High-fat Meal Research Articles

Pharmacokinetics, Bioequivalence, and Safety Studies of Amlodipine Besylate in Healthy Subjects

This study aimed to evaluate the bioequivalence of 2 amlodipine besylate tablet formulations, a generic formulation and an original formulation, and to investigate their pharmacokinetic and safety profiles. This study was designed as a randomized, open-label, single-dose, crossover, dual-period study and was divided into fasting and postprandial human bioequivalence trials. In the first trial after overnight fasting, 28 subjects were given 5-mg amlodipine besylate tablets via oral administration, and blood specimens were obtained up to 144 hours after dosing; another 28 subjects had a high-fat meal 1hour before drug administration and proceeded the same as the fasting trial. Bioequivalence was evaluated using 90%CIs for the ratio test/reference of log area under the concentration-time curve (AUC) from time 0 to the last quantifiable concentration, log AUC from time 0 to infinity, and log peak concentration. The plasma concentrations were measured by high-performance liquid chromatography-tandem mass spectrometry. The safety was assessed throughout the study. The results show that no significant differences were observed between the pharmacokinetic profiles of the test and reference amlodipine besylate tablets in the fasting and postprandial trials. The 90%CIs of the peak concentration, AUC from time 0 to the last quantifiable concentration and AUC from time 0 to infinity of amlodipine in the 2 trials were within the commonly accepted bioequivalence criteria of 80% to 125%. Compared with the pharmacokinetic parameters of the fasting and postprandial trials, food had no significant effect on exposure of amlodipine besylate. There was no significant difference in safety statistical results between the 2 groups. The results suggest that generic and original amlodipine besylate tablets are bioequivalent with similar safety profiles.

Transcriptional Integration of Distinct Microbial and Nutritional Signals by the Small Intestinal Epithelium.

Background & AimsThe intestine constantly interprets and adapts to complex combinations of dietary and microbial stimuli. However, the transcriptional strategies by which the intestinal epithelium integrates these coincident sources of information remain unresolved. We recently found that microbiota colonization suppresses epithelial activity of hepatocyte nuclear factor 4 nuclear receptor transcription factors, but their integrative regulation was unknown.MethodsWe compared adult mice reared germ-free or conventionalized with a microbiota either fed normally or after a single high-fat meal. Preparations of unsorted jejunal intestinal epithelial cells were queried using lipidomics and genome-wide assays for RNA sequencing and ChIP sequencing for the activating histone mark H3K27ac and hepatocyte nuclear factor 4 alpha.ResultsAnalysis of lipid classes, genes, and regulatory regions identified distinct nutritional and microbial responses but also simultaneous influence of both stimuli. H3K27ac sites preferentially increased by high-fat meal in the presence of microbes neighbor lipid anabolism and proliferation genes, were previously identified intestinal stem cell regulatory regions, and were not hepatocyte nuclear factor 4 alpha targets. In contrast, H3K27ac sites preferentially increased by high-fat meal in the absence of microbes neighbor targets of the energy homeostasis regulator peroxisome proliferator activated receptor alpha, neighbored fatty acid oxidation genes, were previously identified enterocyte regulatory regions, and were hepatocyte factor 4 alpha bound.ConclusionsHepatocyte factor 4 alpha supports a differentiated enterocyte and fatty acid oxidation program in germ-free mice, and that suppression of hepatocyte factor 4 alpha by the combination of microbes and high-fat meal may result in preferential activation of intestinal epithelial cell proliferation programs. This identifies potential transcriptional mechanisms for intestinal adaptation to multiple signals and how microbiota may modulate intestinal lipid absorption, epithelial cell renewal, and systemic energy balance.

Development of a Once-Daily Modified-Release Formulation for the Short Half-Life RIPK1 Inhibitor GSK2982772 using DiffCORE Technology

PurposeGSK2982772 is a selective inhibitor of receptor-interacting protein kinase-1 (RIPK1) with a short 2- to 3-h half-life. In a previous modified-release (MR) study, a matrix monolithic formulation (80% GSK2982772 released over 12 h) provided a once-daily (QD) pharmacokinetic (PK) profile in the fasted state; however, it was susceptible to food effects. The current study evaluated the safety and PK of MR formulations using GSK proprietary DiffCORE™ technology.MethodsPart A evaluated PK following single-dose (240 mg) fasted and fed (high-fat meal) administration of three DiffCORE MR formulations within pre-defined in vitro extremes of 80% GSK2982772 released over 12 h (MR-12 h) to 80% GSK2982772 released over 18 h (MR-18 h) versus an immediate-release formulation. Part B evaluated MR-16 h (120–960 mg) in different prandial states.ResultsPharmacokinetic profiles for all MR formulations and doses tested in the fasted and fed states were consistent with QD dosing.ConclusionsThe DiffCORE technology overcame the food effect vulnerability observed with the matrix monolithic formulation. The MR-16 h formulation was selected for further clinical development as a QD dosing regimen (NCT03649412 September 26, 2018).

