Low-fat Meal Research Articles

Real-world Efficacy and Safety of Low-Dose Abiraterone With Food and Standard-Dose Abiraterone in De Novo Metastatic Hormone-Sensitive Prostate Cancer: A Retrospective Analysis

BackgroundThe standard treatment for de novo metastatic hormone-sensitive prostate cancer (mHSPC) involves androgen deprivation therapy (ADT) combined with next-generation hormonal agents and/or docetaxel. While the standard dose (STD) of abiraterone is 1,000 mg administered while fasting, recent evidence suggests that a low dose (LOW) of 250 mg taken with a low-fat meal may achieve comparable pharmacokinetic outcomes. ObjectivesThis study aimed to evaluate the failure-free survival (FFS) and safety of LOW and STD in de novo high-risk mHSPC patients. Materials and MethodsWe conducted a retrospective analysis of males with de novo high-risk mHSPC treated with ADT plus abiraterone (250 mg with a low-fat meal or 1000 mg fasting) at the Vietnam National Cancer Hospital from January 2019 to May 2024. The primary endpoint was FFS, assessed using Kaplan-Meier and multivariate Cox regression analyses. ResultsThe study included 183 patients, with 91 in the LOW group and 92 in the STD group. The rates of patients who achieved undetectable PSA (PSA < 0.2 ng/ml) were 52.7% in the LOW group and 47.8% in the STD group. The median time to undetectable PSA was 6.9 months in the LOW group and 6.4 months in the STD group. The median overall FFS was 28.1 months (95% CI: 21.1 to 35.0) in the LOW group and 25.4 months (95% CI: 15.5 to 35.3) in the STD group (P = .286). Multivariate analysis indicated that visceral metastases and detectable PSA (PSA ≥ 0.2 ng/ml) were significant negative predictors of FFS in both groups. The incidence of grade 3 and grade 4 adverse events was similar between the LOW group and the STD group. ConclusionsThe LOW group and STD group showed effectiveness and safety in de novo high-risk mHSPC. The use of low-dose abiraterone in de novo mHSPC can significantly reduce treatment costs.

Bioavailability of dronedarone tablets administered with or without food in healthy participants

Study objectiveThere is inadequate awareness of the effect of food on the bioavailability of dronedarone. We report results from two phase 1 studies assessing the effect of food on dronedarone's bioavailability. Design, setting and participantsStudy 1; single-center, open-label, randomized study in healthy adults (males and females). Study 2; single-center, open-label, randomized study in healthy males. InterventionsStudy 1; a single 400-mg oral dose of dronedarone (marketed formulation) in fed (high-fat [47.4 g] meal) and fasted states. Study 2; a single 800-mg oral dose of dronedarone (two 400-mg tablets) after fat-rich (37.3 g) and low-fat (5.3 g) meals, and after fasting. Main outcome measuresPharmacokinetic parameters including maximum plasma concentration (Cmax) and area under the curve from time 0 to last measurable time (AUClast) were assessed for dronedarone and its active N-debutyl metabolite. ResultsTwenty-six participants were included in Study 1 and nine in Study 2. In Study 1, administration of 400 mg dronedarone with a high-fat meal vs. fasted state resulted in 2.8-fold and 2.0-fold increases in Cmax and AUClast, respectively. In Study 2, administration of 800 mg dronedarone with a fat-rich or low-fat meal vs. fasted state resulted in 4.6-fold and 3.2-fold increases in Cmax, respectively, and 3.1-fold and 2.3-fold increases, respectively, in AUClast. Results for the N-debutyl metabolite were similar to dronedarone. No adverse events were considered related to dronedarone. ConclusionWith food, the bioavailability of dronedarone is markedly increased. In clinical practice, dronedarone should be administered with a complete meal to maximize drug absorption.

Role of gastrointestinal appetite hormones in the success of body mass loss during interventions based on exercise combined with restricted energy intake diets with different fat and carbohydrate content

