Moderate-fat Meal Research Articles

Pharmacokinetics, pharmacodynamics, safety and tolerability of cilofexor, a novel nonsteroidal Farnesoid Xreceptor agonist, in healthy volunteers.

Cilofexor is a nonsteroidal farnesoid X receptor (FXR) agonist being evaluated for treatment of nonalcoholic steatohepatitis (NASH) and primary sclerosing cholangitis (PSC). This work characterized the pharmacokinetics, pharmacodynamic, safety, and tolerability of cilofexor in healthy participants. Cilofexor single and multiple once-daily doses (10 to 300 mg fasting or fed and twice-daily doses [15 and 50 mg; fed]; tablet formulation) were evaluated. In each cohort, participants were randomized to active drug or placebo in a 4:1 ratio (planned n=15/cohort). Multiple dosing was for 14 days. Pharmacokinetic and pharmacodynamic samples were collected and safety and tolerability were assessed. Overall, 120 participants were enrolled in the study and 118 participants received at least one dose of study drug. Cilofexor pharmacokinetics followed bi-exponential disposition and its exposure increased in a less-than-dose-proportional manner over the 10 to 300 mg dose range, with no significant accumulation with repeated dosing. Moderate-fat meal reduced cilofexor area under the plasma concentration versus time curve (AUC) by 21% to 45%. Cilofexor increased plasma levels of fibroblast growth factor19 (FGF19) and reduced the serum bile acid intermediate 7α-hydroxy-4-cholesten-3-one (C4) and bile acids in an exposure-dependent manner. Cilofexor doses >30 mg appeared to achieve the plateau of intestinal FXR activation. Cilofexor was generally well tolerated; all treatment-emergent adverse events (TEAEs) were mild or moderate in severity, with headache being the most frequently observed TEAE. The pharmacokinetics pharmacodynamic safety, and tolerability results from this study supported further evaluations, and informed dose selection, of cilofexor in phase II studies in patients with NASH and PSC.

Safety, Tolerability, and Pharmacokinetic Profile of Single and Multiple Ascending Doses of GB5121, a CNS-Penetrant BTK Inhibitor, in Healthy Subjects

Background: GB5121 is an oral, brain-penetrant, potent, highly selective, irreversible, small molecule Bruton's tyrosine kinase inhibitor (BTKi) in development for hematologic malignancies with CNS involvement. Preclinical studies demonstrated that GB5121 exhibited several characteristics differentiating it from other BTKis, including rapid equilibrium into the brain, increased brain target occupancy, and fast inactivation rate. These characteristics combined with GB5121's kinase selectivity and activity in in vitro and in vivo DLBCL models support its clinical investigation in BTK-driven CNS lymphomas. This first-in-human study was designed to evaluate the single- and multiple-dose safety, tolerability, pharmacokinetics (PK; including CNS penetrance) and pharmacodynamics (PD), the effect of food, drug interactions, and cardiac safety of GB5121 to inform dosing and concomitant medications in clinical studies. Methods: This is an ongoing Phase 1, double-blind, randomized, placebo-controlled, single ascending and multiple ascending dose (SAD, MAD) study in healthy subjects, with staggered dose escalations and adaptive dose selection. Safety is assessed throughout the study and PK and PD are characterized using serial blood samples collected up to 48 hours post-dose for GB5121 plasma concentrations, BTK target occupancy (TO), and target engagement (TE). Cerebrospinal fluid (CSF) samples are collected at 2 hours post-dose to characterize the relationship between GB5121 plasma concentrations and CNS penetrance. GB5121 PK parameters (e.g., AUClast, AUCinf, Cmax, Tmax, t1/2) are estimated by standard noncompartmental methods. Results: Preliminary PK results from 3 completed SAD cohorts are presented, including 23 subjects (7 receiving 5 mg, 8 receiving 15 mg, and 8 receiving 45 mg: randomized in a 3:1 ratio to receive GB5121 or placebo) in a fed state (moderate-fat meal). A review of blinded safety data thus far indicated that the study drug was generally well tolerated with no serious adverse events or early study discontinuations reported. PK parameters are presented in Table 1. GB5121 was rapidly absorbed following oral administration with mean plasma Tmax ranging from 1-2 hours and exhibited a terminal half-life of approximately 3 hours. Single-dose GB5121 exposure (AUCinf) increased in a greater than dose-proportional manner from 5 to 15 mg and near dose-proportional from 15 to 45 mg. Mean GB5121 CSF:unbound plasma concentration ratios approximated 1, indicating unimpeded access of unbound drug in plasma into the CNS. The observed GB5121 plasma exposure, CNS penetrance, and preliminary TO and TE PD data were consistent with that of a translational PK/PD model. Conclusions: Data from the first 3 SAD cohorts in healthy subjects indicated that low doses of GB5121 provided plasma exposure and CSF penetrance adequate to drive desired BTK inhibition in the CNS. Blinded safety data indicated that single-dose study drug administration was well tolerated across the dose range. PD analysis and additional evaluations are ongoing and final results will be presented. The safety and PK profiles of GB5121 support its continued evaluation in the ongoing Phase 1b/2 open-label, international study in adult subjects with relapsed/refractory primary/secondary CNS lymphoma, or primary vitreoretinal lymphoma (STAR CNS; NCT05242146). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Relative Bioavailability and Food Effect of GSK3640254 Tablet and Capsule Formulations in Healthy Participants.