Sarecycline treatment for acne vulgaris: Rationale for weight-based dosing and limited impact of food intake on clinical efficacy.

Tetracycline‐class antibiotics are frequently prescribed by dermatologists, commonly for acne vulgaris. Gastrointestinal absorption of first and second‐generation tetracycline‐class antibiotics, including doxycycline and minocycline, may be reduced by co‐administration with food, resulting in potentially lower clinical efficacy. Development of novel compounds and formulations that are not impacted by diet could improve compliance, absorption, and effectiveness among patients. The objective of this study is to investigate weight‐based dosing protocols and the impact of food intake, including high‐fat meals, on the absorption, and clinical efficacy of sarecycline, a novel oral narrow‐spectrum third‐generation tetracycline‐class antibiotic approved by the Food and Drug Administration for acne vulgaris treatment. Data from 12 clinical studies were analyzed using population pharmacokinetic modeling, exposure–response modeling and pharmacodynamics to evaluate sarecycline dosing recommendations. The extent of exposure is estimated to decrease by 21.7% following co‐administration of a sarecycline tablet with a high‐fat meal. Based on the PopPK‐PD model, this is equivalent to a decrease in efficacy of 0.9 inflammatory lesions, which is not clinically meaningful. Sarecycline can be administered using weight‐based dosing with or without food. Co‐administration with high‐fat food has a limited impact on clinical efficacy. The pharmacokinetics of oral sarecycline may provide added convenience and support ease of use and improved compliance for acne vulgaris patients.

Dietary Macronutrients Do Not Differently Influence Postprandial Serum and Plasma Brain-Derived Neurotrophic Factor Concentrations: A Randomized, Double-Blind, Controlled Cross-Over Trial.

Objectives: Brain-derived neurotrophic factor (BDNF) plays a role in cognition and metabolism. Specific nutrients can affect fasting BDNF concentrations, which are potentially mediated by insulin and/or glucose. Since macronutrients trigger each a different insulin and glucose response, we examined postprandial effects of meals rich in fat, carbohydrates, or protein on BDNF concentrations. BDNF was analyzed in serum and plasma, since concentration differences can be found between matrices.Methods: Healthy overweight/obese male participants (n = 18) participated in this randomized, double-blind, cross-over trial consisting of three test days with 1 week wash-out periods. Either a high-fat (En% fat, carbohydrates, protein: 52.3, 39.2, 8.0), high-carbohydrate (En% 9.6, 81.5, 8.6) or high-protein meal (En% 10.6, 51.5, 36.9) was consumed on each test day. BDNF concentrations were measured after 0, 60, and 240 min. Glucose and insulin concentrations were measured after 0, 15, 30, 45, 60, 90, 120, and 240 min.Results: BDNF concentrations were higher in serum compared with plasma (P < 0.001). Postprandial BDNF concentrations in serum decreased significantly after the high-fat (P = 0.013) and high-carbohydrate meals (P = 0.040), and showed a trend after the high-protein meal (P = 0.076). No differences were found between meals (P = 0.66). Postprandial BDNF concentrations measured in plasma did not significantly change after the different meals (P = 0.47). As total area under the curve (AUC) for glucose was significantly higher after the high-carbohydrate meal compared with the high-fat (P = 0.003) and high-protein meals (P < 0.001), and the total AUC for insulin was higher after the high-carbohydrate (P < 0.001) and high-protein meals (P < 0.001) compared with the high-fat meal, it seems that acute changes in glucose and insulin do not affect postprandial BDNF concentrations. However, after the high-protein meal, the higher total AUC for glucose correlated with lower serum BDNF concentrations, and a higher maximal increase in glucose correlated with a lower maximal increase in plasma BDNF concentrations. There were no correlations with insulin concentrations after either meal.Conclusion: Serum BDNF concentrations were higher than plasma concentrations. Since postprandial BDNF responses were not different between the meals, we conclude that there is no role for insulin or glucose in regulating postprandial BDNF concentrations.Clinical Trial Registration: [www.ClinicalTrials.gov], identifier [NCT03139890].

