Low-fat Breakfast Research Articles

Abstract A083: Low dose abiraterone in prostate cancer - Safety, efficacy and pharmacoeconomic implications

Abstract Background and aim: Survival has improved in metastatic castration-resistant prostate cancer (mCRPC) because of the development of effective drugs such as abiraterone acetate, but universal accessibility to treatment is not always possible because of cost constraints in lower- and middle-income countries. Abiraterone in fasting state is the standard of care in mCRPC. Despite a large food effect, it was administered under fasting conditions in its pivotal trials. Recently, the National Comprehensive Cancer Network (NCCN) has included low-dose abiraterone (250 mg/day) with food as an alternative treatment option to full-dose abiraterone (1,000 mg/day) fasting. This translates to 75% cost reduction. This study aims to find safety, efficacy and pharmacoeconomic implications of low dose abiraterone in mCRPC. Materials and Methods: In this cohort study mCRPC Patients with progression were offered low dose abiraterone with low fat meal along with prednisone 5 mg twice daily. Prostate-specific antigen (PSA) was assessed monthly and toxicity assessment was made every week. Final PSA response (≥ 50% reduction) and toxicity assessment were done at 12 weeks. In case of grade IV toxicity (Anemia, Hypertension, Hypokalemia, Hypocalcemia – CTC AE V5.0) because of higher drug bioavailability, patient would be offered full dose abiraterone. 10 patients were offered low dose abiraterone in 2022. Results: 6 out of 10 patients achieved desired PSA response at 12 weeks which is a bit on higher side compared to standard dose abiraterone (recent literature). Fortunately, none of the patient developed grade IV toxicity. This finding was assuring, and no patient shifted to standard dosing. Conclusions: Low dose abiraterone (with low-fat breakfast) is noninferior to full dose abiraterone with respect to PSA metrics. Toxicity is the major thing to look at and given the pharmacoeconomic implications it’s imperative to adopt this strategy in places where affordability is the issue. Let the patients have something rather than nothing! Citation Format: Suryakanta Acharya. Low dose abiraterone in prostate cancer - Safety, efficacy and pharmacoeconomic implications [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A083.

Impact of a Low-Carbohydrate Compared with Low-Fat Breakfast on Blood Glucose Control in Type 2 Diabetes: A Randomized Trial

BackgroundIn type 2 diabetes (T2D), consuming carbohydrates results in a rapid and large increase in blood glucose, particularly in the morning when glucose intolerance is highest. ObjectivesWe investigated if a low-carbohydrate (LC) breakfast (∼465 kcal: 25 g protein, 8 g carbohydrates, and 37 g fat) could improve glucose control in people with T2D when compared with a low-fat control (CTL) breakfast (∼450 kcal:20 g protein, 56 g carbohydrates, and 15 g fat). MethodsParticipants with T2D (N = 121, 53% women, mean age 64 y) completed a remote 3-month parallel-group randomized controlled trial comparing a LC with standard low-fat guideline CTL breakfast. The change in HbA1c was the prespecified primary outcome. Continuous glucose monitoring, self-reported anthropometrics, and dietary information were collected for an intention-to-treat analysis. ResultsHbA1c was reduced (−0.3%; 95% CI: −0.4%, −0.1%) after 12 wks of a LC breakfast, but the between-group difference in HbA1c was of borderline statistical significance (−0.2; 95% CI: −0.4, 0.0; P = 0.06). Self-reported total daily energy (−242 kcal; 95% CI: −460, −24 kcal; P = 0.03) and carbohydrate (−73 g; 95% CI: −101, −44 g; P < 0.01) intake were lower in the LC group but the significance of this difference is unclear. Mean and maximum glucose, area under the curve, glycemic variability, standard deviation, and time above range were all significantly lower, and time in the range was significantly higher, in the LC group compared with CTL (all P < 0.05). ConclusionsAdvice and guidance to consume a LC breakfast appears to be a simple dietary strategy to reduce overall energy and carbohydrate intake and improve several continuous glucose monitoring variables when compared with a CTL breakfast in persons living with T2D.The trial was registered at clinicaltrials.gov as NCT04550468.

The Use of Potassium Chloride and Tapioca Starch to Enhance the Flavour and Texture of Phosphate- and Sodium-Reduced Low Fat Breakfast Sausages Manufactured Using High Pressure-Treated Meat.