GSK3640254 is a next‐generation maturation inhibitor with demonstrated potency across HIV‐1 subtypes and a high barrier to emergent resistance. This phase I, 2‐part, randomized, open‐label study (ClinicalTrials.gov identifier, NCT04263142) in healthy participants assessed the relative bioavailability of a single dose of GSK3640254 200 mg in tablet and capsule formulations (part 1) and the effect of food on the pharmacokinetic profile of the tablet formulation (part 2). Overall, 39 participants were randomized to treatment (part 1, n = 18; part 2, n = 21). All participants in part 1 completed the study; 2 participants in part 2 withdrew before study completion (adverse event, n = 1; physician decision, n = 1). In part 1, plasma exposures of the GSK3640254 tablet formulation were not meaningfully different from those of the capsule formulation when administered in the presence of a moderate‐fat meal. In part 2, GSK3640254 plasma exposures increased by ≈3‐ to 4‐fold under high‐ and moderate‐fat conditions, respectively, compared with fasted conditions. No major safety or tolerability findings were observed. The highest incidence of adverse events (24%) was reported under high‐fat conditions. Taken together, these data support the use of the tablet formulation coadministered with food in the clinical development of GSK3640254 for treatment of HIV‐1.

Riceberry rice beverage decreases postprandial glycemic response, inflammatory markers and antioxidant status induced by a high-carbohydrate and moderate-fat meal in overweight and obese men.

Recent clinical studies support the beneficial role of riceberry rice and its food products in controlling the glycemic response in healthy subjects. The aim of the current work was to determine the effects of riceberry rice beverage (RRB) on postprandial glycemic, insulin and triglyceride responses, inflammatory biomarkers, and antioxidant status as well as appetite sensation following a high-carbohydrate and moderate-fat (HCMF) meal in overweight/obese subjects. Thirteen participants, overweight and obese men (age = 24.46 ± 0.90 years and BMI = 25.92 ± 0.69 kg m-2), completed a randomized, crossover intervention study. They consumed an HCMF meal with or without RRB (2 g of riceberry rice extract powder/400 ml). Blood samples and appetite sensation were measured at the fasting state and up to 6 h after meal consumption. The ingestion of the HCMF meal accompanied by RRB had a lower incremental area under the curve (iAUC) for postprandial plasma glucose, insulin, malondialdehyde (MDA) and serum triglyceride concentrations when compared to the control. A significant increase in the ferric reducing ability of plasma (FRAP), Trolox equivalent antioxidant capacity (TEAC), and thiol level, all measures of antioxidant capacity, was also observed in the participants who consumed the HCMF meal accompanied by RRB. The postprandial level of pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) significantly increased at 3 h and 6 h after the HCMF meal intake when compared to the fasting state. Interestingly, these values were significantly decreased upon consumption of RRB. However, there were no statistically significant differences in the rating scores of hunger, fullness, desire to eat, and satiety among the tested meals. In conclusion, RRB intake prevented HCMF meal-induced postprandial glycemic, lipemic, and pro-inflammatory responses and improved plasma antioxidant capacity in overweight and obese participants.