1121. Bioequivalence of Two Formulations of Oral Tebipenem-Pivoxil Hydrobromide in Healthy Subjects

Abstract Background Tebipenem-pivoxil-hydrobromide (TBP-PI-HBr) is a novel oral carbapenem being developed to treat serious bacterial infections including complicated urinary tract infection. The objectives of this study were to assess the bioequivalence (BE) of two tablet formulations of TBP-PI-HBr in healthy adult subjects under fasted conditions and to evaluate the food-drug interactions of the registration drug product. Methods This was an open-label, randomized, single-dose, semi-replicate, 3-sequence, 4-period crossover, BE, and food effect study. Subjects were randomized to one of three sequences where they received a single 600 mg oral dose of TBP-PI-HBr, as either the reference clinical study drug product (Treatment A) or the registration drug product (Treatment B) under fasted conditions. Subsequently, all subjects received a single 600 mg oral dose of TBP-PI-HBr as the registration drug product under fed conditions. There was by a 7-day washout between each period. Whole blood sampling to determine TBP pharmacokinetics (PK) was conducted predose and up to 24 hours post dose in each period. Safety and tolerability were monitored throughout the study. Results Thirty-six healthy, adult male and female subjects were enrolled and completed the study. The TBP-PI-HBr registration product was bioequivalent to the clinical study product (Figure 1). For TBP, 90% confidence intervals (CIs) for AUC0-t, AUC0-inf, and Cmax were within the 80% to 125% BE limits when administered under fasted conditions. A standard high-fat/high-calorie meal had no meaningful effect on the total plasma exposure of TBP after administration of the registration product, thus, overall exposure based on AUC0-t and AUC0-inf was comparable under fed and fasted conditions (Figure 2). Five (14%) subjects reported adverse events of mild severity. No deaths, serious AEs or discontinuations due to AEs were reported, and no clinically relevant ECGs, vital signs or safety laboratory findings were observed. Figure 1. Arithmetic mean plasma TBP concentrations following a 600 mg dose of clinical study drug product (A1 and A2) and registrational drug product (B) – PK population. Figure 2. Arithmetic mean plasma TBP concentrations following a 600 mg dose of registrational drug product (B) under fasted and fed conditions – PK population. Conclusion The TBP-PI-HBr registration product was bioequivalent to the clinical study product under fasted conditions, and no meaningful effect of a high fat meal on TBP PK was observed. Disclosures Vipul K. Gupta, Ph.D., Spero Therapeutics (Employee, Shareholder) Gina Patel, PhD, Spero Therapeutics, Inc. (Consultant) Leanne Gasink, MD, Spero Therapeutics, Inc. (Consultant) Floni Bajraktari, MSc, Spero Therapeutics, Inc. (Employee) Yang Lei, PhD, Spero Therapeutics, Inc. (Employee) Akash Jain, PhD, Spero Therapeutics, Inc. (Employee) Praveen Srivastava, MS, BS, Spero Therapeutics, Inc. (Employee) Angela Talley, MD, Spero Therapeutics, Inc. (Employee)

High-fat meals do not affect thrombin formation and fibrin clot lysis in individuals with obesity during intentional weight loss

Repeated weight loss cycles are associated with increased cardiovascular morbidity. Meal-induced thrombin formation, measured as prothrombin fragment 1+2 (F1+2), is observed in individuals with overweight after weight loss, and postprandial effects can be one of the mechanisms underlying harmful effects during intentional weight loss. We hypothesize that consumption of high-fat meals during intentional weight loss triggers a prothrombotic state by increasing postprandial F1+2 or decreasing fibrin clot lysis in individuals with obesity, and that the response associates with the gut bacteria composition. A cross-over meal study was conducted in patients admitted to bariatric surgery during dietary weight loss (N = 20) and surgical weight loss (N = 16) (weight loss groups). High-fat (67 E%) and low-fat (16 E%) meals were served at 08:15 and 10:00 on 2 study days. Blood samples collected at 08:00 (fasting), 12:00, and 14:00 were analyzed for triglycerides, activated factor VII (FVIIa), F1+2, D-dimer, fibrinogen, tissue factor , and fibrin clot lysis. The proportion of Gram-negative bacteria and bacterial diversity were analyzed in fecal samples obtained less than 24 hours before the meal test. Triglyceride and FVIIa increased after high-fat meals in both weight loss groups, whereas D-dimer (dietary group) and F1+2 decreased and tissue factor and fibrin clot lysis did not change. There was a negative association between the proportion of Gram-negative bacteria and changes in FVIIa in the surgery group. Postprandial FVII activation after high-fat meals is not accompanied by increased F1+2, irrespective of the weight loss intervention, but might be associated with the proportion of Gram-negative gut bacteria.