The objective of this study was to investigate the use of potassium chloride (KCl) and tapioca starch (TS) to reduce salt levels below 1.5% in sausages manufactured using previously high pressure (HP) processed pork (150 MPa). A 3 × 2 × 1 factorial design was used to formulate breakfast sausages with three salt levels (0.5%, 1.0%, and 1.5%), two ingredient levels (no added ingredient or added as a combination of KCl\\TS), and one pressure level (150 MPa). Partial replacement of NaCl with KCl and addition of TS had beneficial effects on the water binding abilities of sausage batters by decreasing (p < 0.05) total expressible fluid (%) and increasing water holding capacity (%). Overall, results indicated that the use of KCl\\TS imparted some beneficial effects to salt-reduced low fat breakfast sausages and has the potential to reduce salt levels in the breakfast sausages to 1.0% while still maintaining the organoleptic and functional properties traditionally associated with these meat products.

Abstract 14044: Virtual Teaching Kitchen: A Feasibility Study of a Nutrition Intervention for Patients With Food Insecurity and Metabolic Disease

Introduction: Food insecurity is a well-established risk factor for cardiometabolic conditions. The objective of this study is to examine the feasibility and acceptability of a virtual teaching kitchen-based intervention to promote healthful food intake, cooking skills, and motivation to make dietary changes. Method: We conducted a single-group study among patients with metabolic syndrome and food insecurity. The intervention consisted of four classes delivering dietary education promoting healthy food intake, diet strategies, and practical cooking skills, facilitated by a physician and a registered dietician chef. An internet-capable tablet was provided for remote participation via the zoom platform. Interviewer-administered surveys measured food intake and internal motivation via Likert scale screeners at baseline and at immediate post-intervention time points. Interviews were conducted to explore acceptability. Results: Of 100 participants invited, 22 were recruited and 10 attended the intervention. Mean age was 61.2 years, nine were female, nine self-identified as Black, and two were Hispanic. Mean BMI was 32.7, all ten participants had hypertension, eight had both diabetes and obesity and seven had hyperlipidemia. Mean attendance per class was seven and five attended all four sessions. From baseline to post-intervention, there was a significant increase in consumption of low-fat milk (0.14 to 0.50, p=0.02), whole grains (0.28 to 0.99, p=0.01), breakfast (0.37 to 1.60, p=0.002) and home cooking (1.09 to 1.88, p=0.04). Internal motivation score was high at baseline and unchanged at follow-up (5.6 to 5.9, p=0.9). Qualitative analysis revealed the following themes: Increase in knowledge of healthy recipes; Barriers to healthy eating including competing household and childcare responsibilities; and Convenience of a virtual group while interacting with group members. Conclusions: Our virtual nutrition education intervention addressing cardiometabolic disease in a safety net hospital was deemed feasible and acceptable. Participants made modest changes to their diet. Future directions include measuring health outcomes and primary and secondary prevention of cardiovascular disease.

Abstract 641: Clinical assessment of the bioavailability of venetoclax tablet and powder formulations

Abstract Venetoclax is a first in class BCL-2 inhibitor that is approved for treatment of CLL and AML. It is currently under evaluation in other indications in adult and pediatric populations. Venetoclax is available as 10 mg, 50 mg, and 100 mg film-coated tablets. While the 100 mg tablet is most commonly used, the smaller size of the lower strength tablets is preferred by patients experiencing difficulty swallowing large tablets. Moreover, two powder formulations for suspension (0.72% and 7.2%) to be mixed with delivery vehicles were developed. In this abstract we present data from clinical studies that evaluated the bioavailability of the different venetoclax formulations relative to the commercially available 100 mg tablet. Three open-label, single-dose, crossover bioavailability studies in healthy female subjects were conducted. The first study evaluated the bioavailability of the commercially available 10 and 50 mg tablets relative to the 100 mg tablet. Forty subjects received a 100 mg dose of venetoclax (1x100 mg tablet, 2x50 mg tablets or 10x10 mg tablets) at the start of each period after a low-fat breakfast. The second study evaluated the bioavailability of the two powder formulations relative to the 100 mg tablet. Sixteen subjects received a 100 mg dose of venetoclax (1x100 mg film-coated tablet; 100 mg 0.72% powder formulation; 100 mg 7.2% powder formulation; and 4x25 mg dispersible tablets for oral suspension used in the Phase 1 study) in each of the 4 periods after a high fat breakfast. The third study evaluated the bioavailability of the two powder formulations when administered with different dosing vehicles relative to water. Twenty-four subjects (12 per cohort) received 100 mg of venetoclax (0.72% powder formulation or the 7.2% powder formulation) with either water, apple juice, apple sauce or yogurt in each of the 4 periods after a moderate fat breakfast. Bioavailability assessment of the commercial tablets demonstrated that ten 10 mg tablets were bioequivalent to one 100 mg tablet, two 50 mg tablets were bioequivalent to one 100 mg tablet, and two 50 mg tablets were bioequivalent to ten 10 mg tablets. The two powder formulations for oral suspension (0.72% and 7.2%) met the bioequivalence criteria (0.80-1.25) to the commercial 100 mg tablet with respect to AUCt and AUC∞, but the lower bound of the 90% CI of the Cmax extended slightly below 0.80. The delivery vehicles (water, apple juice, apple sauce and yogurt) did not affect the bioavailability of venetoclax 0.72% or 7.2% oral suspensions Citation Format: Mohamed Badawi, Bo Tong, Xin Chen, Tammy Palenski, Su Young Kim, Divya Samineni, David Hoffman, Rajeev Menon, Ahmed Hamed Salem. Clinical assessment of the bioavailability of venetoclax tablet and powder formulations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 641.