Lack of pharmacokinetic interaction between the HIV-1 maturation inhibitor GSK3640254 and combination oral contraceptives in healthy women.

AimsGSK3640254 is a next‐generation maturation inhibitor likely to be coadministered with combined oral contraceptives in HIV‐positive women.MethodsThis phase I, open‐label, 1‐way study assessed pharmacokinetic and pharmacodynamic interactions of GSK3640254 200 mg and ethinyl oestradiol 0.03 mg/levonorgestrel 0.15 mg once daily in healthy female participants who received ethinyl oestradiol/levonorgestrel for 10 days with a moderate‐fat meal after which GSK3640254 was added from Days 11 to 21. Primary endpoints were area under the plasma concentration–time curve to the end of the dosing interval (AUC0‐t), maximum observed concentration (Cmax) and plasma concentration at the end of the dosing interval (Cτ) for ethinyl oestradiol and levonorgestrel. Serum follicle‐stimulating hormone, luteinizing hormone and progesterone concentrations were determined. Adverse events were monitored.ResultsAmong 23 enrolled participants, 17 completed the study. Geometric least squares mean ratios (with vs. without GSK3640254) of AUC0‐t, Cmax and Cτ were 0.974, 0.970 and 1.050 for ethinyl oestradiol and 1.069, 1.032 and 1.083 for levonorgestrel, respectively. Three participants had elevated progesterone levels, which occurred before GSK3640254 administration in 2 participants. No participants had elevated follicle‐stimulating hormone or luteinizing hormone values. Fourteen participants (61%) reported adverse events. Four participants reported asymptomatic elevated transaminase levels meeting liver‐stopping criteria; of these, 3 events occurred before GSK3640254 administration and led to study withdrawal.ConclusionEthinyl oestradiol/levonorgestrel plus GSK3640254 coadministration did not affect steady‐state pharmacokinetics or pharmacodynamics of ethinyl oestradiol and levonorgestrel in healthy female participants. No major tolerability findings were reported. Elevated liver transaminase levels were probably due to ethinyl oestradiol/levonorgestrel.

Acute Effects of Wild Blueberry Intake on Metabolic Markers and Cognitive Performance in Middle‐Aged Adults

BACKGROUNDConsumption of polyphenols has been associated with improvements in cognitive function in children (aged 8–10 years old), young adults (18–21 years old) and older adults (65–80 years old). In this study, we investigated the effect of wild blueberry (WBB) consumption on cognitive performance in middle aged adults (45–60 years old) and examined the relationship of cognitive outcomes with metabolic control.METHODSIn this randomized, single‐blind, 2‐arm, cross‐over trial, 29 middle aged men and women were asked to consume a high carbohydrate, moderate fat meal with 1 cup fresh weight equivalent freeze dried WBB drink or control beverage (flavored lemonade). Cognitive tests measuring response interference, executive/working memory, and performance in learning, memory recall and recognition were performed immediately before and every 2 hours after meal consumption for 8 h. Blood samples were collected at defined time points over 8 h after meal intake.RESULTSPreliminary analysis showed significant effects for treatment (p=0.01) and time (p=0.02) with respect to response inhibition on a task assessing executive function. Response inhibition was significantly higher after WBB consumption compared to control (p<0.05) at the 2 hour time point and a trend for higher response inhibition was observed at the 4 hour time point (p = 0.08). Changes in postprandial insulin were significantly different by treatment (mean ± SE; WBB, 35.0 ± 3.0 uIU/mL, Control, 40.0 ± 3.0 uIU/mL, p=0.02) and time (p<0.0001), whereas glucose and TG were different by time only (p<0.0001 for both). Incremental area under the curve analysis also showed significantly reduced insulin exposure (control, 236.3 ± 32.7 uIU/mL*h vs WBB, 204.8 ± 33.4 uIU/mL*h, p=0.0431) with no significant change in glucose or TG (p>0.05) between WBB and control.CONCLUSIONThese results support a role of WBB in acute facilitation of cognitive performance on the more demanding conditions of a response inhibition task and enhancing insulin action when consumed with a meal in middle aged adults. These findings, in conjunction with similar reports in young and older aged groups, support the notion that wild blueberry supplementation can be beneficial with respect to neurocognitive and metabolic function throughout the life span.Support or Funding InformationWild Blueberry Association of North America

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.