Restriction of energy intake is an effective strategy for achieving body mass loss(1). However, it leads to gastrointestinal appetite hormonal changes, which are expected to enhance hunger, reduce satiety, and possibly impair the ability to comply with prescribed intervention(2). Exercise interventions, on the other hand, did not modify gastrointestinal appetite hormones(3) and there is some evidence that postprandial appetite hormone responses after a low carbohydrate-high fat meal (LCHF) are more favorable than after high carbohydrate-low fat meal (HCLF) meal (4). This study investigated how energy-restricted diets based on LCHF and HCLF meals and combined with exercise affect body weight, and gastrointestinal appetite hormones and explored the relationship between body mass changes and changes in gastrointestinal appetite hormones.Twenty-seven overweight and obese females (age: 35 ± 9.35 years, BMI: 31.64 ± 5.08 kg/m2) completed a randomized parallel design study and underwent a 4-week intervention consisting of brisk walking combined with either consumption of calorie-restricted HCLF or LCHF diet. Participants underwent a 5-hour experimental trial before and after the interventions, which included body weight measurements and fasting and postprandial blood sample collection for gastrointestinal appetite hormone measurements.Both interventions significantly reduced body mass (HCLF group, −2.1 ± 1.7 Kg: LCHF group, -1.7 ± 1.7 Kg, P &lt; 0.05 for both groups), but changes between the groups were not significant (P&gt;0.05). Body mass changes were individual and ranged from -0.4 kg to −5.3 kg and from +1 kg to −4.4 kg in the HCLF and LCHF groups, respectively. The interventions had no impact on mean values of time- averaged postprandial concentrations of ghrelin, PYY, and GLP-1 but there was large individual variability in changes of these hormones. Results combined from both groups revealed that changes in ghrelin ranged from +549.3 to -407.7 pg/ml, in PYY from −132.5 to + 96.4 pg/ml and in GLP-1 from −6.6 to +19.5 pg/ml. Correlation, investigated on the data from both groups combined, between changes in body mass and changes in ghrelin (r = −0.18, P= 0.41), PYY (r = −0.04, P =0.87), and GLP-1 (r = 0.11, P = 0.64) were not significant.In conclusion, the extent of body mass loss during interventions based on restricted energy intake diets combined with exercise is not related to the carbohydrate and fat content of the diet. Our findings also suggest that the success of body mass loss cannot be predicted by changes in postprandial concentrations of gastrointestinal appetite hormones.

A Population Pharmacokinetic Assessment of the Effect of Food on Selumetinib in Patients with Neurofibromatosis Type 1-Related Plexiform Neurofibromas and Healthy Volunteers.

Selumetinib is clinically used for pediatric patients with neurofibromatosis type 1 and symptomatic, inoperable plexiform neurofibromas. Until recently, selumetinib had to be taken twice daily, after 2 hours of fasting and followed by 1 hour of fasting, which could be inconvenient. This population analysis evaluated the effect of low- and high-fat meals on the pharmacokinetic (PK) parameters of selumetinib and its active metabolite N-desmethyl selumetinib. The dataset comprised 511 subjects from 15 clinical trials who received ≥1 dose of selumetinib and provided ≥1 measurable postdose concentration of selumetinib and N-desmethyl selumetinib. A 2-compartment model with sequential 0- and 1st-order delayed absorption and 1st-order elimination adequately described selumetinib PK characteristics. A 1-compartment model reasonably described N-desmethyl selumetinib PK characteristics over time simultaneously with selumetinib. Selumetinib geometric mean area under the concentration-time curveratio (1-sided 90% confidence interval [CI] lower bound) was 76.9% (73.3%) with a low-fat meal and 79.3% (76.3%) with a high-fat meal versus fasting. The lower bound of the 1-sided 90% CI demonstrated a difference of <30% between fed and fasted states. Considering the flat exposure-response relationship within the dose range (20-30mg/m2), the observed range of exposure, and the variability in the SPRINT trial, this was not considered clinically relevant.

Physiologically Based Pharmacokinetic Absorption Model for Pexidartinib to Evaluate the Impact of Meal Contents and Intake Timing on Drug Exposure.

Pexidartinib is a systemic treatment for patients with tenosynovial giant cell tumor not amenable to surgery. Oral absorption of pexidartinib is affected by food; administration with a high-fat meal (HFM) or low-fat meal (LFM) increases absorption by approximately 100% and approximately 60%, respectively, compared with the fasted state. Pexidartinib is currently dosed 250mg orally twice daily with an LFM (approximately 11-14 g of total fat). We developed a physiologically based pharmacokinetic model to determine the impact on drug exposure of dose timing with respect to meals, meal type, and caloric content. A 15%-16% increase in plasma exposure was predicted when consuming an HFM 1hour after dosing with an LFM, but almost no effect on pharmacokinetics was predicted when an HFM was consumed 3 hours or more before or after pexidartinib dosing with an LFM. Exposure was not significantly affected when pexidartinib was taken with a 500-kcal LFM over the range of fat (approximately 11-14 g of total fat; 20%-25% calories from fat) for an LFM. These findings on timing of pexidartinib dose with respect to meals should be considered by patients and physicians to reduce the potential for side effects.

