Low-fat Meal Research Articles

Evidence that meal fat content does not impact hemodynamic reactivity to or recovery from repeated mental stress tasks.

The magnitude (reactivity) and duration (recovery) of hemodynamic stress responses are predictive of cardiovascular risk, and fat intake has been shown to enhance hemodynamic reactivity to psychological stress tasks. The objective of this study was to determine the impact of a high-fat meal (HFM) on the magnitude and stability of hemodynamic stress reactivity and recovery. This was assessed by: (i) the peak changes from baseline to during stress for heart rate (HR); mean, systolic, and diastolic blood pressure; cardiac output; and total peripheral resistance; and (ii) the residual arousal in hemodynamic parameters at 2 points post-stress ("early" and "late" recovery). On different days, 10 healthy males (aged 23.2 ± 3.3 years) consumed either a HFM (54 g fat) or low-fat meal (LFM; 0 g fat) (∼1000 calories each), followed by 4 hourly 10-min stress tasks (mental arithmetic and speech tasks). Pre-stress (baseline) parameters did not differ between HFM and LFM conditions (all P > 0.05). Plasma triglycerides were greater following the HFM versus the LFM (P = 0.023). No reactivity or recovery parameters differed between meals (all P > 0.05). Stress reactivity and recovery parameters were stable over the 4 stress tasks (main effects of time, all P > 0.05), with the exception of HR (P < 0.05). Contrary to previous reports, meal fat content did not impact hemodynamic reactivity to laboratory stressors. These data also provide the first evidence that meal fat content does not impact hemodynamic recovery from repeated mental stress tasks.

Novel insulin delivery profiles for mixed meals for sensor-augmented pump and closed-loop artificial pancreas therapy for type 1 diabetes mellitus.

Maintaining euglycemia for people with type 1 diabetes is highly challenging, and variations in glucose absorption rates with meal composition require meal type specific insulin delivery profiles for optimal blood glucose control. Traditional basal/bolus therapy is not fully optimized for meals of varied fat contents. Thus, regimens for low- and high-fat meals were developed to improve current insulin pump therapy. Simulations of meals with varied fat content demonstrably replicated published data. Subsequently, an insulin profile library with optimized delivery regimens under open and closed loop for various meal compositions was constructed using particle swarm optimization. Calculations showed that the optimal basal bolus insulin profiles for low-fat meals comprise a normal bolus or a short wave. The preferred delivery for high-fat meals is typically biphasic, but can extend to multiple phases depending on meal characteristics. Results also revealed that patients that are highly sensitive to insulin could benefit from biphasic deliveries. Preliminary investigations of the optimal closed-loop regimens also display bi- or multiphasic patterns for high-fat meals. The novel insulin delivery profiles present new waveforms that provide better control of postprandial glucose excursions than existing schemes. Furthermore, the proposed novel regimens are also more or similarly robust to uncertainties in meal parameter estimates, with the closed-loop schemes demonstrating superior performance and robustness.

Omega-3 fatty Acids in cardiovascular disease – An uphill battle

In cardiology, results of recent large intervention trials with eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA) supplements were neutral. In contrast, in epidemiologic studies, an inverse relation between clinical events and intake of EPA+DHA was found which was steeper for higher levels of EPA+DHA. A standardized way of determining levels is the Omega-3 Index, which is the percentage of EPA+DHA of a total of 26 fatty acids measured in erythrocytes. According to current criteria, a low Omega-3 Index is a cardiovascular risk factor. What can explain this contradiction? Trial participants were recruited irrespective of their baseline status in EPA+DHA - an important predictor of events. Levels of EPA+DHA have a statistically normal distribution; together with the large inter-individual variability of levels' responding to increased intake, this created a large overlap of EPA+DHA levels between intervention and control groups. Moreover, trial participants were advised to take EPA+DHA supplements with breakfast, frequently a low fat meal, resulting in poor bioavailability. As a result, there is an urgent need for new intervention trials in cardiology, for which participants with a low baseline omega-3 index are recruited, and then treated with individually tailored doses of EPA+DHA to a prespecified target range.