Post-prandial systemic 8-isoprostane increases after consumption of moderate and high-fat meals in insufficiently active males

A single high-fat meal (HFM) leads to an increase in triglycerides and oxidative stress. Oxidative stress can be assessed via 8-isoprostane generation, which is associated with the development of asthma and cardiovascular disease. No previous research has investigated whether airway and systemic 8-isoprostane increases postprandially in nonasthmatic participants according to the energy and fat content of a meal. Our purpose was to assess airway and systemic 8-isoprostane after a HFM and a true-to-life moderate-fat meal (MFM). We hypothesized that airway and systemic 8-isoprostane would increase after a HFM and a MFM, with the greatest increase in the HFM condition. Eight nonasthmatic men (25.8±6.9years) completed the HFM and MFM trials in a randomized crossover design. After a 10-hour fast, participants consumed either a HFM (71.13kJ/kg body mass, 60% fat, 23% CHO) or a MFM (35.56kJ/kg body mass, 30% fat, 52% CHO). Exhaled breath condensate to assess airway 8-isoprostane was collected at baseline and at 3 and 6hours postmeal. Venous blood samples were collected at baseline and hourly until 6hours postmeal to assess triglycerides, and every 3hours for systemic 8-isoprostane. Airway 8-isoprostane responses were not significant as a main effect of time (P=.072), between conditions (P=.365), or between time and condition (P=.319) postmeal. Systemic 8-isoprostane increased over time (P<.001), but not between conditions (P=.124) or between time and condition (P=.649) postmeal. Triglyceride incremental area under the curve was different in the HFM compared to the MFM condition (P=.013). After a HFM and a MFM, 8-isoprostane increases systemically; however, airway 8-isoprostane does not change.

Novel Gastroretentive Controlled Release Formulations for Once-Daily Administration: Assessment of Clinical Feasibility and Formulation Concept for Raltegravir.

Raltegravir is an integrase strand transfer inhibitor indicated in combination with other anti-retroviral medicinal products for the treatment of HIV-1 infection, given twice daily. Although a BCS class II compound, raltegravir exhibits low colonic absorption, thus making development of modified release formulations challenging. It was hypothesized that a gastroretentive (GR) formulation would increase trough (C24 h) concentrations of raltegravir, hence being amenable to a once-daily (QD) regimen. Iterative prototype GR formulations were developed in monolithic, bilayer, and trilayer tablet designs. Four phase I studies in healthy subjects were conducted to provide proof of formulation concept. Raltegravir C24 h was increased by a GR formulation with scintigraphy data supporting gastric retention. Single-dose exposures from a trilayer tablet administered in the morning with a high-fat meal resulted in acceptable C24 h values. However, C24 h values for evening dosing with a high-fat meal did not meet the success criteria for QD administration. Raltegravir C24 h and area under the curve (AUC) values after AM dosing with a low-fat meal were significantly lower than after dosing with a moderate-fat meal. Skipping, delaying, or giving a low-fat, low-calorie lunch after dosing with a high-calorie breakfast also resulted in an unacceptable decline in C24 h values. The requirements for consistent product performance under varying conditions of diet, timing of dosing, and dose were not favorable when given as GR tablets. The findings from these studies offer valuable insights into modifying the absorption of candidate drugs with limiting colonic permeability and solubility characteristics and the interplay between meal, dose timing, and GR formulation performance.

Pharmacokinetics of dolutegravir when administered with mineral supplements in healthy adult subjects.

All commercially available integrase inhibitors are 2-metal binders and may be affected by co-administration with metal cations. The purpose of this study was to evaluate the effect of calcium and iron supplements on dolutegravir pharmacokinetics and strategies (dose separation and food) to attenuate the effects if significant reductions in dolutegravir exposure were observed. This was an open-label, crossover study that randomized 24 healthy subjects into 1 of 2 cohorts to receive 4 treatments: (1) dolutegravir alone, fasting; (2) dolutegravir with calcium carbonate or ferrous fumarate, fasting; (3) dolutegravir with calcium carbonate or ferrous fumarate with a moderate-fat meal; (4) dolutegravir administered 2 hours before calcium carbonate or ferrous fumarate, fasting. Plasma dolutegravir AUC(0–∞), Cmax, and C24 were reduced by 39%, 37%, and 39%, respectively, when co-administered with calcium carbonate while fasting and were reduced by 54%, 57%, and 56%, respectively, when co-administered with ferrous fumarate while fasting. Dolutegravir administration 2 hours before calcium or iron supplement administration (fasted), as well as administration with a meal, counteracted the effect. Dolutegravir and calcium or iron supplements can be co-administered if taken with a meal. Under fasted conditions, dolutegravir should be administered 2 hours before or 6 hours after calcium or iron supplements.