Pecan-enriched diets increase energy expenditure and fat oxidation in adults at-risk for cardiovascular disease in a randomised, controlled trial.

Research indicates that diets enriched with unsaturated fatty acids improve energy metabolism, although studies on tree nuts, which are a rich source of those fats, are limited. The present study aimed to examine the impact of daily pecan consumption for 8 weeks on energy metabolism in adults with hypercholesterolaemia or at higher risk for cardiovascular disease (CVD) (body mass index ≥ 28 kgm-2 ). For this randomised, controlled trial, 56 sedentary adults were randomised into one of three treatments for an 8-week intervention: two pecan groups and a nut-free control group (n = 18). The ADD group (n = 16) consumed pecans as part of a free-living diet, whereas the SUB group (n = 18) substituted the pecans for isocaloric foods from their habitual diet. At baseline and 8 weeks, a high saturated fat meal was consumed along with indirect calorimetry measurements at fasting and for 4 h postprandially to determine changes in resting metabolic rate (RMR), diet induced thermogenesis (DIT) and substrate utilisation (primary outcomes). Forty-seven participants completed the trial and were included in analyses. In the SUB group, there was an increase in fasting RMR (1607 ± 117 to 1701 ± 114 kcalday-1 ; p = 0.01) and fasting fat oxidation (0.83 ± 0.08 to 0.99 ± 0.08 g/15 min; p = 0.009) and a decrease in fasting respiratory exchange ratio (0.85 ± 0.01 to 0.83 ± 0.01; p = 0.05) from pre- to post-intervention. In the ADD group, there was an increase in postprandial DIT (p < 0.001). There were no changes within the control group or between groups for any outcome measure. Daily consumption of pecans may increase select measures of energy expenditure and fat oxidation in adults at-risk for CVD.

Abstract 10758: Individuals with Normal-Weight Obesity Exhibit Higher Postprandial Triglycerides, but Similar Endothelial Function and Inflammation Compared to Normal-Weight Controls

Introduction: Normal-weight obesity (NWO) is defined as having a normal BMI yet high body fat % and is linked to increased cardiovascular disease (CVD) risk. However, the current understanding of NWO’s risk profile is incomplete and, in many cases, their clinical presentation is arguably unremarkable based on common risk factors. Hypothesis: We hypothesized that other indictors of CVD risk such as postprandial triglycerides (TG), flow-mediated dilation (FMD), and inflammatory cytokines would be elevated in NWO, consistent with their future CVD risk. Methods: Individuals were recruited into 3 groups (n = 10/ group): healthy controls (Con), NWO, and metabolic syndrome (MetS) based on results from a fasting metabolic panel, blood pressure, and DEXA. All participants underwent an abbreviated fat tolerance test where fasting TG were measured, a high-fat shake was consumed (9 kcal/kg; 73% fat), and then TG measured again 4 hrs later. Brachial FMD was measured during the fasted state and postprandially, and a high-sensitivity T cell cytokine bioplex (Millipore; Burlington, MA) was performed with fasting serum. Data were analyzed using one-way ANOVA followed by Fisher’s LSD. Results: NWO and MetS had similar body fat % and both were higher than Con ( p &lt; 0.01). All groups differed with respect to visceral adipose tissue mass, with MetS &gt; NWO &gt; Con ( p &lt; 0.01). Despite having similar fasting TG to Con, NWO (122.5 ± 46.4 mg/dL) had 4-hr TG intermediate to Con (73.7 ± 13.9 mg/dL) and MetS (178.3 ± 76.4 mg/dL; p &lt; 0.01). Across the entire sample, FMD decreased ( p &lt; 0.01) after the high-fat meal. MetS (3.3 ± 1.2 %) displayed lower fasting FMD than Con (5.1 ± 1.1 %), and NWO (4.5 ± 2.0 %) was similar to both groups ( p &lt; 0.05). No group differences were observed with postprandial FMD. The majority of cytokines assessed were not different across groups. However, MetS (7.8 ± 2.1 pg/mL) exhibited higher TNF-α than Con (4.8 ± 1.9 pg/mL; p &lt; 0.05), and NWO (6.6 ± 3.4 pg/mL) was not different from either group. Conclusions: In conclusion, NWO was associated with higher postprandial TG than Con, but displayed little evidence of impaired vascular health or inflammation. MetS had the greatest 4-hr TG, as well as impaired vascular function and signs of inflammation compared to Con.