A phase I study of oral ixabepilone in patients with advanced solid tumors

Intravenous infusion of ixabepilone is Food and Drug Administration-approved for treatment of patients with metastatic breast cancer. The aim of this study was to establish the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), safety, and pharmacokinetics (PK) of a novel oral formulation of ixabepilone in patients with advanced solid tumors. Forty-four patients received one of six daily doses of oral ixabepilone (5, 10, 15, 20, 25, or 30 mg) on days 1-5 of a 21-day cycle. PK parameters were evaluated in cycle 1 for all treated patients and in cycle 1 and cycle 2 for patients participating in assessments of food and gastric pH effects. The most common DLTs (reported in at least one patient) were neutropenia, neutropenic fever, diarrhea, ileus, and hypokalemia. The MTD of oral ixabepilone was 25 mg. Plasma concentrations of ixabepilone showed high variability; coefficients of variation for the area under the curve and the peak plasma concentration ranged from 61 to 131 % and from 17 to 172 %, respectively. The mean half-life of ixabepilone calculated after day 5 of cycle 1 ranged from 24 to 47 h. Ixabepilone exposure was higher when administered with a low-fat meal compared with the fasted state, and when administered 2 h after the histamine H2 receptor antagonist famotidine. The MTD of oral ixabepilone when administered once daily for five consecutive days every 21 days was 25 mg. Ixabepilone exposure was highly variable; therefore, safety and efficacy of this novel oral formulation might not be reliably predicted.

(427) Single-dose pharmacokinetics, bioavailability, and safety of 2 tablets of MNK-155, an extended-release hydrocodone bitartrate and acetaminophen combination analgesic (HB/APAP ER), under fed and fasted conditions

MNK-155 is a bilayer, immediate-release (IR)/extended-release (ER) tablet formulation of hydrocodone bitartrate 7.5 mg/acetaminophen 325 mg (HB/APAP ER), utilizing gastroretentive drug delivery technology. MNK-155 is currently under development for the management of moderate to moderately severe acute pain. The purpose of this study was to evaluate the effect of fed (high- and low-fat meals) versus fasted conditions on single-dose pharmacokinetics and bioavailability following administration of MNK-155 (HB 7.5 mg/APAP 325 mg) given as 2 tablets.

The combined influence of fat consumption and repeated mental stress on brachial artery flow‐mediated dilatation: a preliminary study

Experienced separately, both acute mental stress and high-fat meal consumption can transiently impair endothelial function, and the purpose of the present study was to investigate their combined impact. On four separate days, 10 healthy men (23 years old) underwent brachial artery flow-mediated dilatation (FMD) tests, before and hourly for 4 h post-consumption of a high-fat (HFM; 54 g fat) or low-fat meal (LFM; 0 g fat; each meal ∼ 1000 calories), with hourly mental stress (mental arithmetic, speech) or control (counting) tasks (conditions HFM+S, LFM+S, HFM and LFM). Data are presented as means ± SD. Plasma triglycerides increased and remained elevated after the high-fat but not the low-fat meal (P = 0.004) and were not affected by mental stress (P = 0.329). Indices of stress reactivity increased during mental stress tasks (mean arterial pressure, ∼ 20 mmHg; heart rate, ∼ 22 beats min(-1); salivary cortisol, ∼ 2.37 nmol l(-1); and plasma noradrenaline, ∼ 0.17 ng ml(-1)) and were not influenced by meal (P > 0.05). There was no effect of the type of meal on FMD (P = 0.562); however, FMD was 4.5 ± 0.5% in the control conditions and 5.8 ± 0.6% in the mental stress conditions (P = 0.087), and this difference was significant when normalized for the shear stress stimulus (FMD/area under the curve of shear stress, P = 0.045). Overall, these preliminary data suggest that postprandial FMD was augmented with mental stress irrespective of meal type. These results are contrary to previous reports of impaired endothelial function after mental stress or fat consumption independently and highlight the need to further investigate the mechanisms underlying the interactions between these factors.

Population pharmacokinetic assessment of the effect of food on piperaquine bioavailability in patients with uncomplicated malaria.