The effect of dolutegravir on the pharmacokinetics of metformin in healthy subjects.

Introduction Dolutegravir (DTG) is an HIV integrase strand transfer inhibitor approved for use in combination with other antiretrovirals for the treatment of HIV-infection in adults and adolescents. Metformin is a drug frequently used in diabetic HIV-infected patients, which requires titration to optimize dosing. In vitro, DTG inhibits organic cation transporter 2 (OCT2) and multidrug and toxin extrusion transporter 1 (MATE 1) which are known to be involved in the disposition of metformin. The objective of this study was to assess the drug interaction between DTG and metformin.Materials and Methods This was an open-label, parallel-group, three-period crossover study in healthy adult subjects. Eligible subjects were enrolled into one of the two treatment cohorts (15 subjects/cohort). Subjects received metformin 500 mg q12h for 5 days in Period 1; metformin 500 mg q12h plus DTG 50 mg q24h (Cohort 1) or 50 mg q12h (Cohort 2) for 7 days in Period 2; and metformin 500 mg q12h for 10 days in Period 3. There were no washout periods between treatments. All doses of study drug were taken with a moderate-fat meal. Serial plasma PK samples and safety assessments were obtained throughout the study. Non-compartmental PK analysis was performed and geometric least squares (GLS) mean ratios and 90% confidence intervals (CI) were generated by the mixed effect model for within-subject treatment comparisons for each cohort.Results Fourteen and thirteen subjects completed study in Cohort 1 and Cohort 2, respectively. Plasma exposures of metformin were significantly increased when co-administered with DTG (Table 1).There were no apparent changes in metformin half-life and tmax. Increased metformin plasma exposure returned to normal levels observed in Period 1 after DTG was discontinued in Period 3. No Grade 3 or 4 adverse events (AEs), deaths or serious AEs were reported during the study. Most frequently reported drug-related AEs were headache (9), loose stools (8), and nausea (7). All AEs were mild or Grade 1 with the exception of one Grade 2 headache.Conclusions Co-administration of DTG and metformin was well tolerated, yet significantly increased metformin plasma exposure; effects were DTG dose dependent. Though metformin has a wide therapeutic index and alone is not associated with hypoglycemia, close monitoring is recommended when co-administering metformin and DTG. Dose adjustments of metformin may be considered.

463P - Effect of Food on the Bioavailability of Palbociclib 125 Mg Capsules in Healthy Volunteers

ABSTRACT Aim: Palbociclib (P), a selective oral cyclin-dependent kinase 4/6 inhibitor that blocks G1/S cell cycle progression, is in phase 2 and 3 clinical trials across multiple oncology indications. P has low solubility and high permeability. This completed phase 1 study estimated the effect of food on P bioavailability. Methods: This randomized, open-label, 4-sequence, 4-period crossover study (NCT01904747) in 28 healthy adult volunteers estimated the relative bioavailability of single-dose P 125 mg (free base capsule) administered 30 min after a high fat/calorie meal, 30 min after a low fat/calorie meal, or between 2 moderate fat/standard calorie meals (1 h after/2 h before) versus after fasting ≥10 h overnight (washout: ≥10 d between study periods). No food was allowed ≥4 h postdose (all conditions except moderate fat meal). Pharmacokinetic (PK) samples were collected predose and serially up to 144 h postdose; P concentrations were measured using validated high-performance liquid chromatography tandem mass spectrometry. PK data were analyzed using a non-compartmental approach based on a mixed effects model. Results: Time to maximum P concentration (Tmax) and terminal plasma half-life (t1/2) values were similar across fed and fasted conditions (median Tmax: 8 h, all; mean t1/2: 22.03–23.90 h). Relative to the fasted condition, ratios of adjusted geometric means for high fat, low fat, and moderate fat conditions were 121%, 112%, and 113%, respectively, for AUCinf and 138%, 127%, and 124%, respectively, for Cmax; the slight increase in exposure in the fed versus fasted conditions was driven mainly by a subgroup of subjects (n = 3) with significantly lower exposure in the fasted condition. PK variability (% coefficient of variation) was reduced in the fed (AUCinf, 23%–27%; Cmax, 21%–24%) versus fasted (AUCinf, 39%; Cmax, 73%) conditions. In a supplemental analysis excluding the 3 subjects with significantly lower exposure in the fasted condition, food intake did not affect P exposure, and PK variability was similar across fed and fasted conditions. Conclusions: Overall, P exposure was marginally affected, but PK variability was greatly reduced, in the fed versus the fasted condition. Thus, P should be administered with food. Disclosure: A. Ruiz-Garcia: Employment: Pfizer Inc Stock ownership: Pfizer Inc.; A. Plotka: Employment: Pfizer Stock ownership: Pfizer; S. Pawlak: Speakers’ bureau: Pfizer Employment: Pfizer Stock ownership: Pfizer; M. O'Gorman, S. Nidadavolu and S. Phillips: Employment: Pfizer; M. Kosa: Employment: Contractor at Pfizer (Clinical Assay Group) through Atrium Services. D.D. Wang: Employment: Pfizer Stock ownership: Pfizer.