Urinary Pharmacokinetic Profile of Cannabidiol (CBD), Δ9-Tetrahydrocannabinol (THC) and Their Metabolites following Oral and Vaporized CBD and Vaporized CBD-Dominant Cannabis Administration.

The market for products containing cannabidiol (CBD) is booming globally. However, the pharmacokinetics of CBD in different oral formulations and the impact of CBD use on urine drug testing outcomes for cannabis (e.g., 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (Δ9-THCCOOH)) are understudied. This study characterized the urinary pharmacokinetics of CBD (100 mg) following vaporization or oral administration (including three formulations: gelcap, pharmacy-grade syrup and or Epidiolex) as well as vaporized CBD-dominant cannabis (containing 100 mg CBD and 3.7 mg Δ9-THC) in healthy adults (n = 18). A subset of participants (n = 6) orally administered CBD syrup following overnight fasting (versus low-fat breakfast). Urine specimens were collected before and for 58 h after dosing on a residential research unit. Immunoassay (IA) screening (cutoffs: 20, 50 and 100 ng/mL) for Δ9-THCCOOH was performed, and quantitation of cannabinoids was completed via LC-MS-MS. Urinary CBD concentrations (ng/mL) were higher after oral (mean Cmax: 734; mean Tmax: 4.7 h, n = 18) versus vaporized CBD (mean Cmax: 240; mean Tmax: 1.3 h, n = 18), and oral dose formulation significantly impacted mean Cmax (Epidiolex = 1,274 ng/mL, capsule = 776 ng/mL, syrup = 151 ng/mL, n = 6/group) with little difference in Tmax. Overnight fasting had limited impact on CBD excretion in urine, and there was no evidence of CBD conversion to Δ8- or Δ9-THC in any route or formulation in which pure CBD was administered. Following acute administration of vaporized CBD-dominant cannabis, 3 of 18 participants provided a total of six urine samples in which Δ9-THCCOOH concentrations ≥15 ng/mL. All six specimens screened positive at a 20 ng/mL IA cutoff, and two of six screened positive at a 50 ng/mL cutoff. These data show that absorption/elimination of CBD is impacted by drug formulation, route of administration and gastric contents. Although pure CBD is unlikely to impact drug testing, it is possible that hemp products containing low amounts of Δ9-THC may produce a cannabis-positive urine drug test.

High-Fat Breakfast Increases Bioavailability of Albendazole Compared to Low-Fat Breakfast: Single-Dose Study in Healthy Subjects.

Purpose: Albendazole is a benzimidazole carbamate drug with anthelmintic and antiprotozoal activity against intestinal and tissue parasites. It has been described that the administration with meals increases albendazole absorption. Our aim was to compare the systemic exposure in healthy volunteers of two albendazole formulations after a single oral dose under fed conditions and to evaluate the effect of breakfast composition on albendazole and albendazole sulfoxide bioavailability. Methods: 12 healthy volunteers were included in a 4-period, 4-sequence, crossover, open, randomized, bioequivalence clinical trial, including two stages to compare two formulations of albendazole. Single oral doses of 400 mg albendazole were administered under fed conditions (a low-fat breakfast in first stage and a high-fat breakfast in the second) separated by 7-day washout periods. Plasma albendazole and albendazole sulfoxide concentrations were measured by HPLC-MS/MS. Findings: Albendazole absorption was clearly influenced by the meal composition. A high-fat breakfast increased albendazole and albendazole sulfoxide area under the concentration–time curve (AUC) and maximum concentration (Cmax) by double, compared to a low-fat breakfast. The bioavailability of the two formulations was very similar, although the sample size was not sufficient to demonstrate bioequivalence because the intraindividual variability of albendazole was approximately 60%. Implications: The higher albendazole and albendazole sulfoxide levels when administered with a high-fat meal could be of importance in clinical practice. Since albendazole labeling recommends its administration with meals, it is necessary to insist on taking it with a fatty meal so that the effectiveness of albendazole is not compromised.