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.

Small bowel water content assessed by MRI in health and disease: a collation of single-centre studies.

New developments in MRI have allowed the non-invasive, accurate measurement of the small bowel water content (SBWC). To collate studies measuring SBWC following ingestion of a range of foods in both health and disease to provide data for adequately powering future studies in this area. This collation brings together 29 studies including 954 participants (530 healthy, 54 diverticulosis, 255 IBS, 53 functional constipation, 12 cystic fibrosis, 15 Crohn's disease, 20 coeliac disease, 15 scleroderma) which have been carried out in a single centre using comparable study designs. Fasting SBWC (mean 82 [SD 65]mL) shows high variability with a small decline with advancing age (healthy volunteers only; individual patient data). Fasting values are increased in untreated coeliac disease (202 [290]mL, P=0.004). Post-prandial SBWC shows less intra-individual variability than fasting values in healthy volunteers. SBWC is increased by eating, most markedly by high fat meals but also by fibre, both viscous and particulate. Indigestible residue accumulates in late post-prandial period but empties soon after ingestion of a high calorie meal which produces a significant drop (by 50 [52]mL) in healthy volunteers. The associated fall in SBWC is abnormal in people with cystic fibrosis (SBWC reduced by 10 [121]mL, P=0.002) and in people with irritable bowel syndrome with diarrhoea (SBWC reduced by 17 [43] mL, P=0.007). SBWC as assessed by MRI is a valuable biomarker indicating the balance of secretion and absorption in health and disease and the impact of treatments.

The influence of metabolic states and a high fat meal on circulating chemerin

The influence of metabolic states and a high fat meal on circulating chemerin

Postprandial endothelial dysfunction and CIMT after oral fat challenge in patients with type 2 diabetes mellitus with and without macrovascular disease - A preliminary study

BackgroundVery few studies have reported on association of postprandial lipids and endothelial dysfunction among patients with diabetes. Whether endothelial dysfunction particularly postprandial FMD is worse in patients with T2DM with macrovascular disease compared to those without and whether this difference is related to postprandial hypertriglyceridemia (PPHTg) is unclear. Therefore, present study was aimed to assess the relationship between PPHTg and endothelial function in patients with T2DM with and without macrovascular disease. MethodEndothelial dysfunction by FMD and CIMT were compared in patients with T2DM with and without macrovascular disease (n = 13 each group) and 13 age, sex and BMI matched healthy individuals after an oral fat challenge. ResultsThere was significant postprandial deterioration of FMD 4-hr after fat challenge in patients with diabetes (P < 0.001) as well as healthy individuals (P = 0.004). Patients with diabetes with macrovascular disease had significantly lower fasting (5.7 ± 6.1% vs. 22.7 ± 10.0% and vs. 24.7 ± 5.3%) as well as postprandial (4-hr) (3.1 ± 5.0% vs. 15.3 ± 8.1% and vs. 15.4 ± 5.7%) FMD compared to other two groups. Fasting, postprandial as well as change in FMD and CIMT in patients with diabetes correlated significantly with fasting as well as postprandial triglycerides with stronger correlation in those with macrovascular disease. ConclusionStudy found significant endothelial dysfunction by FMD that shows substantial further deterioration postprandially following high fat meal in patients with diabetes with macrovascular disease compared to patients with diabetes without macrovascular disease and healthy individuals. Study also indicates that PPHTg is a contributor to endothelial dysfunction. However, more studies are required to corroborate these findings.

First-in-Human, Single-Ascending Dose and Food Effect Studies to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Cetagliptin, a Dipeptidyl Peptidase-4 Inhibitor for the Treatment of Type 2 Diabetes Mellitus.