Steady-State Pharmacokinetics of Lopinavir Plus Ritonavir When Administered Under Different Meal Conditions in HIV-Infected Ugandan Adults

We investigated the effect of food on the steady-state pharmacokinetics of lopinavir and ritonavir in 12 Ugandan patients receiving lopinavir coformulated with ritonavir (LPV/r) tablets using a crossover design. Intensive pharmacokinetic sampling was performed 7 days apart after LPV/r dosing under moderate fat, high fat, and fasted meal conditions. Lopinavir and ritonavir concentrations were determined by liquid chromatography and tandem mass spectrometry. Compared with the fasted state, a high fat meal reduced lopinavir and ritonavir area under the curve by 14% and 29%, respectively. With a moderate fat meal, area under the curve for both drugs was similar to the fasted state.

Strawberry anthocyanin and its association with postprandial inflammation and insulin

The present study investigates the effect of strawberry antioxidants in beverage form on meal-induced postprandial inflammatory and insulin responses in human subjects. Overweight adults (n 24) consumed a high-carbohydrate, moderate-fat meal (HCFM) accompanied by either a strawberry or a placebo beverage in a cross-over design. Postprandial changes in plasma anthocyanins, their metabolites, insulin, glucose and inflammatory markers were assessed for 6h. The postprandial concentrations of pelargonidin sulfate and pelargonidin-3-O-glucoside were significantly increased when the strawberry beverage was consumed concurrently with the HCFM compared with the placebo beverage (P<0·001). The strawberry beverage significantly attenuated the postprandial inflammatory response as measured by high-sensitivity C-reactive protein and IL-6 (P<0·05) induced by the HCFM. It was also associated with a reduction in postprandial insulin response (P<0·05). Collectively, these data provide evidence for favourable effects of strawberry antioxidants on postprandial inflammation and insulin sensitivity.

Pro-atherogenic postprandial profile: Meal-induced changes of lipoprotein sub-fractions and inflammation markers in obese boys

Background and aimsObesity is a pro-atherogenic condition and postprandial lipoprotein profile and circulating cytokines changes may contribute to promote the process. The aim of this study is to investigate postprandial metabolic response, lipoprotein oxidation and circulating cytokine levels, after the ingestion of two different meals with different fat/carbohydrate ratio. Methods and resultsTen prepubertal obese boys consumed two meals with the same energy and protein content but with a different carbohydrate to fat ratio: 1) moderate fat (MF): 61% carbohydrate, 27% fat; 2) high fat (HF): 37% carbohydrate, 52% fat. The AUC of glucose and insulin were significantly (p < 0.05) lower after the HF meal. HF meal was followed by a significant decrease in the cholesterol carried in the HDL fractions, while cholesterol in the small, dense LDL and in the VLDL particles increased, as compared to baseline (p < 0.05 for all). No differences were found in the cholesterol distribution after the MF meal. Moreover, HDL-C concentration was lower (p < 0.05) at 300 min after HF vs. MF meal. Oxidized LDL (ox-LDL) concentration increased after the HF meal but not after the MF meal [9.3(2.2) vs 1.8(2.2)% from baseline, P < 0.02)]. A positive association (r > 0.3, P < 0.05) was observed between the densest LDL particles and the ox-LDL plasma levels. A reduction of IL-6 was found at 120 min after the MF [−23.3(5.5) vs −8.4(3.8)% from baseline, P < 0.05)] compared with the HF meal. ConclusionA simple change of ≈25% of energy load from fat to carbohydrate in a meal significantly improves postprandial pro-atherogenic factors in obese boys.