Previously published literature reports various impacts of food on the oral bioavailability of piperaquine. The aim of this study was to use a population modeling approach to investigate the impact of concomitant intake of a small amount of food on piperaquine pharmacokinetics. This was an open, randomized comparison of piperaquine pharmacokinetics when administered as a fixed oral formulation once daily for 3 days with (n = 15) and without (n = 15) concomitant food to patients with uncomplicated Plasmodium falciparum malaria in Thailand. Nonlinear mixed-effects modeling was used to characterize the pharmacokinetics of piperaquine and the influence of concomitant food intake. A modified Monte Carlo mapped power approach was applied to evaluate the relationship between statistical power and various degrees of covariate effect sizes of the given study design. Piperaquine population pharmacokinetics were described well in fasting and fed patients by a three-compartment distribution model with flexible absorption. The final model showed a 25% increase in relative bioavailability per dose occasion during recovery from malaria but demonstrated no clinical impact of concomitant intake of a low-fat meal. Body weight and age were both significant covariates in the final model. The novel power approach concluded that the study was adequately powered to detect a food effect of at least 35%. This modified Monte Carlo mapped power approach may be a useful tool for evaluating the power to detect true covariate effects in mixed-effects modeling and a given study design. A small amount of food does not affect piperaquine absorption significantly in acute malaria.

Effects of low-fat and high-fat meals on steady-state pharmacokinetics of lapatinib in patients with advanced solid tumours

To quantify the effect of food on the systemic exposure of lapatinib at steady state when administered 1 h before and after meals, and to observe the safety and tolerability of lapatinib under these conditions in patients with advanced solid tumours. This was a three-treatment, randomised, three-sequence cross-over study. Lapatinib was administered 1 h after a low- [B] or a high-fat [C] meal and systemic exposure was compared with that obtained following administration 1 h before a low-fat meal [A]. In total, 25 patients were included, of whom 12 were evaluable for the pharmacokinetic analysis. Both low-fat and high-fat meals affected lapatinib exposure. Lapatinib AUC0-24 increased following lapatinib administration 1 h after a low-fat meal by 1.80-fold (90 % CI: 1.37-2.37) and after a high-fat meal by 2.61-fold (90 % CI: 1.98-3.43). Lapatinib Cmax increased following lapatinib administration 1 h after a low-fat meal by 1.90-fold (90 % CI: 1.49-2.43) and after a high-fat meal by 2.66-fold (90 % CI: 2.08-3.41). The most commonly occurring treatment-related toxicity was diarrhoea (8/25, 32 % CTCAE grade 1 and 2/25, 8 % grade 2) and one treatment-related grade ≥ 3 event occurred (fatigue grade 3, 4 %). Both low-fat and high-fat food consumed 1 h before lapatinib administration increased lapatinib systemic exposure compared with lapatinib administration 1 h before a low-fat meal. In order to administer lapatinib in a fasted state, it is advised to administer the drug 1 h before a meal.

Both Dietary Protein and Fat Increase Postprandial Glucose Excursions in Children With Type 1 Diabetes, and the Effect Is Additive

OBJECTIVETo determine the separate and combined effects of high-protein (HP) and high-fat (HF) meals, with the same carbohydrate content, on postprandial glycemia in children using intensive insulin therapy (IIT).RESEARCH DESIGN AND METHODSThirty-three subjects aged 8–17 years were given 4 test breakfasts with the same carbohydrate amount but varying protein and fat quantities: low fat (LF)/low protein (LP), LF/HP, HF/LP, and HF/HP. LF and HF meals contained 4 g and 35 g fat. LP and HP meals contained 5 g and 40 g protein. An individually standardized insulin dose was given for each meal. Postprandial glycemia was assessed by 5-h continuous glucose monitoring.RESULTSCompared with the LF/LP meal, mean glucose excursions were greater from 180 min after the LF/HP meal (2.4 mmol/L [95% CI 1.1–3.7] vs. 0.5 mmol/L [−0.8 to 1.8]; P = 0.02) and from 210 min after the HF/LP meal (1.8 mmol/L [0.3–3.2] vs. −0.5 mmol/L [−1.9 to 0.8]; P = 0.01). The HF/HP meal resulted in higher glucose excursions from 180 min to 300 min (P < 0.04) compared with all other meals. There was a reduction in the risk of hypoglycemia after the HP meals (odds ratio 0.16 [95% CI 0.06–0.41]; P < 0.001).CONCLUSIONSMeals high in protein or fat increase glucose excursions in youth using IIT from 3 h to 5 h postmeal. Protein and fat have an additive impact on the delayed postprandial glycemic rise. Protein had a protective effect on the development of hypoglycemia.