Evaluation of the Effects of Meal Type and Acid-Reducing Agents on the Pharmacokinetics of Cilofexor, a Selective Nonsteroidal Farnesoid X Receptor Agonist.

Cilofexor is a nonsteroidal farnesoid X receptor agonist being developed in combination with firsocostat/semaglutide for the treatment of nonalcoholic steatohepatitis. This phase 1 study evaluated the effects of food and acid-reducing agents (ARAs) on the pharmacokinetics of cilofexor (100- or 30-mg fixed-dose combination with firsocostat) in healthy participants. Cohorts 1 (n = 20, 100mg) and 2 (n = 30, 30mg) followed a 3-period, 2-sequence crossover design and evaluated effects of light-fat and high-fat meals. Cohort 3 (n = 30, 100mg fasting) followed a 2-period, 2-sequence crossover design and evaluated the effects of a 40-mg single dose of famotidine. Cohort 4 (n = 18, 100mg) followed a 3-period, 2-sequence crossover design and evaluated the effects of a 40-mg once-daily regimen of omeprazole administered under fasting conditions or following a light-fat meal. Administration with light-fat or high-fat meals resulted in no change and an ∼35% reduction in cilofexor AUC, respectively, relative to the fasting conditions. Under fasting conditions, famotidine increased cilofexor AUC by 3.2-fold and Cmax by 6.1-fold, while omeprazole increased cilofexor AUC by 3.1-fold and Cmax by 4.8-fold. With a low-fat meal, omeprazole increased cilofexor exposure to a lesser extent (Cmax 2.5-fold, AUC 2.1-fold) than fasting conditions. This study suggests that caution should be exercised when cilofexor is administered with ARAs under fed conditions; coadministration of cilofexor (100 or 30mg) with ARAs under fasting conditions is not recommended with the current clinical trial formulations.

Effect of food on selumetinib pharmacokinetics and gastrointestinal tolerability in adolescents with neurofibromatosis type 1-related plexiform neurofibromas.

Selumetinib is approved for the treatment of pediatric patients with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas (PN) in multiple countries, including the USA (≥ 2 years). Until recently, individuals had to take selumetinib twice daily (BID) in a fasted state. This study evaluated the effect of a low-fat meal on selumetinib PK parameters and gastrointestinal (GI) tolerability in adolescent participants with NF1-PN. Eligible participants aged ≥ 12 to< 18 years took 25mg/m2 selumetinib BID with a low-fat meal (T1) for 28 days, followed by a 7-day washout, and then administration in a fasted state (T2) for another 28 days. Primary objectives were to evaluate the effect of a low-fat meal on AUC0-12,ss and GI tolerability after multiple selumetinib doses in T1 versus T2. Key secondary objectives were additional PK parameters and adverse events (AEs). At primary data cut-off, all 24 participants completed T1, and 23 participants completed T2. There were no significant differences in AUC0-12,ss between T1 and T2. In T1 and T2, 29.2% and 33.3% participants, respectively, reported ≥ 1 GI AE. No GI AEs Grade ≥ 3, or serious AEs, or GI AEs resulting in treatment interruptions, discontinuation, or dose reductions were reported in T1 and T2. Dosing selumetinib with a low-fat meal had no clinically relevant impact on selumetinib AUC0-12,ss nor GI tolerability in adolescents with NF1-PN. NCT05101148.

A Man with Primary Hyperchylomicronemia with Triglyceride Levels Exceeding 11,000 mg/dL was Well Controlled by Pemafibrate Combined with Dietary Therapy: A Case Report.

A 50-year-old man with a triglyceride (TG) level of 11,397 mg/dL was admitted to our hospital. He consumed a high-fat and high-carbohydrate diet as well as more than 100 g of alcohol per day. He had type 2 diabetes and obesity and had previously suffered from severe acute pancreatitis twice. A genetic analysis revealed compound heterozygous mutations in APOA5 (c.56C>G and c.553G>T). In addition to low-fat meals and alcohol cessation, administration of pemafibrate lowered his triglyceride levels to <150 mg/dL.