Is the effect of prior exercise on postprandial lipaemia the same for a moderate-fat meal as it is for a high-fat meal?

Moderate-intensity exercise can lower the TAG response to a high-fat meal; however, the British diet is moderate in fat, and no study to date has compared the effect of such exercise on responses to high-fat and moderate-fat meals. The present work investigated the effect of brisk walking performed 13h before intake of both high-fat and moderate-fat meals on postprandial plasma TAG concentrations. Eight inactive, overweight men completed four separate 2d trials, i.e. rest (Con) or a 90-min treadmill walk (Ex) on the evening of day 1, followed by the ingestion of a moderate-fat (Mod) or high-fat (High) meal on the morning of day 2. High-fat meals contained 66% of total energy as fat, while the percentage was 35% for moderate-fat meals; both the meals were, however, isoenergetic. On day 2, venous blood was sampled in the fasted state, 30 and 60min after ingesting the test meal and then hourly until 6h post-meal. Exercise reduced plasma TAG concentrations significantly (P<0·001), with no exercise×meal interaction (P=0·459). Walking reduced the total TAG response to a high-fat meal by 29% (relative to High Con); the same bout of exercise performed before ingesting a moderate-fat meal lowered total TAG by 26% (compared with Mod Con). The ability of a single moderate-intensity aerobic exercise bout to lower postprandial TAG concentrations is just as great, in percentage terms, when the test meal ingested is of a moderate rather than a high fat content.

A High‐fat vs. a Moderate‐fat Meal in Obese Boys: Nutrient Balance, Appetite, and Gastrointestinal Hormone Changes

Meal composition is a contributing factor to fat gain. In this study, we investigated the relationship between postprandial nutrient balance, satiety, and hormone changes induced by a high-fat meal vs. a moderate-fat meal. Ten prepubertal obese boys (BMI z-score range: 1.3-3.0) were recruited. Two meals (energy: 590 kcal) were compared: (i) high-fat (HF) meal: 12% protein, 52% fat, 36% carbohydrates; (ii) moderate-fat (MF) meal: 12% protein, 27% fat, 61% carbohydrates. Pre- and postprandial (5 h) substrate oxidation (indirect calorimetry), appetite (visual analogue scale), biochemical parameters and gastrointestinal hormone concentrations were measured. Carbohydrate balance was significantly (P < 0.001) lower (31.3 (5.7) g/5 h vs. 66.9 (5.9) g/5 h) and fat balance was significantly (P < 0.001) higher (11.5 (3.3) g/5 h vs. -0.7 (2.9) g/5 h) after HF than MF meal. Appetite (area under the curve (AUC)) was significantly reduced after an MF than an HF meal (494 (55) cm.300 min vs. 595 (57) cm.300 min, P < 0.05). Postprandial triglyceride concentration (AUC) was significantly (P < 0.05) higher after an HF than an MF meal: 141.1 (30.3) mmol.300 min/l vs. 79.3 (23.8) mmol.300 min/l, respectively. Peptide YY (PYY), cholecystokinin (CCK), and ghrelin concentrations (AUC) were not significantly different after an HF and MF meal. Glucagon-like peptide-1 (GLP-1) was significantly (P < 0.05) higher after an HF than after an MF meal (72.3 (9.8) ng/ml vs. 22.7 (7.6) ng/ml, respectively), but it did not affect subjective appetite. In conclusion, an MF meal induced a better postprandial metabolic nutrient balance, triglyceride levels, and appetite suppression than an HF meal. Gastrointestinal hormones were not related to clinically assessed hunger suppression after both meals.