Olive oil aroma extract modulates cerebral blood flow in gustatory brain areas in humans

Low- and high-fat meals affect homeostatic and gustatory brain areas differentially. In a previous study, we showed that a high-fat meal decreased cerebral blood flow (CBF) in homeostatic brain areas (hypothalamus), whereas a low-fat meal increased CBF in gustatory regions (anterior insula). The aim of this study was to investigate the long-lasting effect of fat-free flavor-active compounds of olive oil on the brain and whether those aroma components can trigger fat-associated brain responses in homeostatic and gustatory regions. Eleven healthy male subjects participated in a functional magnetic resonance imaging study. On 2 measurement days, subjects consumed single-blinded a plain low-fat yogurt or low-fat yogurt mixed with a fat-free aroma extract of olive oil. Resting CBF was measured before and 30 and 120 min after yogurt intake. Hunger was rated before each measurement. Blood samples were collected at 6 time points. The extract-containing yogurt elicited higher CBF in the frontal operculum 30 and 120 min after a meal. Furthermore, the activity change in the anterior insula after 30 min correlated positively with the glucose change in the extract condition only. No effects were observed in the hypothalamus. The anterior insula and the frontal operculum are regarded as the primary taste cortex. Modulation of the frontal operculum by the yogurt containing the olive oil extract suggests that it might be possible to simulate fat-triggered sensations in the brain on the gustatory level, possibly by ingredients the body implicitly associates with fat. This trial was registered at clinicaltrials.gov as NCT01716286.

Effect of meal and antisecretory agents on the pharmacokinetics of danoprevir/ritonavir in healthy volunteers

To evaluate the effect of a low- and high-fat meal and co-administration of ranitidine or omeprazole on the pharmacokinetics of ritonavir-boosted danoprevir (DNVr). In this randomised, open-label, cross-over study, healthy subjects received a single dose of DNVr. In group 1, DNVr was administered while fasting or with a low-fat or high-fat meal. In group 2, DNVr was administered alone or with ranitidine 150 mg (single dose) or omeprazole 40 mg (multiple doses). Group 1 (n = 16): relative to fasting conditions, food slightly prolonged absorption but did not alter the extent of absorption. DNV area under the plasma concentration-time curve extrapolated to infinity (AUC0-∞), maximum plasma concentration (C(max)), and plasma concentration 12 h after administration (C12h) geometric mean ratios (GMR%) (90% confidence interval (CI)) with a low-fat meal were 92.3 (80.2-106), 61.8 (51.0-74.9) and 95.2 (80.9-112), versus fasting conditions, and with a high-fat meal 99.5 (86.4-115), 58.9 (48.5-71.6) and 101 (86.0-119). Group 2 (n = 13): ranitidine or omeprazole had no clinically significant effect on DNV pharmacokinetics. DNV AUC0-∞, Cmax and C12h GMR% (90% CI) with ranitidine: 81.9 (68.3-98.1), 104 (86.9-123) and 87.5 (69.3-111), and with omeprazole: 83.0 (67.4-102), 92.7 (70.6-122) and 93.3 (65.6-133). The absence of clinically relevant effects of food, ranitidine or omeprazole on DNVr pharmacokinetics suggests that DNVr can be administered without regard to meals and in combination with H2 antagonists or proton pump inhibitors.

