terminal half-life of yimitasvir was 13.4-19.7h in each cohort, supporting once-daily dosing. Faecal excretion of parent yimitasvir was the major route of elimination. Steady state was achieved following 5days of dosing with minimal accumulation. A standardized high-fat meal decreased the rate and extent of absorption. All doses of yimitasvir were well tolerated. Yimitasvir, at single doses of 30-400mg and multiple doses of 100-200mg for 7days, was well tolerated in healthy Chinese subjects. The results of this study formed the basis for the dosing schemes evaluated in a phase Ib study and subsequent phase II and phase III clinical studies. This study was registered at the China Food and Drug Administration (Registration numbers: 2014L02064 and 2014L02065) and at http://www.chictr.org.cn (Nos. CTR20140854, CTR20150048 and CTR20150123).

Food Effect Study Design With Oral Drugs: Lessons Learned From Recently Approved Drugs in Oncology.

Evaluation of the effect of food on the pharmacokinetics of oral oncology drugs is critical to drug development, as food can mitigate or exacerbate toxicities and alter systemic exposure. Our aim is to expand on current US Food and Drug Administration (FDA) guidance and provide data-driven food-effect study design recommendations specific to the oncology therapeutic area. Data for recently approved small-molecule oncology drugs was extracted from the clinical pharmacology review in the sponsor's FDA submission package. Information on subject selection, meal types, timing of the study relative to the pivotal trial, and study outcomes was analyzed. The number of subjects enrolled ranged from 12 to 60, and the majority of studies (19 of 29) were conducted in healthy volunteers. Using AstraZeneca cost data, healthy volunteer studies were estimated to cost 10-fold less than cancer patient studies. Nine of 29 (31%) studies included meals with multiple levels of fat content. Analysis of a subset of 16 drugs revealed that final results for the food-effect study were available before the start of the pivotal trial for only 2 drugs.Conducting small food-effect studies powered to estimate effect, rather than confirm no effect, with only a standardized high-fat meal according to FDA guidance may eliminate unnecessary studies, reduce cost,and improve efficiency in oncology drugdevelopment. Starting food-effect studiesas early as possible is key to inform dosing in pivotal trials.

Increased usual physical activity is associated with a blunting of the triglyceride response to a high-fat meal

Postprandial lipemia (PPL), defined as a prolonged or elevated rise in triglycerides that accompanies fat feeding, is a significant risk factor for coronary heart disease and associated comorbidities. The impact of PPL on coronary heart disease risk is underscored by the preponderance of each day spent in the postprandial state. In this study, we evaluated cross-sectionally the association between usual (ie, noninterventional) physical activity and the 6-hour triglyceride response to a standardized high-fat meal. The high-fat meal intervention was carried out in 671 apparently healthy individuals as part of the Heredity and Phenotype Intervention Heart Study. Triglyceride levels were measured in the fasting state and during 6 hours after administration of a standardized fat challenge. We defined PPL response as the triglyceride area under the fat load curve (AUC) and measured physical activity using accelerometers that were worn continuously over a 7-day period. Physical activity levels decreased with increasing age and were higher in men than women (both P<.001). The triglyceride AUC increased with increasing age in both men and women (both P<.001) and was also higher in men than in women (age-adjusted P=9.2×10-12). Higher physical activity levels were associated with a lower triglyceride AUC (P=.003), adjusting for age, sex, body mass index, and fasting low-density lipoprotein. These results suggest that the protective benefits of physical activity on cardiovascular health may operate, at least in part, through reduction of the PPL triglyceride response.

Metabolic and inflammatory biomarkers are associated with epigenetic aging acceleration estimates in the GOLDN study

BackgroundRecently, epigenetic age acceleration—or older epigenetic age in comparison to chronological age—has been robustly associated with mortality and various morbidities. However, accelerated epigenetic aging has not been widely investigated in relation to inflammatory or metabolic markers, including postprandial lipids.MethodsWe estimated measures of epigenetic age acceleration in 830 Caucasian participants from the Genetics Of Lipid Lowering Drugs and diet Network (GOLDN) considering two epigenetic age calculations based on differing sets of 5′-Cytosine-phosphate-guanine-3′ genomic site, derived from the Horvath and Hannum DNA methylation age calculators, respectively. GOLDN participants underwent a standardized high-fat meal challenge after fasting for at least 8 h followed by timed blood draws, the last being 6 h postmeal. We used adjusted linear mixed models to examine the association of the epigenetic age acceleration estimate with fasting and postprandial (0- and 6-h time points) low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglyceride (TG) levels as well as five fasting inflammatory markers plus adiponectin.ResultsBoth DNA methylation age estimates were highly correlated with chronological age (r > 0.90). We found that the Horvath and Hannum measures of epigenetic age acceleration were moderately correlated (r = 0.50). The regression models revealed that the Horvath age acceleration measure exhibited marginal associations with increased postprandial HDL (p = 0.05), increased postprandial total cholesterol (p = 0.06), and decreased soluble interleukin 2 receptor subunit alpha (IL2sRα, p = 0.02). The Hannum measure of epigenetic age acceleration was inversely associated with fasting HDL (p = 0.02) and positively associated with postprandial TG (p = 0.02), interleukin-6 (IL6, p = 0.007), C-reactive protein (C-reactive protein, p = 0.0001), and tumor necrosis factor alpha (TNFα, p = 0.0001). Overall, the observed effect sizes were small and the association of the Hannum residual with inflammatory markers was attenuated by adjustment for estimated T cell type percentages.ConclusionsOur study demonstrates that epigenetic age acceleration in blood relates to inflammatory biomarkers and certain lipid classes in Caucasian individuals of the GOLDN study. Future studies should consider epigenetic age acceleration in other tissues and extend the analysis to other ethnic groups.