Supporting patients in the transition to the revised pexidartinib dosing regimen: perspectives from the multidisciplinary clinical and allied health professional team

Pexidartinib is a colony-stimulating factor-1 receptor inhibitor approved in the United States for treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and not amenable to improvement with surgery. Because of the risk of severe and potentially fatal hepatotoxicity, pexidartinib is only available through a Risk Evaluation and Mitigation Strategy (REMS) program. Pexidartinib pharmacokinetics are influenced by the fat content of meals: compared with the fasted state, consuming a high-fat meal with pexidartinib increases pexidartinib absorption by 100%; a low-fat meal increases absorption by approximately 60%. Pexidartinib was initially authorized to be taken at 800 mg/day on an empty stomach; therefore, if this same dose of pexidartinib is taken with food, there is a risk of overexposure and potential toxicity. To reduce the risk of hepatotoxicity and improve patient compliance, pexidartinib has undergone a revised dosing regimen, from 800 mg/day (400 mg twice daily) fasted to 500 mg/day (250 mg twice daily) with a low-fat meal (approximately 11–14 g of total fat). The objective of this report is to educate clinical and allied health professionals on the revised dosing regimen and the importance of patient compliance with a low-fat meal. Healthcare professionals need to understand the rationale for the switch from pexidartinib dosing on an empty stomach to dosing with a low-fat meal and how meal composition and timing influence pharmacokinetics. Finally, we provide guidance for the healthcare team of prescribing providers, nurses, pharmacists, and dietitians who are caring for patients with TGCT on pexidartinib. It is important for healthcare providers to deliver consistent messaging on the low-fat meal requirement and help patients fit pexidartinib into their regular meal schedules. Consulting a dietitian may be helpful for patients, especially those with complex dietary needs. We provide an overview of the roles and responsibilities of each healthcare professional and outline steps to best support patients, including key questions and answers related to the revised dosing regimen. This report provides the information necessary to guide the multidisciplinary team caring for patients with TGCT and to support them through the pexidartinib dosing regimen change.

Effect of Two Different Meal Compositions on 1-hour Plasma Ghrelin Levels in Young Men

Introduction: Calorie restriction is the main strategy for loosing body weight in obese individuals. However, persistence to this strategy is a major challenge. Ghrelin, a hormone that influences an individual to consume food by modulating the feelings of hunger. This effect may be influenced by the % fat composition of a meal. Materials and Methods: Twelve young male participants with normal BMI, were administered in random order one of 2 isocaloric meals after an overnight fast. The 2 meals contained either 31 or 52% fat. After a 7 day gap, cross-over of the participants was carried out and they consumed the other meal similarly. Ghrelin levels were measured after fasting and 1 hour after diet consumption. An appetite rating on a visual analogue scale (VAS) was used to measure perceived hunger and satiety before and after the meal. Results: When compared to the baseline values, an average of 34% and 20% decrease in ghrelin levels were noted after the high-fat meal (p&lt;0.025), and low-fat meal respectively. Analysis of the VAS showed that feelings of hunger decreased, while feelings of satiety increased after the meal, however there was no difference between the two meals. Conclusion: Thus, within this study group, though the feelings of hunger and satiety was comparable, consumption of isocaloric high fat caused ghrelin levels to decrease within one hour post meal. This shows that manipulation of % fat of the diet can achieve lower post-meal ghrelin levels.

A single high-fat Western meal modulates vascular responsiveness to sympathetic activation at rest and during exercise in humans: a randomized controlled trial.

A single high-fat Western meal transiently reduces endothelium-dependent vasodilation at rest but the interaction with sympathetic vasoconstrictor activity during exercise remains unknown. Herein, we tested the hypothesis that a single high-fat Western meal would impair the ability of contracting skeletal muscle to offset vascular responsiveness to sympathetic activation during exercise, termed functional sympatholysis. In 18 (10F/8M) healthy young adults, forearm blood flow (Doppler ultrasound) and beat-to-beat arterial pressure (photoplethysmography) were measured during lower-body negative pressure (LBNP; -20 mmHg) applied at rest and simultaneously during low- (15% maximum contraction) and moderate-intensity (30% maximum contraction) rhythmic handgrip. The magnitude of sympatholysis was calculated as the difference of LBNP-induced changes in forearm vascular conductance (FVC) between handgrip and rest. Experiments were performed preprandial and 1h, 2h, and 3h after a high- or low-fat meal. In the preprandial state, LBNP decreased resting FVC (∆-54±10%), and these responses were attenuated during low- (∆-17±7%) and moderate-intensity handgrip (∆-8±6%). Following a high-fat meal, LBNP induced attenuated decreases in resting FVC (3h postprandial: ∆-47±10%, P=0.002 vs. preprandial), and blunted attenuation of FVC during low- (3h postprandial: ∆-23±8%, P=0.001 vs. preprandial) and moderate-intensity handgrip (3h postprandial: ∆-16±6%, P<0.001 vs. preprandial). The high-fat meal attenuated the magnitude of sympatholysis during low- (preprandial: 38±7% vs. 3h postprandial: 23±8%, P<0.001) and moderate-intensity handgrip (preprandial: 46±11% vs. 3h postprandial: 31±10%, P<0.001). The low-fat meal had no impact on these responses. In conclusion, a single high-fat Western meal modulates sympathetic vasoconstriction at rest and during low- and moderate-intensity handgrip exercise in young healthy adults.