Effects of food on the pharmacokinetics of ponatinib in healthy subjects

What is known and objectivePonatinib is a potent oral tyrosine kinase inhibitor with activity against BCR-ABL, the primary driver of chronic myeloid leukaemia and Philadelphia chromosome–positive acute lymphoblastic leukaemia. This single-centre, single-dose, randomized, open-label, three-period crossover study evaluated the pharmacokinetics and bioavailability of a single oral dose of ponatinib (45-mg tablet) under fasting conditions and following consumption of high- and low-fat meals by healthy subjects.MethodsSubjects were randomly assigned to one of the six possible treatment sequences, each evaluating three ponatinib 45-mg treatments: administered under fasting conditions; administered after a high-fat meal; or administered after a standardized low-fat meal. The high-fat meal derived approximately 50% of its total caloric content from fat, with approximately 150, 250 and 500–600 calories derived from protein, carbohydrates and fat, respectively (total of approximately 900–1000 calories). The standardized low-fat meal derived no more than 20% of total caloric content from fat, with approximately 56, 428 and 63 calories derived from protein, carbohydrates and fat, respectively (total of approximately 547 calories). During each of the three treatment periods, blood samples were collected predose and at 13 time points over the 96-h post-dose interval. Plasma concentrations of ponatinib were measured by liquid chromatography/tandem mass spectrometry. Mixed-model analyses of variance (anova) were performed on natural log-transformed PK parameters Cmax and AUC0-∞.Results and discussionGeometric mean maximum plasma concentration (Cmax) values for the fasted, low-fat and high-fat regimens were 54·7, 51·6 and 51·5 ng/mL, respectively. Geometric mean area under the concentration–time curve from time zero to infinity (AUC0-∞) values for the fasted, low-fat and high-fat regimens were 1273, 1244 and 1392 h × ng/mL, respectively. All limits of the 90% CIs of the estimated geometric mean ratios for Cmax and all AUC comparisons fell within the 80%–125% margins. These results indicate that consumption of a high- or low-fat meal within 30 min prior to administration of ponatinib had no effect on the single-dose pharmacokinetics of ponatinib.What is new and conclusionFood does not affect the single-dose pharmacokinetics of ponatinib. These data demonstrate that ponatinib may be administered with or without food.

Evaluation of Food Effect on Pharmacokinetics of Vismodegib in Advanced Solid Tumor Patients

Vismodegib, an orally bioavailable small-molecule Smoothened inhibitor, is approved for treatment of advanced basal cell carcinoma (BCC). We conducted a pharmacokinetic study of vismodegib in patients with advanced solid tumors to explore the effects of food on drug exposure. In part I, patients were randomized to fasting overnight (FO), a high fat meal (HF), or a low fat meal (LF) before a single dose of vismodegib 150 mg. Plasma concentrations of vismodegib were determined by a validated liquid chromatography-tandem mass spectrometry assay. Primary endpoints were C(max) and area under the curve (AUC(0-168)). In part II, patients randomized to FO or HF in part I took vismodegib 150 mg daily after fasting; those randomized to LF took it after a meal. Primary endpoints after two weeks were C(max) and AUC(0-24). Sixty (22 FO, 20 HF, 18 LF) and 52 (25 fasting, 27 fed) patients were evaluable for primary endpoints in parts I and II, respectively. Mean C(max) and AUC(0-168) after a single dose were higher in HF than FO patients [ratios of geometric means (90% CI) = 1.75 (1.30, 2.34) and 1.74 (1.25, 2.42), respectively]. There were no significant differences in C(max) or AUC(0-24) between fasting and fed groups after daily dosing. The frequencies of drug-related toxicities were similar in both groups. A HF meal increases plasma exposure to a single dose of vismodegib, but there are no pharmacokinetic or safety differences between fasting and fed groups at steady-state. Vismodegib may be taken with or without food for daily dosing.

Odanacatib, a selective cathepsin K inhibitor to treat osteoporosis: safety, tolerability, pharmacokinetics and pharmacodynamics – results from single oral dose studies in healthy volunteers

To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of odanacatib (ODN), a cathepsin K inhibitor, in humans. Two double-blind, randomized, placebo-controlled, single oral dose studies were performed with ODN (2-600 mg) in 44 healthy volunteers (36 men and eight postmenopausal women). Adverse experiences (AEs) with single doses of ODN were transient and mild to moderate, with the exception of one severe AE of gastroenteritis. Headache was the most frequent AE. After absorption of ODN (initial peak concentrations 4-6 h postdose), plasma concentrations exhibited a monophasic decline, with an apparent terminal half-life of ∼40-80 h. The area under the curve0-24 hours (AUC(0-24 h)), concentration at 24 hours (C(24 h)) and maximum concentration (C(max,overal)) increased in a less than dose-proportional manner from 2 to 600 mg. Administration of ODN with a high-fat meal led to ∼100% increases in AUC(0-24 h), C(max,day1), C(max,overall) and C(24 h) relative to the fasted state, while administration with a low-fat meal led to a ∼30% increase in those parameters. Reduction of biomarkers of bone resorption, the C- and N-telopeptides of cross-links of type I collagen, (CTx and NTx, respectively), was noted at 24 h for doses ≥5 mg and at 168 h postdose for ≥10 mg. In postmenopausal women administered 50 mg ODN, reductions in serum CTx of -66% and urine NTx/creatinine (uNTx/Cr) of -51% relative to placebo were observed at 24 h. At 168 h, reductions in serum CTx (-70%) and uNTx/Cr (-78%) were observed relative to baseline. Pharmacokinetic/pharmacodynamic modeling characterized the ODN concentration/uNTx/Cr relation, with a modeled EC50 value of 43.8 nM and ∼80% maximal reduction. Odanacatib was well tolerated and has a pharmacokinetic and pharmacodynamic profile suitable for once weekly dosing.