Functionality and consumer acceptability of low-fat breakfast sausages processed with non-meat ingredients of pulse derivatives.

Owing to recent changes in consumer eating behaviours as well as potential cost savings for processors, pulse ingredients are finding more application in the meat processing industry. In this study, pea ingredients (pea fibre, FB; pea starch, ST; pea flour, PF) and chickpea flour (CF) were used, at 4% addition level, as fat replacers in low-fat breakfast sausages. The impact of these substitutions on processing and sensory characteristics of breakfast sausage was evaluated. While reduction in fat content in breakfast sausage resulted in some detrimental changes in cooking as well as textural characteristics of the product, addition of binders significantly improved these attributes in low-fat breakfast sausages. Overall, treatment formulation did not significantly affect the pH and the instrumental colour attributes of cooked breakfast sausage. Addition of all binders resulted in reduced cooking loss and increased moisture retention in low-fat breakfast sausage (P < 0.05), whereas, FB and ST were significantly more effective in improving water holding capacity of low-fat breakfast sausage. Furthermore, while both FB and ST increased the hardness, cohesiveness and chewiness parameters of low-fat breakfast sausage (P < 0.05), PF and CF had no impact. Generally, the consumer overall liking and flavour acceptability of FB and ST in low-fat breakfast sausage were significantly higher than those of PF and CF. The use of ST or FB as a fat replacer in breakfast sausages offers processors improved cook yield without negatively impacting the important sensory attributes of breakfast sausages. © 2021 Society of Chemical Industry.

Impact of prolonged sitting and physical activity breaks on cognitive performance, perceivable benefits, and cardiometabolic health in overweight/obese adults: The role of meal composition

Physical activity (PA) breaks may effectively attenuate the detrimental impact of prolonged sitting on acute cognitive performance, perceivable benefits (e.g. mood), vascular function, and metabolic health. To date, the impact of meal composition on the effects of sedentary behavior and/or PA breaks on health has been scarcely studied. Therefore, our aim was to investigate whether meal composition alters how sedentary behavior and PA breaks affect these acute health outcomes. A total of 24 overweight and obese, sedentary adults completed four conditions in randomized order in a cross-over design: [a] high-protein, low-fat breakfast (HPLF)+4hrs uninterrupted sitting (SIT), [b] HPLF+4hrs interrupted sitting (ACT; 5-min cycling every 30min), [c] Western breakfast (WEST; higher in fats/simple sugars, lower in protein/fiber)+SIT, [d] WEST+ACT. WEST and HPLF were isocaloric. Linear mixed models were used to examine changes in cognitive performance (Test of Attentional Performance), perceivable benefits (Likert-scales, Profile of Mood States questionnaire), vascular health (carotid artery reactivity, blood pressure), and metabolic health (post-breakfast glucose, insulin, lipids). Independent of meal composition, we did not observe any effect of PA breaks on cognitive performance, vascular health and post-breakfast lipid responses. PA breaks delayed post-breakfast mood and vigor decrements, as well as increases in fatigue and sleepiness (all p<0.05), but effects were independent of meal composition (p>0.05). WEST resulted in higher post-breakfast glucose levels compared to HPLF (p<0.05), while PA breaks did not impact this response (p>0.05). PA breaks reduced post-breakfast insulin (p<0.05), which did not differ between meals (p>0.05). The acute impact of PA breaks and/or prolonged sitting on cognitive performance, perceivable benefits, and vascular and metabolic health was not altered by the composition of a single meal in overweight/obese, sedentary adults. Possibly, breaking up prolonged sitting, rather than meal composition, is a more potent strategy to impact acute health outcomes, such as perceivable benefits and insulin levels.

High-protein meals require 30% additional insulin to prevent delayed postprandial hyperglycaemia.