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.

A single high-fat meal impairs functional sympatholysis in young healthy adults

Introduction: A high-fat diet increases the risk of cardiovascular disease and mortality, but the underlying mechanisms remain incompletely understood. During exercise, sympathetically mediated vasoconstriction is dampened in active skeletal muscle due to the counteracting vasodilatory effects of metabolic by-products from muscle contraction. This phenomenon, termed functional sympatholysis, plays a critical role in the redistribution of cardiac output to contracting skeletal muscles to meet the metabolic demands of exercise. Whether a high-fat meal modulates the magnitude of sympatholysis is currently unknown. Herein, we tested the hypothesis that a high-fat meal would acutely impair functional sympatholysis in young healthy adults. Methods: In a randomized, controlled, and cross-over design, 14 healthy adults (8 women, 26±4 years), consumed either a high- (1030kcals, 91g fat) or a low-fat (1006kcals, 1g fat) meal on two separate days. Forearm blood flow (FBF; Doppler ultrasound) and beat-to-beat mean arterial pressure (MAP; finger photoplethysmography) were measured during sympathetic activation induced by -20 mmHg lower-body negative pressure (LBNP) applied at rest and simultaneously during rhythmic handgrip exercise at 15% and 30% maximum voluntary contraction (MVC). Measurements were taken pre-meal and at 1-, 2-, and 3-hours post-prandial. Forearm vascular conductance (FVC) was calculated as FBF/MAP and the magnitude of sympatholysis as the difference of LBNP-induced changes in FVC between handgrip and rest. Results: Prior to the high-fat meal, LBNP decreased resting FVC (Δ-57±10%), and this response was attenuated during exercise at 15% (Δ-18±8%) and 30% MVC (Δ-9±7%). After the high-fat meal, LBNP induced smaller decreases in resting FVC (1h: Δ-43±12%, 2h: Δ-45±12%, 3h: Δ-49±8%, all P≤0.01 vs. pre), but during exercise greater decreases in FVC were observed at both 15% (1h: Δ-22±10%, 2h: Δ-23±8%, 3h: Δ-25±8%, all P≤0.04 vs. pre) and 30% MVC (1h: Δ-15±8%, 2h: Δ-15±6%, 3h: Δ-16±6%, all P≤0.04 vs. pre). As a result, the high-fat meal decreased the magnitude of sympatholysis during rhythmic handgrip exercise at 15% (pre-prandial: 39±8%, 1h: 20±10%, 2h: 21±8%, 3h: 24±7%, all P≤0.001) and 30% MVC (pre-prandial: 48±11%, 1h: 28±10%, 2h: 30±11%, 3h: 33±8%, all P≤0.001). The low-fat meal did not change the magnitude of sympatholysis at either 15% (pre-prandial: 37±6%, 1h: 39±6%, 2h: 38±7%, 3h: 37±8%, all P≥0.07) or 30% MVC (pre-prandial: 45±10%, 1h: 47±8%, 2h: 47±9%, 3h: 46±7%, all P≥0.39). Conclusion: These findings demonstrate the capacity of a high-fat meal to acutely impair the ability of contracting skeletal muscle to offset the vascular responsiveness to α1-adrenoreceptor activation during low- and moderate-intensity rhythmic handgrip exercise. Natural Science and Engineering Research Council (NSERC) of Canada Discovery Grant (P.J.M) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Dosing Recommendation Based on the Effects of Different Meal Types on Pexidartinib Pharmacokinetics in Healthy Subjects: Implementation of Model-informed Drug Development Strategy.