Abstract P065: Changes in Lysophosphatidic Acids and Lysophosphatidylcholines with Fish Oil Consumption wnd their Correlates with Platelet Aggregation

Background: Lysophosphatidic acids (LPA) and lysophosphatidylcholines (LPC) are phospholipids, each containing one fatty acid, and have effects on atherogenic mechanisms. No data currently exist regarding the effects of aspirin and fish oil (FO) ingestion on these potent lipid mediators in humans with diabetes mellitus (DM). We hypothesized that ingestion of these agents alter LPA and LPC concentrations and that these effects correlate with platelet function. Methods: Using a sequential clinical trial approach, 30 adults with type 2 DM were treated with 81 mg/d of aspirin for 7 days, then with a 28-day regimen of FO (4g/day containing 1600 mg EPA and 800 mg DHA) after which they restarted 81 mg/d of aspirin for another 7 days. After the ingestion of a standard low-fat meal, phlebotomies were performed at baseline, 4 hours and 7 days after the ingestion of aspirin alone, 28 days after FO alone, and 4 hours and 7 days after aspirin and FO ingestion together. Eleven LPCs and 11 LPAs were analyzed using a modified Bligh and Dyer extract of plasma and infusion into an ABI QTrap 2000 via an Advion Nanomate robotic device. Platelet function was measured using whole blood aggregometry and via assays. Changes in concentrations of LPAs and LPCs compared to baseline were assessed using mixed models accounting for statin use, blood draw, BMI, presence of HTN, gender, race, smoking status, alcohol use, fish consumption, and education. Pearson’s correlations (r) were calculated for comparing LPAs and LPCs with platelet function. P-values less than 0.05 were considered statistically significant. Results: FO ingestion reduced concentrations of all 11 LPAs, including EPA (20:5n3) and DHA (22:6n3) species. EPA and DHA LPC concentrations significantly increased by FO alone and in combination with aspirin. Stearic acid (18:0) and alpha-linolenic acid (18:3n3) LPCs were significantly reduced by FO combined with aspirin after 4 hours and 7 days. Changes in 18:0 and oleic acid (18:1) LPAs after FO moderately correlated with the platelet aggregation agonist collagen (r=0.41, p=0.02 and r=0.39, p=0.03, respectively) whereas changes in EPA and DHA LPCs did not correlate with platelet aggregation or function. However, EPA changes with FO and aspirin moderately correlated with the platelet aggregation agonist ADP after 4 hours (r=0.46, p=0.01) but not 7 days (r=0.04, p=0.83). Conclusions: The ingestion of FO with and without aspirin has significant effects on plasma lysophospholipid levels in subjects with DM. Given the pleiotropic roles of lysophospholipids in platelet function and atherogenesis, these results suggest that the formation of potent lipid mediators- derived from ingested fats- may be more important than the simple ingestion of the fats. Our results should be used to generate new hypotheses applying different phospholipids in the evaluation of atherogenic mechanisms.

Effects of Food Intake on the Pharmacokinetic Properties of Mirabegron Oral Controlled-Absorption System: A Single-Dose, Randomized, Crossover Study in Healthy Adults