To determine the amount of additional insulin required for a high-protein meal to prevent postprandial hyperglycaemia in individuals with type 1 diabetes using insulin pump therapy. In this randomized cross-over study, 26 participants aged 8-40years, HbA1c <65mmol/mol (8.1%), received a 50g protein, 30g carbohydrate, low-fat (<1g) breakfast drink over five consecutive days at home. A standard insulin dose (100%) was compared with additional doses of 115, 130, 145 and 160% for the protein, in randomized order. Doses were commenced 15-min pre-drink and delivered over 3h using a combination bolus with 65% of the standard dose given up front. Postprandial glycaemia was assessed by 4h of continuous glucose monitoring. The 100% dosing resulted in postprandial hyperglycaemia. From 120min, ≥130% doses resulted in significantly lower postprandial glycaemic excursions compared with 100% (P<0.05). A 130% dose produced a mean (sd) glycaemic excursion that was 4.69(2.42)mmol/l lower than control, returning to baseline by 4h (P<0.001). From 120 min, there was a significant increase in the risk of hypoglycaemia compared with control for 145% [odds ratio (OR) 25.4, 95% confidence interval (CI) 5.5-206; P<0.001) and 160% (OR 103, 95% CI 19.2-993; P<0.001). Some 81% (n=21) of participants experienced hypoglycaemia following a 160% dose, whereas 58% (n=15) experienced hypoglycaemia following a 145% dose. There were no hypoglycaemic events reported with 130%. The addition of 30% more insulin to a standard dose for a high-protein meal, delivered using a combination bolus, improves postprandial glycaemia without increasing the risk of hypoglycaemia.

A Fatty Acid Mouth Rinse Decreases Self-Reported Hunger and Increases Self-Reported Fullness in Healthy Australian Adults: A Randomized Cross-Over Trial

Fatty acid (FA) chemoreception in the oral cavity, known as fat taste, may trigger a satiety response that is homologous to FA chemoreception in the gastrointestinal tract. In addition, individuals with an impaired fat taste sensitivity are more likely to have an impaired satiety response. This study aimed to assess the effect of an FA mouth rinse on self-reported appetite, and to determine if the effect is modified by fat taste sensitivity. Thirty-one participants (age, 32.0 ± 8.4 y; body mass index (BMI), 26.1 ± 8.1 kg/m2) were studied on four separate days to evaluate the effect of a 20 mM oleic acid (OA) mouth rinse (in duplicate) compared to a control (in duplicate) on self-reported appetite by using a visual analogue scale (VAS) every 30 min for three hours following a standardized low-fat breakfast. The area under the curve ratings for fullness were greater (p = 0.003), and those for hunger were lower (p = 0.002) following the OA rinse compared to the control. The effect of the OA rinse was greater in individuals who were hypersensitive to fat taste compared to moderately sensitive and hyposensitive individuals for fullness (p < 0.010) and hunger (p < 0.010) ratings. In summary, an OA mouth rinse decreases self-reported hunger and increases self-reported fullness, particularly in those who are more sensitive to fat taste. FA receptors in the oral cavity may be potential targets to regulate appetite.

Vitamin D bioavailability from different lipid delivery systems

AbstractIntroductionData modelling studies confirm a role for food fortification to improve vitamin D intakes and status. However, there is very little research reporting the bioavailability of vitamin D from foods to inform food fortification strategies. There is some evidence to suggest that the lipid component of foods impacts vitamin D uptake in cells; however, no studies have examined the absorption kinetics of vitamin D from different lipid delivery systems in humans. The aim of this research is to compare changes in serum vitamin D concentrations using different vitamin D emulsions as delivery systems.MethodsA single blind, controlled, 4-way crossover postprandial study was conducted. Participants consumed 4 different 20μg vitamin D enriched emulsion drinks (olive oil emulsion, fish oil emulsion, mixed micelle emulsion and a non-fat control drink) with a low-fat breakfast on 4 occasions separated by a 1-week washout. Serum 25-hydroxyvitamin D (25(OH)D3) concentrations and cardiometabolic risk markers were measured at baseline and 2, 4, 6 and 8 hours after consuming the drink. Statistical analysis was performed in IBM SPSS Statistics, Version 24 (SPSS Inc. Chicago, IL, USA). Repeated measures ANOVA was performed to assess the effects of the 4 treatments.ResultsSix males and six females aged between 22 and 65 years completed the study. All participants were healthy with a mean BMI of 24.7 ± 4.1kg/m2 for males and 25.1 ± 4.5kg/m2 for females. Each 100 ml drink contained 106 kcal, 4 g fat, 11.9 g carbohydrate and 5.5 g protein, apart from the control which contained 70kcal and 0 g fat. The breakfast contained 321 kcal, 0.7 g fat, 66 g carbohydrate and 10.3 g protein. There was an increase in 25(OH)D3 concentrations over the 8-hour assessment period following consumption of all 4 drinks. Two-way repeated measures ANOVA showed a significant drink*time interaction. No participants experienced any negative side effects after consuming any of the drinks.DiscussionThe absorption kinetics of vitamin D is different depending on the lipid delivery system. This is the first human study demonstrating the bioavailability of vitamin D3 from various emulsions including a novel mixed micelle emulsion. All emulsions were palatable, effective and safe to consume.

Effect of Food on the Pharmacokinetics of 2 Formulations of DRL-17822, a Novel Selective Cholesteryl Ester Transfer Protein (CETP) Inhibitor, in Healthy Males.