Cetagliptin is a highly selective dipeptidyl peptidase-4 inhibitor under development to treat type 2 diabetes mellitus. This first-in-human study was conducted to characterise the pharmacokinetics, pharmacodynamics and tolerability of single-ascending oral doses of cetagliptin in healthy subjects. In addition, the effect of food on pharmacokinetics was evaluated. Study 1 enrolled 66 healthy subjects in a double-blind, randomised, placebo-controlled, single-dose escalation study; sitagliptin was employed as a positive open-label control. Forty-four subjects were assigned to seven cohorts (cetagliptin 12.5, 25, 50, 100, 200, 300 or 400 mg); 12 subjects were assigned to the placebo group. The remaining ten subjects received sitagliptin 100 mg as the positive control. Blood, urine and faeces were collected for the pharmacokinetic analysis and determination of plasma dipeptidyl peptidase-4 inhibition, active glucagon-like peptide-1, glucose and insulin levels. In Study 2, 14 healthy subjects were assigned to a randomised, open-label, two-period crossover study, and received a single oral dose of cetagliptin 100 mg in the fasted state or after a high-fat meal, with a 14-day washout period between treatments. Blood samples were collected to evaluate the effects of food on the pharmacokinetics of cetagliptin. Following administration of a single oral dose, cetagliptin was rapidly absorbed, presenting a median time to maximum concentration of 1.0-3.25 h. The terminal half-life ranged between 25.8 and 41.3 h, which was considerably longer than that of sitagliptin. The area under the plasma concentration-time curve was approximately dose proportional between 25 mg and 400 mg, and the increase in maximum concentration was greater than dose proportional. The unchanged drug was mainly excreted in the urine (27.2-46.2% of dose) and minimally via the faeces (1.4% of dose). Dipeptidyl peptidase-4 inhibition, an increase in active glucagon-like peptide-1 and a slight decrease in blood glucose were observed, whereas insulin was not significantly altered when compared with placebo. The weighted average dipeptidyl peptidase-4 inhibition by cetagliptin 100 mg was higher than that mediated by sitagliptin 100 mg. Cetagliptin was well tolerated up to a single oral dose of 400 mg. No food effects were noted. Cetagliptin inhibited plasma dipeptidyl peptidase-4 activity, increased levels of active glucagon-like peptide-1 and was well tolerated at single doses up to 400 mg, eliciting no dose-limiting toxicity in healthy volunteers. Food did not affect the pharmacokinetics of cetagliptin. The studies were registered at http://www.chinadrugtrials.org.cn (Nos. CTR20180167 and CTR20181331).

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.

Pharmacokinetics of Asciminib When Taken With Imatinib or With Food

Asciminib, a first-in-class, Specifically Targeting the Abelson kinase Myristoyl Pocket (STAMP) inhibitor with the potential to overcome resistance to adenosine triphosphate-competitive tyrosine kinase inhibitors, is being investigated in leukemia as monotherapy and in combination with tyrosine kinase inhibitors including imatinib. This phase 1 study in healthy volunteers assessed the pharmacokinetics of asciminib (40mg single dose) under 2 conditions: when taken with imatinib (steady state; 400 mg once daily) and a low-fat meal (according to imatinib prescription information), or when taken as single-agent under different food conditions. Asciminib plus imatinib with a low-fat meal increased asciminib area under the plasma concentration-time curve from time 0 to infinity and maximum plasma concentration (geometric mean ratios [90% confidence interval], 2.08 [1.93-2.24] and 1.59 [1.45-1.75], respectively) compared with asciminib alone under the same food conditions. Asciminib plus food decreased asciminib area under the plasma concentration-time curve from time 0 to infinity compared with asciminib taken under fasted conditions (geometric mean ratios: low-fat meal, 0.7 [0.631-0.776]; high-fat meal, 0.377 [0.341-0.417]). Asciminib plus imatinib was well tolerated with no new safety signals. Overall, coadministration of asciminib with imatinib and a low-fat meal results in a moderate increase in asciminib exposure compared with asciminib alone under the same food condition. Food itself decreases asciminib exposure, indicating that single-agent asciminib should be administered in the fasted state to prevent potential suboptimal exposures.