BackgroundMirabegron is a β3-adrenoceptor agonist used for the treatment of overactive bladder. Mirabegron is formulated as an extended-release tablet using oral controlled-absorption system (OCAS) technology. ObjectiveThis study was designed to assess the effects of food on the pharmacokinetic properties of mirabegron OCAS in accordance with regulatory requirements to support dosing recommendations. MethodsIn this single-dose, randomized, open-label, 3-period, parallel-dose-group, crossover study, mirabegron OCAS 50 or 100 mg was administered orally to healthy adult subjects in the fasted state or after a high- or low-fat breakfast. Dose administrations were separated by a washout period of at least 10 days. Blood samples were drawn up to 96 hours after dosing, and plasma concentrations of mirabegron were analyzed by LC/MS-MS. PK properties were determined using noncompartmental methods. Primary end points for the assessment of food effects were Cmax and AUC0–∞. For tolerability assessment, adverse events (AEs) were monitored using investigators' questionnaires and subjects' spontaneous reports, vital sign measurements, hematology, clinical chemistry, and ECG. ResultsThirty-eight subjects (male, 50%; mean age, 32.1 years; mean weight, 77.3 kg; race, 76.3% white) were enrolled in the 50-mg dose group and 38 subjects (male, 52.6%; mean age, 30.9 years; mean weight, 74.5 kg; race, 63.2% white) in the 100-mg dose group. With either fed condition or dose, the 90% CIs for the fed/fasted ratios of both Cmax and AUC0–∞ of mirabegron fell below the predetermined range for bioequivalence (80.0%–125.0%), suggesting that food had no effect on exposure to mirabegron OCAS. With the 50-mg dose, mirabegron Cmax was reduced by 45% with a high-fat breakfast compared with fasted conditions (geometric mean ratio [GMR], 54.8% [90% CI, 43.7%–68.6%]) and AUC0–∞, by 17% (GMR, 83.2% [90% CI, 74.2%–93.4%]). With the 100-mg dose, mirabegron Cmax and AUC0–∞ were reduced by 39% (GMR, 61.3% [90% CI, 47.8%–78.7%]) and 18% (82.4% [72.6%–93.5%]), respectively, after a high-fat breakfast. With the 50-mg dose, mirabegron Cmax was decreased by 75% (GMR, 25.0% [90% CI, 19.9%–31.3%]) and AUC0–∞ by 51% (48.7% [43.3%–54.7%]) after a low-fat breakfast. Corresponding reductions with the 100-mg dose were 64% (GMR, 36.3% [90% CI, 28.2%–46.8%]) for Cmax and 47% (GMR, 53.2% [90% CI, 46.8%–60.5%]) for AUC0–∞. The fed/fasted ratios for mirabegron Cmax and AUC0–∞ were in general independent of dose or sex. Food delayed Tmax compared with the fasted state, with similar increases with the high- and low-fat meals (0.9 hours with 50 mg and 1.5–2.0 hours with 100 mg). Mirabegron was generally well tolerated, with no apparent difference in AE frequency between the fasted and fed states. ConclusionsMirabegron OCAS tablets exhibited a decrease in mirabegron plasma exposure with food that was independent of dose (50 or 100 mg) or gender but dependent on meal composition. A greater reduction in mirabegron exposure was observed after a low-fat breakfast compared with after a high-fat breakfast. Based on findings from previous studies, the effects of food observed in this study do not warrant dose adjustment in clinical practice. ClinicalTrials.gov identifier: NCT00939757.

Meal conditions affect the absorption of supplemental vitamin D3 but not the plasma 25-hydroxyvitamin D response to supplementation

It is sometimes assumed that dietary fat is required for vitamin D absorption, although the impact of different amounts of dietary fat on vitamin D absorption is not established. This study was conducted to determine whether the presence of a meal and the fat content of the meal influences vitamin D absorption or the 25-hydroxyvitamin D [25(OH)D] response to supplemental vitamin D3 . Based on earlier studies in rats we postulated that absorption would be greatest in the low-fat meal group. Sixty-two healthy older men and women were randomly assigned to one of three meal groups: no meal, high-fat meal, or low-fat meal; each was given a monthly 50,000 IU vitamin D3 supplement with the test breakfast meal (or after a fast for the no-meal group) and followed for 90 days. Plasma vitamin D3 was measured by liquid chromatography-mass spectroscopy (LC/MS) before and 12 hours after the first dose; plasma 25(OH)D was measured by radioimmunoassay at baseline and after 30 and 90 days. The mean 12-hour increments in vitamin D3 , after adjusting for age and sex, were 200.9 nmol/L in the no-meal group, 207.4 nmol/L in the high-fat meal group, and 241.1 nmol/L in the low-fat meal group (p = 0.038), with the increase in the low-fat group being significantly greater than the increases in the other two groups. However, increments in 25(OH)D levels at 30 and 90 days did not differ significantly in the three groups. We conclude that absorption was increased when a 50,000 IU dose of vitamin D was taken with a low-fat meal, compared with a high-fat meal and no meal, but that the greater absorption did not result in higher plasma 25(OH)D levels in the low-fat meal group.