DRL-17822 is a novel selective cholesteryl ester transfer protein inhibitor that showed an increased exposure, including an increase of >20-fold of maximum concentration and area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration, following a high-fat breakfast using a nanocrystal formulation. To reduce this effect of food, we generated an amorphous solid dispersion formulation. In this study, we compared the food effect of both formulations of DRL-17822 in a 2-part randomized, open-label, 4-way crossover study involving healthy adult males 18-45 years of age. In both parts of the study, 12 subjects received both formulations of DRL-17822 in both the fasted and fed states; a low-fat breakfast was provided in the first part and a high-fat breakfast in the second part. Compared to the nanocrystal formulation, the amorphous solid dispersion formulation substantially increased DRL-17822 exposure in the fasted state, including increased maximum concentration, area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration, and area under plasma concentration-time curve from time zero to infinity. Following a high-fat breakfast, DRL-17822 exposure was increased to a lesser extent in the amorphous solid dispersion formulation compared to the nanocrystal formulation (P < .001). Moreover, compared to the nanocrystal formulation the amorphous solid dispersion formulation caused a more pronounced increase in high-density lipoprotein in the fasted state. Consuming breakfast increased the effect of DRL-17822 on high-density lipoprotein. Taken together, our results indicate that by improving its formulation, DRL-17822 has a favorable exposure profile and therefore a more predictable food effect profile.

Plasma stearoyl-CoA desaturase activity indices and bile acid concentrations after a low-fat meal: association with a genetic variant in the FTO gene.

PurposeDietary macronutrient composition, stearoyl-CoA desaturase (SCD) activity indices, and primary bile acid (BA) concentrations are among the factors that have been associated with lipid metabolism and contributed to obesity. We investigated the association between the polymorphic expression of the fat mass and obesity-associated (FTO) gene and its relationship with SCD activity indices and primary BA concentrations after a low-fat meal.Subjects and methodsBlood plasma samples were collected from 56 young (20–36 years) healthy subjects with different rs9939609 FTO genotypes. Fasting and post-meal (2 hours after a low-fat breakfast) blood samples were collected on the subsequent morning for the analysis of DNA methylation, SCD activity indices (product-to-precursor fatty acid ratios; 16:1n-7/16:0 and 18:1n-9/18:0), and chenodeoxycholic acid (CDCA) and cholic acid (CA) concentrations. Expression of lipogenic genes was investigated post-meal to assess the relationship between the CDCA and CA concentrations and mRNA levels of lipogenic genes.ResultsThe FTO AA (obesity risk) genotype group (n=18) had higher (P<0.05) post-meal SCD-16 activity index than the FTO TT (wild type) genotype group (n=26). In both the FTO TT (n=16) and AA (n=8) genotype groups, the post-meal concentrations of CDCA and CA were lower (P<0.05) compared with the fasted state. No difference in BA concentrations between the FTO TT and AA genotype groups in both meal states was observed. After adjusting for the body mass index, the highest 50% post-meal concentrations of CA were inversely (P=0.010) correlated with the level of mRNA SCD expression.ConclusionFTO AA carriers may be at a higher risk for obesity through higher SCD activity in a low-fat diet environment. This effect may be partly pronounced by very low CA concentrations.

Maternal Postprandial Triglycerides in the Home Setting

Background and Aims: Elevated maternal triglycerides (TG) have been associated with adverse pregnancy outcomes including an increased risk of preeclampsia and macrosomia. Maternal TG are primarily measured in the fasting state and at single time points during pregnancy. Temporal and prandial changes in TG levels during pregnancy are not well described. The purpose of this study was to examine flux of capillary glucose and TG in late pregnancy, how they are influenced by high and low fat meals, and whether they relate to infant body composition. Materials and Methods: Women in the third trimester of pregnancy completed 4 days of home capillary glucose and TG monitoring (4 times a day (fasting and two hours post each meal)). Using the Roche Accutrend Plus meter. Each woman consumed an isocaloric high fat (41%) and a low fat (25%) breakfast meal on different days during the study period. Area under the curve (AUC) for the capillary glucose and TG measures after the standardized meals was calculated using trapezoidal approximation. AUC for women with and without GDM was compared for each meal and metabolic measure. Infant body fat % was measured by air displacement plethysmography. Results: To date, thirteen women, 7 with GDM and 6 normoglycaemic have completed the study. Median capillary glucose levels: fasting 5.0 (95% CI 4.6-5.2) mmol/L and postprandial 6.0 (95% CI 5.7-6.2) mmol/L. Median capillary TG: fasting 3.3 (95% CI 2.9-3.8) mmol/L and postprandial 3.6 (95% CI 3.2-3.8) mmol/L. Mean infant body fat % 10.6 (SD4.9)%. There were no significant differences in capillary glucose or triglycerides between the meals although capillary glucose trended higher with the low fat meal. GDM status did not affect the AUC glucose or AUC triglycerides for either meal. Conclusion: This study demonstrates that capillary triglycerides can be monitored at home in a similar fashion to capillary glucose. Capillary triglyceride levels were not related to infant anthropometry and did not vary significantly with meal fat content. Recruitment is ongoing. Disclosure H.L. Barrett: None. M. Dekker: Speaker's Bureau; Self; Abbott. Other Relationship; Self; Nestlé. S.J. de Jersey: None. M.C. d'Emden: Advisory Panel; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company, Boehringer Ingelheim GmbH. Advisory Panel; Self; Sanofi. Speaker's Bureau; Self; Sanofi, Novo Nordisk A/S, Novartis Pharmaceuticals Corporation. L. Callaway: None. H. McIntyre: Speaker's Bureau; Self; Novo Nordisk Inc.. Research Support; Self; Danish Diabetes Academy.