Pexidartinib, an oral small molecule inhibitor of the colony-stimulating factor 1 receptor, is approved for treatment of adults with symptomatic tenosynovial giant cell tumor associated with severe morbidity or functional limitations and not amenable to improvement with surgery. The original dosing regimen is 400mg of pexidartinib (2×200-mg capsules) twice daily, administered on an empty stomach at least 1hour before or 2hours after a meal or snack. Because pexidartinib is likely to be taken over an extended period of time, the ability to take pexidartinib with a meal would simplify timing of administration and potentially improve compliance. Since administering 400mg of pexidartinib with alow-fatmeal increases exposure by ≈60% relative to the fasted state, administering 250mg of pexidartinib with a low-fatmeal (low-fat meal dosing regimen) was predicted to achieve an exposure similar to 400mg administered during a fasted state (original dosing regimen). Based on clinical trial simulations with two one-sided t-tests and bootstrapping (ie, resampling) analyses, a bioequivalence study (n=24) would have >90% power to conclude that the original dosing regimen (400mg fasted twice daily) and thelow-fatmeal dosing regimen (250mg with alow-fatmeal twice daily) are bioequivalent. This report provides the outcome of the implementation of the model-informed drug development strategy to recommend and justify alow-fatmeal dosing regimen for pexidartinib that has the potential to improve patient compliance while maintaining drug exposure.

Localized activity attenuates the combined impact of a high fat meal and prolonged sitting on arterial stiffness: A randomized, controlled cross-over trial.

Exposure to acute prolonged sitting and consumption of a high fat (HF) meal have been shown to independently and additively impair central and peripheral cardiovascular function. This study sought to determine whether localized activity, namely leg fidgeting, offers a protective effect to these deleterious effects. Using a randomized crossover design with three trials, 18 healthy males sat uninterrupted for 180min following the consumption of a low fat (LF, trial 1) or HF meal (trial 2). The third trial consisted of a HF meal but sitting was interrupted with 1min of leg fidgeting (isolated bilateral plantar flexion) consisting of -250 taps per min every 5min for the 180min duration. Carotid-femoral pulse wave velocity (cfPWV), aortic-femoral stiffness gradient (af-SG), superficial femoral blood flow, shear-rate and PWVβ, triglyceride concentrations and lower-limb venous pooling (HHb) were assessed pre and post sitting in all trials. General linear mixed model found that following the uninterrupted HF trial, there was a significant worsening of cfPWV (mean difference (MD) = 0.57mˑs-1; d = 1.04) and the af-SG (MD = 0.14, d = 0.50), and femoral artery blood flow (MD = 18mlˑmin-1; d = 0.48) and shear rate (MD = 15 S1; d = 0.67) decreased. However, leg fidgeting was enough to prevent the combined deleterious effects of prolonged sitting following a HF meal. As there were no significant changes in the LF trial, the HF meal maybe the predominant driver when uninterrupted sitting is combined with a HF meal.

Effect of Food (Low and High Fat) on Pharmacokinetics of FCN-159, a Selective MEK Inhibitor, in Healthy Chinese Males.

FCN-159 is a novel, oral, potent, selective MEK1/2 inhibitor in clinical development for the treatment of NRAS-mutant advanced melanoma and neurofibromatosis type 1. We investigated the effect of food on the pharmacokinetics (PK), safety, and tolerability of FCN-159. In this single-center, open-label, phase 1 study with a three-period, three-sequence, crossover design, healthy Chinese male subjects (n = 24) were randomized (1:1:1) to receive a single, oral 8mg dose of FCN-159 in the fasted state (overnight, > 10h), and with a low-fat and a high-fat meal, separated by a 10-day washout. PK parameters including time to maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) were compared using geometric least-squares mean ratios (GLSMR), with the fasted state as the reference. A 90% CI for the GLSMR within 80-125% indicated no significant food effect. A low-fat meal (n = 23) did not affect the PK profile of FCN-159: G LSMR for AUC from time 0 to t (AUC0-t), 106.9% (90% CI 99.9-114.4%); AUC from time 0 to infinity (AUC0-∞), 106.8% (90% CI 100.0-114.0%); Cmax, 96.4% (90% CI 83.9-110.8%). A high-fat meal (n = 24) did not affect exposure to FCN-159 (GLSMR for AUC0-t, 99.4%; 90% CI 99.0-106.3%; AUC0-∞, 99.5 5%; 90% CI 93.2-106.1%), but modestly reduced Cmax by 15% (GLSMR 84.9%; 90% CI 74.0-97.3%). Both the low-fat and high-fat meals slightly prolonged the median time to Cmax by 0.5h (90% CI 0.5-1.0h). FCN-159 was generally well tolerated, with a lower incidence of treatment-emergent adverse events following administration in the fasted state than with a low-fat or high-fat meal (20.8%, 39.1%, and 37.5%, respectively). Food did not affect the PK profile of FCN-159 to a clinically meaningful extent compared with administration in the fasted state.