Effect of Food on the Pharmacokinetics of Rosuvastatin after Administration of a Single Oral Dose in Dogs

Rosuvastatin is a highly effective inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and is used for the treatment of patients with hyperlipidemia. We examined the effect of food on the pharmacokinetics of rosuvastatin by administering it while fasting and after intake of low-fat and high-fat meals. We administered a single 10-mg oral dose of rosuvastatin while fasting and after intake of a low-fat and high-fat meal in a parallel design. The plasma concentrations of rosuvastatin were measured using liquid chromatography tandem mass spectrometry (LC-MS/MS), and the pharmacokinetics of rosuvastatin was analyzed using both noncompartmental and compartmental models. The values of area under the curve at 24 h (AUC 24 h ) and peak plasma concentration (C max) in fed conditions were significantly lower than the corresponding values in the fasting conditions. In addition, consumption of a high-fat meal significantly delayed the time required to achieve the maximum concentration (T max) of rosuvastatin. Both the models sufficiently explained the effect of food on the pharmacokinetics of rosuvastatin and showed that the volume of distribution (V c) was increased and absorption rate constant (K a) was decreased in fed dogs. These findings suggest that food intake affects both the rate and extent of absorption of rosuvastatin, and that rosuvastatin should be administered on an empty stomach to avoid food effect.

Lipoprotein abnormalities in compound heterozygous lipoprotein lipase deficiency after treatment with a low-fat diet and orlistat

The treatment of familial hyperchylomicronemia presenting in early childhood with episodes of pancreatitis has been ineffective, and affected patients remain at risk for pancreatitis. To report on the effect of orlistat in siblings with severe inherited hyperchylomicronemia and to assess posttreatment lipoprotein concentrations and composition. Serial observations of plasma lipid levels and hospitalizations after treatment with orlistat and lipoprotein studies on a single fasting posttreatment sample. The affected siblings inherited a lipoprotein lipase gene mutation from each of their parents: a novel mutation from their father (c.542G > C, p.G181R) and a known missense mutation from their mother (c.644G > A, p.G215E). When the boy presented to us at age 9 years of age and his sister at age 7 years, we found that addition of orlistat, a pancreatic lipase inhibitor, at a dose of 120 mg given before three low-fat meals a day was effective in reducing episodes of pancreatitis in the boy and in maintaining the triglyceride at lower levels in both children. During treatment, the children were observed to have elevations in apolipoprotein (apo)B, low-density lipoprotein particle concentration, abnormal apoB-containing subclasses, and deficiencies in apoA-I and apoA-II-containing lipoproteins, changes consistent with continuing increased cardiovascular risk. The data support the need for more effective long-term treatments that not only prevent pancreatitis but also offset cardiovascular risk. Orlistat can be considered effective in augmenting the effect of a low-fat diet and reducing risk for pancreatitis.

Abstract 18572: Do Obese Children Consume More Energy at Mealtime Compared to Lean Children?

Overweight in childhood is known to lead to cardiac structural, functional, and vascular abnormalities making childhood obesity a major public health concern. It is often assumed that overeating at mealtime contributes to the excess weight gain, but there is limited data in pediatric populations. HYPOTHESIS: We assessed the hypothesis that obese children would consume greater kilocalories than their lean counterparts when exposed to identical food choices during a single meal, under semi-controlled conditions. METHODS: Children were provided a standardized low fat meal and allowed to eat ad lib. The meal provided significantly higher calories than what most children could comfortably eat, in order to discourage seeking additional unapproved food. The meal preparation was supervised by a dietitian and sent home with the family. The family returned the leftover food so that calorie consumption could be calculated. RESULTS: 40 young people (23 obese, 17 lean) ages 8-19 years old (average 13.5 +/- 3.6 yrs) were recruited. The average calories consumed by the obese children were significantly lower than the amount consumed by the lean children when provided similar meals (p &lt;0.01) (Figure). The obese children also consumed significantly less protein, carbohydrates, and fat (p &lt; 0.05). The study was repeated on a subsequent day with similar results. CONCLUSIONS: When provided with a low fat meal, obese children repeatedly consumed fewer calories compared to lean children. These findings may be due to a variety of factors, such as taste and research participation, but may have important implications for calorie consumption and intervention in obese children.