A prospective international randomized phase II study evaluating the food effect on the pharmacokinetics (PK) and pharmacodynamics (PD) of abiraterone acetate (AA) in men with castration-resistant prostate cancer (CRPC).

176 Background: AA is a standard of care for the treatment of metastatic CRPC, with an approximate retail cost of $8000/month. Despite a large food effect (~17-fold increase in CMax with a high-fat meal), AA was administered under fasting conditions in its pivotal trials. There are no randomized continuous dosing studies examining prandial state dosing on AA PK/PD. We sought to test the hypothesis that LOW (250mg w/food) would have similar PK/PD and safety to standard (STD, 1000mg fasting) in patients with progressive CRPC. Methods: Patients (n = 72) with progressive CRPC from seven institutions in the US and Singapore were randomized to treatment with STD or LOW (with low-fat breakfast). Both arms received prednisone 5mg twice daily. PSA was assessed monthly, and testosterone, DHEA/DHEAS were assessed every 12 weeks along with standard disease burden assessments. PK samples were collected at day 1, 8 and months 2, 3, 4. Log change in PSA response rate from baseline to week 12 was examined as the primary endpoint, with a non-inferiority design based on a non-inferiority margin of 15%. This margin corresponds to a 0.51 standard deviation (SD) difference in the mean log changes between the groups. Results: Accrual was completed with n = 36 on STD and n = 36 on LOW. Median (range) age was 74 (52-89) and baseline PSA was 39.2(range 0.6-1789). Mean log-change in PSA at 12 weeks was nominally greater in the LOW arm (-1.59 vs. -1.19). The 95% confidence for the difference (STD-LOW) ranged from -0.40 to 1.19, with lower limit corresponding to -0.24SD. Thus, non-inferiority of LOW was established. Median time to PSA progression was ~14 month in both arms (p = 0.53). Preliminary analysis of PK showed no difference in CMaxbeyond the first cycle with lower PK variability in the LOW arm. Conclusions: Low-dose (250mg/day) abiraterone acetate with a low-fat breakfast is non-inferior to standard dosing in a fasted state with respect to PSA and PK metrics. Although PSA response and progression are not clinically validated surrogates, given the pharmacoeconomic implications, these data warrant consideration by prescribers and payors. Clinical trial information: NCT01543776.

Effect of Low‐ and High‐Fat Meals on the Pharmacokinetics of Venetoclax, a Selective First‐in‐Class BCL‐2 Inhibitor

Venetoclax is a selective, first-in-class, B-cell lymphoma-2 inhibitor that has demonstrated clinical efficacy in several hematological malignancies. Two studies evaluated the relative bioavailability of venetoclax in healthy subjects: (1) a bioequivalence study to compare the bioavailability of the film-coated tablet with that of an earlier uncoated tablet and (2) a food effect study to evaluate the effect of food on venetoclax pharmacokinetics. Both studies were open-label, single-dose, crossover studies. In the bioequivalence study, 15 subjects received a single dose of venetoclax 50mg under nonfasting conditions, in each of 2periods; one period used the uncoated tablet, and the other used the film-coated tablet. In the food effect study, 24subjects received a single dose of venetoclax film-coated 100-mg tablet under fasting conditions, after a low-fat breakfast or after a high-fat breakfast in different periods. The venetoclax film-coated tablet was bioequivalent to the uncoated tablet, which indicates that the film coating does not affect bioavailability. The median Tmax of venetoclax was delayed by about 2 hours when administered with food. Compared with fasting conditions, Cmax and AUC increased by approximately 3.4-fold following a low-fat breakfast. High-fat meals increased Cmax and AUC by approximately 50% relative to low-fat meals. The mean terminal half-life was comparable between the high-fat meal and fasting conditions (19.1 versus 16.1hours). Based on these results and the venetoclax exposure-response profile, venetoclax should be administered with food and without specific recommendations for fat content to ensure adequate and consistent bioavailability.