594. An Open-Label Study in Healthy Volunteers to Determine the Absolute Bioavailability of, the Effect of Food and Dosing by Nasogastric Tube upon the Pharmacokinetics of a Single Oral Dose of Olorofim (OLO)

Abstract Background OLO is a novel antifungal active vs. Aspergillus (including azole-resistant strains), resistant moulds (e.g., Lomentospora prolificans), and dimorphic moulds. Information on absolute bioavailability and effect of food upon the pharmacokinetics (PK) of OLO when administered as a 30 mg tablet, including feasibility of alternative enteral delivery, is required for appropriate guidance on dosing. Methods Healthy male and female subjects in Cohorts A and B (6/cohort; high carbohydrate /low fat meals at 8 and 24 h for Cohort A and low carbohydrate/high fat meals for Cohort B ) participated in 3 treatment periods; single doses of 150 mg OLO as a 2-h IV infusion, a fasted PO dose (after overnight fast), and a fed single PO dose (30 min after starting a high fat breakfast). Healthy subjects in Cohort C participated in 2 treatment periods and received fasted single doses of 150 mg OLO either PO as intact tablets or via NG tube (tablets dispersed in water). PK sampling was performed for 120 h after each dose, with at least 10 days between dosing occasions per subject. Results The absolute bioavailability of a fasted single PO dose of OLO was found to be 67%. Administering OLO in the presence of food resulted in slight reduction in overall exposure, with an approximate 30% reduction in Cmax (Table 1). Multiple post-dose OLO peaks were observed for most subjects regardless of dose route or fed state; peaks typically coincided with meal times (Figure). OLO systemic exposure was similar for intact tablets given PO and tablets dispersed in water given via NG tube (Table). Statistical Analysis of Olorofim PK parameters for Cohorts A, B and C Conclusion OLO (30 mg tablet) has good oral bioavailability and based upon the minimal impact of a high-fat breakfast upon overall exposure, can be administered with or without food. No dose adjustment is needed if switching from oral dosing with intact tablets to dosing tablet in water via NG tube. Disclosures Karen Cornelissen, PhD, F2G: Employee Paul A. Newell, MB BS, AstraZeneca: Stocks/Bonds|F2G: Stocks/Bonds John H. Rex, MD, Advent Life Sciences: Operating Partner|Advent Life Sciences: Ownership Interest|AMR Action Fund: Advisor/Consultant|AstraZeneca: Stocks/Bonds|Basilea Pharmaceutica: Advisor/Consultant|Bugworks Research, Inc.: Advisor/Consultant|F2G, Limited: Employee|F2G, Limited: Stocks/Bonds|Forge Therapeutics: Advisor/Consultant|GlaxoSmithKline: Advisor/Consultant|Pfizer Pharmaceuticals: Honoraria|Sumitovant: Advisor/Consultant Samuel Israel, MBBS, Labcorp: Eemployee James Bush, MB ChB, PhD, Labcorp: Employee (Salaried)|Labcorp: Stocks/Bonds.

Food Effect Study to Assess the Impact on Edaravone Pharmacokinetic Profiles in Healthy Participants

The safety and efficacy of intravenous edaravone, a neuroprotectant used for the treatment of amyotrophic lateral sclerosis (ALS), have been shown in clinical trials. An oral suspension of edaravone has been developed, but the food effect on its pharmacokinetic profile has not been evaluated. This study aimed to assess the food effect on the pharmacokinetic profile of edaravone after oral administration and to investigate dosing regimens and administration instructions with different meal intake and timing. Data from 3 Phase I clinical studies were used to evaluate the effect of food on the pharmacokinetic profiles of a single dose of edaravone oral suspension. In all 3 studies, participants received a single dose of edaravone with various meal conditions. Healthy Japanese adult male participants (Studies 1, 2, and 3) or female participants (Study 3) aged 20 to 45 years at the time of informed consent were included. In Study 1, 6 participants were enrolled and 5 completed the study. Nine and 16 participants were treated in Studies 2 and 3, respectively, and all completed the study. The Cmax and AUC0-∞ of edaravone were lower when administered 30 minutes after a high-fat meal compared with those in a fasted condition (Study 1). Lower plasma edaravone concentrations (approximately within the first hour) and subsequent lower Cmax and AUC0-∞ were observed after administration of edaravone 4 hours after a high-fat meal (Study 2) or 2 hours after a low-fat meal (Study 3). The Cmax and AUC0-∞ of oral edaravone were generally similar and not affected when administered 8 hours after a high-fat meal, 4 hours after a low-fat meal, or 2 hours after a light meal relative to the fasted condition. Administration of edaravone 1 hour before a high-fat meal resulted in no effect on Cmax or AUC0-∞ relative to the fasted condition. Administration of edaravone in the fed or fasted conditions resulted in a similar urine pharmacokinetic profile. Oral administration of edaravone with a meal decreased the plasma concentration of edaravone. Oral administration of edaravone 8 hours after a high-fat meal, 4 hours after a low-fat meal, 2 hours after a light meal, and 1 hour before a high-fat meal showed no effect of food on the PK profile of unchanged edaravone compared with that observed under a fasted condition. gov identifiers: NCT04481750, NCT04481789, and NCT05342597.