Post-prandial hyperlipidaemia results in systemic nitrosative stress and impaired cerebrovascular function in the aged.

Post-prandial hyperlipidaemia (PPH) acutely impairs systemic vascular endothelial function, potentially attributable to a free radical-mediated reduction in vascular nitric oxide (NO) bioavailability (oxidative-nitrosative stress). However, it remains to be determined whether this extends to the cerebrovasculature. To examine this, 38 (19 young (≤35 years) and 19 aged (≥60 years)) healthy males were recruited. Cerebrovascular function (middle cerebral artery velocity, MCAv) and cerebrovascular reactivity to hypercapnea (CVRCO2Hyper) and hypocapnea (CVRCO2Hypo) were determined via trans-cranial Doppler ultrasound and capnography. Venous blood samples were obtained for the assessment of triglycerides (photometry), glucose (photometry), insulin (radioimmunoassay), ascorbate free radical (A•-, electron paramagnetic resonance spectroscopy) and nitrite (NO2-, ozone-based chemiluminescence) in the fasted state prior to and 4 h following consumption of a standardized high-fat meal (1362 kcal; 130 g of fat). Circulating triglycerides, glucose and insulin increased in both groups following the high-fat meal (P<0.05), with triglycerides increasing by 1.37 ± 1.09 mmol/l in the young and 1.54 ± 1.00 mmol/l in the aged (P<0.05). This resulted in an increased systemic formation of free radicals in the young (P<0.05) but not the aged (P>0.05) and corresponding reduction in NO2- in both groups (P<0.05). While the meal had no effect on MCAv in either age group, CVRCO2Hyper was selectively impaired in the aged (P<0.05). These findings indicate that PPH causes acute cerebrovascular dysfunction in the aged subsequent to systemic nitrosative stress.

Realistic Test-Meal Protocols Lead to Blunted Postprandial Lipemia but Similar Inflammatory Responses Compared with a Standard High-Fat Meal

BackgroundA substantial increase in triglycerides (TGs) after a meal is associated with an increased risk of cardiovascular disease. Most studies investigating the effects of a meal on TGs have not used meals that reflect typical consumption. ObjectiveThe objective of this study was to compare the TG and inflammatory responses of true-to-life meals, containing moderate fat and energy contents, with a high-fat, high-energy, low-carbohydrate meal (HFM) typically used to test TG responses. MethodsNine healthy, insufficiently active men [mean ± SD age: 25.1 ± 6.7 y; body mass index (in kg/m2): 25.8 ± 7.0; <150 min moderate- to vigorous-intensity physical activity/wk] completed 3 meal trials in random order: an HFM (17 kcal/kg, 60% fat), a moderate-fat meal (MFM; 8.5 kcal/kg, 30% fat), and a biphasic meal (BPM), in which participants consumed the full MFM at baseline and 3 h postmeal. Blood samples were collected via an indwelling catheter at baseline and hourly for 6 h. ResultsPeak blood TGs were significantly greater (P = 0.003) after the HFM (285.2 ± 169.7 mg/dL) than after the MFM (156.0 ± 98.7 mg/dL), but the BPM (198.3 ± 182.8 mg/dL) was not significantly different from the HFM (P = 0.06) or the MFM (P = 0.99). Total area under the curve for TGs was greater after the HFM (1348.8 ± 783.7 mg/dL × 6 h) than after the MFM (765.8 ± 486.8 mg/dL × 6 h; P = 0.0005) and the BPM (951.8 ± 787.7 mg/dL × 6 h; P = 0.03), although the MFM and BPM were not significantly different (P = 0.72). There was a significant time-by-meal interaction for interferon γ, but not for interleukins 6, 8, or 10. ConclusionThese findings in insufficiently active, healthy young men suggest that the large TG response after HFMs in previous studies may not reflect the metabolic state of many individuals in daily life.