Contribution of dietary advanced glycation end products (AGE) to circulating AGE: role of dietary fat

The purpose of this pilot study was to determine whether macronutrient content (low-fat v. high-fat diet) influences an indicator of advanced glycation end products (AGE), N(ε) carboxymethyl-lysine (CML), in the context of a 1-d, high-AGE diet. The effect of the diets on inflammatory markers was also assessed. A total of nineteen overweight and obese adults (nine men and ten women) without known disease were recruited to participate in a crossover challenge of a high-fat, high-AGE (HFHA) and low-fat, high-AGE (LFHA) diet. In each phase patients had fasting blood drawn, followed by consumption of a high-fat or low-fat breakfast test meal, then three postprandial blood draws at 1, 2 and 3 h after consuming the test meal. After consuming high-AGE meals for the remainder of the day, participants returned the next day for a follow-up analysis. A different pattern in the 3-h post-meal CML and soluble receptor for AGE response to the two diets was observed (P=0·01 and 0·05, respectively). No change in serum CML was observed following consumption of a LFHA breakfast (535 (25th-75th percentile 451-790) to 495 (25th-75th percentile 391-682) ng/ml; P=0·36), whereas a rise in CML occurred after the HFHA breakfast (463 (25th-75th percentile 428-664) to 578 (25th-75th percentile 474-865) ng/ml; P=0·05). High sensitivity C-reactive protein and high molecular weight adiponectin were not affected by either diet. These findings suggest that dietary CML may not be as important in influencing serum CML as other dietary factors. In addition, acute exposure to dietary CML may not influence inflammation in adults without diabetes or kidney disease. This is contrary to previous findings.

Bioequivalence and Food effect of heat-stressed and non-heat-stressed Dapagliflozin Tablets

August 2015 e105 fed state; a low fat breakfast was provided in Part A and a high breakfast in Part B. Results: In both parts, the new formulation substantially increased DRL-17822 exposure in fasted state, characterised by Cmax, AUC0-t and AUC0-∞, compared to the current formulation. Following high fat breakfast, DRL-17822 exposure was significantly less using the new formulation compared to the current formulation (P < 0.01). In addition, the new formulation resulted in similar ratios fed/fasted for AUC0-t in following both types of breakfast while the current formulation had a higher ratio after high fat breakfast compared to a low fat breakfast (Table 1, similar ratios were seen for Cmax and AUC0-∞). Conclusion: The new formulation had favourable pharmacokinetic characteristics compared to the current formulation, showing a food effect of only 3-fold, which may relate in more predictable effect profile.

Slower Rate of Fat Absorption at Dinner versus Lunch is Associated with Lower Concentrations of Triacylglycerols (TG) the Following Morning

High postprandial TG are a risk factor for cardiovascular disease (CVD) and little is known about the impact of successive meals on the circadian TG pattern. Here, we measured the rate of fat absorption during two sequential meals to determine how lipid processing after dinner contributes to fasting TG concentrations the next morning. Non-diabetic adults (n=6, BMI 20-49, fasting TG 50-198 mg/dL) were fed a low-fat breakfast, followed by a lunch and dinner of identical composition (35% fat, 46% carbohydrates and 18% protein). Stable isotopes were added to lunch (d31-tripalmitin) and dinner (13C4-tripalmitin) to measure the kinetics of dietary fat absorption in TRL-TG by GC/MS. Blood samples were taken intermittently throughout the day and through the next morning. For insulin and glucose, the AUCs were not significantly different between the two meals. However, the rate of fat absorption was 1.9-fold higher after lunch than dinner (0.27±0.03 vs 0.14±0.04 mmol/L/h, respectively; P=0.04). Interestingly, faster dinner absorption rates were strongly correlated with higher 5h incremental contributions of dinner fat to TRL-TG (r2=0.996; P=0.0001). These data suggest that faster absorption contributes to poor tolerance to dietary fat. Further, faster absorption correlated with subsequently higher fasting TG (r2=0.975; P=0.0002). In summary, isotopic labelling of successive meals allows for the identification of diurnal control of TG metabolism. These data provide a mechanism to explain why therapies that lower evening meal TG absorption rates, such as increased fiber content or reduced fat content of meals, may reduce CVD risk.