Abdominal and gluteofemoral fat depots show opposing associations with postprandial lipemia

High postprandial lipemia is associated with increased risk of cardiovascular disease, independently of fasting lipid concentrations. Abdominal and gluteofemoral fat depots handle lipoproteins differently, which could affect postprandial lipemia and contribute to the relation between abdominal fat distribution and cardiovascular disease risk. We aimed to study the influences of higher abdominal compared with gluteofemoral fat on postprandial lipemia after a high-fat meal in individuals with obesity. A total of 755 adults with obesity from a randomized controlled trial in 7 European countries consumed a liquid high-fat meal. Concentrations of triglycerides (TG), glycerol, free fatty acids, and the cholesterol component of remnant-like particles (RLP), LDL, and HDL were measured postprandially for 3 h. Associations of waist circumference (WC), hip circumference (HC), and waist-hip ratio (WHR) with changes in postprandial lipid concentrations, adjusted for fasting concentrations and BMI, were examined using linear regression models. To assess whether the association of WHR with postprandial lipemia could be causal, we performed instrumental variable analyses using a genetic score of 442 variants known to be associated with WHR adjusted for BMI in 2-stage least-squares regression models. WHR was associated with higher TG and RLP cholesterol concentrations, independent of fasting lipid concentrations and BMI. Instrumental variable analyses suggested that the associations of WHR with postprandial TG (β=0.038 μmol/L*min, SE=0.019 μmol/L*min, P=0.044) and RLP cholesterol concentrations (β=0.059 mmol/L, SE=0.025mmol/L, P=0.020) may be causal. WC and HC showed opposite effects: higher WC was associated with higher TG and RLP cholesterol concentrations whereas higher HC was associated with lower concentrations. Our results suggest that higher fat deposition abdominally versus gluteofemorally may be causally associated with elevated postprandial lipemia after a high-fat meal, independent of fasting lipid concentrations and BMI. Furthermore, higher abdominal and gluteofemoral fat depots show opposing effects on postprandial lipemia.This trial was registered at www.isrctn.com as ISRCTN25867281.

Pecan-Enriched Diets Alter Cholesterol Profiles and Triglycerides in Adults at Risk for Cardiovascular Disease in a Randomized, Controlled Trial

BackgroundResearch indicates that tree nuts are cardioprotective, but studies on pecans are limited. ObjectivesWe examined the impact of daily pecan consumption on blood lipids and glycemia in adults at-risk for cardiovascular disease (CVD). MethodsThis was a randomized, controlled trial where 56 adults (BMI ≥28 kg/m2 or hypercholesterolemia) were randomly allocated into a control group (n = 18) or 1 of 2 pecan groups. The ADD group (n = 16) consumed pecans (68 g) as part of a free-living diet. The SUB group (n = 18) substituted the pecans (68 g) for isocaloric foods from their diet. At baseline and 8 wk, a high-fat meal was consumed with 4-h postprandial blood draws to determine changes in blood lipids and glycemia. ResultsThere was a significant reduction from baseline to 8 wk in fasting total cholesterol (TC) (204 ± 8.76 to 195 ± 8.12; 205 ± 8.06 to 195 ± 6.94 mg/dL), LDL cholesterol (143 ± 8.09 to 129 ± 7.71; 144 ± 6.60 to 135 ± 6.16 mg/dL), triglycerides (TGs) (139 ± 12.1 to 125 ± 14.6; 133 ± 10.7 to 120 ± 10.3 mg/dL), TC/HDL cholesterol ratio (3.92 ± 0.206 to 3.58 ± 0.175; 4.08 ± 0.167 to 3.79 ± 0.151), non–HDL cholesterol (151 ± 8.24 to 140 ± 7.95; 155 ± 6.87 to 143 ± 6.00 mg/dL), and apolipoprotein B (99.1 ± 5.96 to 93.0 ± 5.35; 104 ± 3.43 to 97.1 ± 3.11 mg/dL) in the ADD and SUB groups, respectively (P ≤ 0.05 for all), with no changes in control. There was a reduction in postprandial TGs (P ≤ 0.01) in ADD, and a reduction in postprandial glucose (P < 0.05) in SUB. ConclusionsPecan consumption improves fasting and postprandial blood lipids in CVD at-risk adults. This trial was registered at clinicaltrials.gov as NCT04376632.

Clitoria ternatea Flower Extract Attenuates Postprandial Lipemia and Increases Plasma Antioxidant Status Responses to a High-Fat Meal Challenge in Overweight and Obese Participants.