The effect of food with varying fat content on the clinical pharmacokinetics of gabapentin after oral administration of gabapentin enacarbil

Gabapentin enacarbil, an actively transported prodrug of gabapentin, provides sustained and dose-proportional exposure to gabapentin. To evaluate the effect of food of varying fat content on the pharmacokinetics and tolerability of gabapentin enacarbil. METHODS, MATERIALS AND SUBJECTS: A randomized, open-label, crossover study of 1,200 mg gabapentin enacarbil was conducted in 12 healthy adults, under four conditions: fasted, or following low-fat (200 - 300 kcal total, approximately 6% from fat), moderate-fat (500 - 600 kcal total, approximately 30% from fat) or high-fat meals (1,000 kcal total, approximately 50% from fat), separated by a washout period of >or= 5 days. Ten subjects completed treatment under all four conditions. Data from all subjects were used for pharmacokinetic and safety analyses unless stated otherwise. Mean (standard deviation) bioavailability (based on urinary recovery) of gabapentin from gabapentin enacarbil was 42.0 (6.1)% (fasted), 64.3 (13.2)% (low-fat meal), 64.9 (16.9)% (moderate-fat meal), and 76.1 (14.4)% (high-fat meal). Gabapentin exposures (AUC(inf)) in fed conditions were 23% (low-fat meal), 31% (moderate-fat meal), and 40% (high-fat meal) greater than the exposure under fasted condition. Fed conditions did not significantly delay median t(max), but a trend for delayed gabapentin enacarbil absorption was seen in t(max) ranges following moderate- and high-fat meals compared with the fasted state or low-fat meal. The most commonly reported treatment-emergent adverse events (TEAEs) were dizziness (4 subjects), balance disorder (4 subjects) and somnolence (3 subjects). All TEAEs were rated as mild in intensity. Administration of gabapentin enacarbil with food enhanced gabapentin exposure compared with fasted conditions, regardless of the fat or caloric content, and gabapentin enacarbil was generally well tolerated.

Postprandial effects of supplementing a moderate-fat meal with long-chain n-3 PUFA on measures of arterial stiffness

Postprandial effects of supplementing a moderate-fat meal with long-chain <i>n</i>-3 PUFA on measures of arterial stiffness

Minimal Pharmacokinetic Interaction between the Human Immunodeficiency Virus Nonnucleoside Reverse Transcriptase Inhibitor Etravirine and the Integrase Inhibitor Raltegravir in Healthy Subjects

Etravirine, a next-generation nonnucleoside reverse transcriptase inhibitor, and raltegravir, an integrase strand transfer inhibitor, have separately demonstrated potent activity in treatment-experienced, human immunodeficiency virus (HIV)-infected patients. An open-label, sequential, three-period study with healthy, HIV-seronegative subjects was conducted to assess the two-way interaction between etravirine and raltegravir for potential coadministration to HIV-infected patients. In period 1, 19 subjects were administered 400 mg raltegravir every 12 h (q12 h) for 4 days, followed by a 4-day washout; in period 2, subjects were administered 200 mg etravirine q12 h for 8 days; and in period 3, subjects were coadministered 400 mg raltegravir and 200 mg etravirine q12 h for 4 days. There was no washout between periods 2 and 3. Doses were administered with a moderate-fat meal. Etravirine had only modest effects on the pharmacokinetics of raltegravir, while raltegravir had no clinically meaningful effect on the pharmacokinetics of etravirine. For raltegravir coadministered with etravirine relative to raltegravir alone, the geometric mean ratio (GMR) and 90% confidence interval (CI) were 0.90 and 0.68 to 1.18, respectively, for the area under the concentration curve from 0 to 12 h (AUC(0-12)), 0.89 and 0.68 to 1.15, respectively, for the maximum concentration of drug in serum (C(max)), and 0.66 and 0.34 to 1.26, respectively, for the trough drug concentration (C(12)); the GMR (90% CI) for etravirine coadministered with raltegravir relative to etravirine alone was 1.10 (1.03, 1.16) for AUC(0-12), 1.04 (0.97, 1.12) for C(max), and 1.17 (1.10, 1.26) for C(12). All drug-related adverse clinical experiences were mild and generally transient in nature. No grade 3 or 4 adverse experiences or discontinuations due to adverse experiences occurred. Coadministration of etravirine and raltegravir was generally well tolerated; the data suggest that no dose adjustment for either drug is necessary.