Incidence of Presenting Hepatitis A in the Peja Regional Hospital during 2019–2020

Introduction: Hepatitis is a very common inflammation of the cells of the liver. Hepatitis can be temporary (acute) or long-term (chronic) depending on whether it lasts less than or more than six months. The hepatitis A virus infects humans and some primates and is the cause of infectious hepatitis. Purpose and objectives: Viral hepatitis infections are also present in our country, so the purpose of working on this topic is to expand knowledge in terms of Viral Hepatitis A, Their Epidemiology, and Preventive Measures. Materials and Methods: In the realization of this paper, the method of the literature review was used, in addition, information was presented on the number of patients with viral hepatitis A in the regional hospital of Peja, the Republic of Kosovo for the period 2019/2020. Results: From the results obtained it is clear that the number of patients with Hepatitis A was low and thankfully in non-significant values. However, the fact that the number of Hepatitis B patients is increasing, and especially the increase in the number of Hepatitis C cases, remains a matter of concern, and it is worth noting that care should be taken to prevent the spread of these viruses at a very high rate. Conclusion: Given the risk posed by these infections, the prevention of viral hepatitis requires an organized and ongoing program of education and treatment. Recommended measures for the prevention of viral hepatitis are: Ensuring adequate sanitary and personal hygiene. Drink only water that is controlled, Avoid drinking alcohol, Avoiding any non-particularly recommended medication acetaminophen (Tylenol) and sedatives for 3-12 months because such medications are hepatotoxic, Frequent breaks during the day and a good night's sleep. Eating small, frequent, high-carbohydrate, low-fat meals. Following the guideline for preventing the transmission of the disease to patients and other persons who are not infected, Timely immunization reports all cases of hepatitis to the health department.

Population pharmacokinetic and pharmacodynamic modeling of evobrutinib in healthy adult participants.

Evobrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, has shown therapeutic potential in relapsing multiple sclerosis. This analysis aimed to develop pharmacokinetic (PK) and pharmacodynamic (PD; BTK occupancy [BTKO]) models of evobrutinib and simulate PK and BTKO profiles under alternative dosing regimens. Data were obtained from two phase I evobrutinib studies in healthy adult participants (Japanese and non-Japanese). Overall, 2326 observations were available from 76 participants; n =42 from Study MS200527_0017 Part A received evobrutinib 25, 75, or 200 mg once-daily oral doses for 6 days while fasted; n = 18 from Study MS200527_0019 and n =16 from Study MS200527_0017 Part B received single evobrutinib 75 mg oral doses with food (low-fat meal) and while fasted. Population PK/PD modeling for evobrutinib concentrations and BTKO (fraction unbound) were performed using nonlinear mixed-effects modeling. The effect of once-daily/twice-daily regimens and doses of 10-200 mg on BTKO were simulated. A two-compartment model with sequential zero-first order absorption and first-order elimination adequately described the data. Bioavailability increased by 49% with food compared with when fasted. There was no difference in PK parameters between Japanese and non-Japanese participants. The BTKO profile of evobrutinib was described by the irreversible binding population model. The simulated percentage of participants with minimum BTKO increased in a dose-dependent manner across the BTKO thresholds of interest (70%, 80%, 90%, and 95% occupancy). Evobrutinib doses of 25 mg once-daily, 50 mg twice-daily, or 75 mg twice-daily while fasted are possible choices for further development, assuming BTKO ≥70% at trough is needed to achieve efficacy.