Simple SummarySupplementation of high-fat meals with edible plants is the principal strategy to control postprandial dysmetabolism and inflammation. This study demonstrated that consumption of Clitoria ternatea flower extract (CTE) decreased postprandial serum triglyceride and serum free fatty acids, and improved plasma antioxidant status and glutathione peroxidase activity responses to a high-fat meal challenge in overweight and obese participants. However, CTE could not reduce the effect of HF meal-induced increase in postprandial glycemia and the level of pro-inflammatory cytokines. The findings of the present study suggest that CTE may be used as an effective ingredient to suppress postprandial lipemia and improve the antioxidant status in overweight and obese individuals that frequently consume HF diets.High-fat (HF) meal-induced postprandial lipemia, oxidative stress and low-grade inflammation is exacerbated in overweight and obese individuals. This postprandial dysmetabolism contributes to an increased risk of cardiovascular disease and metabolic disorders. Clitoria ternatea flower extract (CTE) possesses antioxidant potential and carbohydrate and fat digestive enzyme inhibitory activity in vitro. However, no evidence supporting a favorable role of CTE in the modulation of postprandial lipemia, antioxidant status and inflammation in humans presently exists. In the present study, we determine the effect of CTE on changes in postprandial glycemic and lipemic response, antioxidant status and pro-inflammatory markers in overweight and obese men after consumption of an HF meal. Following a randomized design, sixteen participants (age, 23.5 ± 0.6 years, and BMI, 25.7 ± 0.7 kg/m2) were assigned to three groups that consumed the HF meal, or HF meal supplemented by 1 g and 2 g of CTE. Blood samples were collected at fasting state and then at 30, 60, 90, 120, 180, 240, 300 and 360 min after the meal consumption. No significant differences were observed in the incremental area under the curve (iAUC) for postprandial glucose among the three groups. Furthermore, 2 g of CTE decreased the iAUC for serum triglyceride and attenuated postprandial serum free fatty acids at 360 min after consuming the HF meal. In addition, 2 g of CTE significantly improved the iAUC for plasma antioxidant status, as characterized by increased postprandial plasma FRAP and thiol levels. Postprandial plasma glutathione peroxidase activity was significantly higher at 180 min after the consumption of HF meal with 2 g of CTE. No significant differences in the level of pro-inflammatory cytokines (interleukin-6, interleukin-1β and tumor necrosis factor-α) were observed at 360 min among the three groups. These findings suggest that CTE can be used as a natural ingredient for reducing postprandial lipemia and improving the antioxidant status in overweight and obese men after consuming HF meals.

First-in-human study of milvexian, an oral, direct, small molecule factor XIa inhibitor.

Milvexian (BMS‐986177/JNJ‐70033093) is a small molecule, active‐site inhibitor of factor XIa (FXIa) being developed to prevent and treat thrombotic events. The safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of milvexian were assessed in a two‐part, double‐blind, placebo‐controlled, sequential single ascending dose (SAD) and multiple ascending dose (MAD) study in healthy adults. Participants in SAD panels (6 panels of 8 participants; n = 48) were randomized (3:1) to receive milvexian (4, 20, 60, 200, 300, or 500 mg) or placebo. The 200‐ and 500‐mg panels investigated the pharmacokinetic impact of a high‐fat meal. Participants in MAD panels (7 panels of 8 participants; n = 56) were randomized (3:1) to receive milvexian (once‐ or twice‐daily) or placebo for 14 days. All milvexian dosing regimens were safe and well‐tolerated, with only mild treatment‐emergent adverse events and no clinically significant bleeding events. In SAD panels, maximum milvexian plasma concentration occurred 3 h postdose in all fasted panels. The terminal half‐life (T1/2) ranged from 8.3 to 13.8 h. In fasted panels from 20 to 200 mg, absorption was dose‐proportional; results at higher doses (300 and 500 mg) were consistent with saturable absorption. Food increased milvexian bioavailability in a dose‐dependent fashion. In MAD panels, steady‐state milvexian plasma concentration was reached within 3 and 6 dosing days with once‐ and twice‐daily dosing, respectively. Renal excretion was less than 20% in all panels. Prolongation of activated partial thromboplastin time was observed and was directly related to drug exposure. These results suggest that the safety, tolerability, PK, and PD properties of milvexian are suitable for further clinical development.