Bridging the Gap between Food Effects under Clinical Trial Conditions and Real Life: Modeling Delayed Gastric Emptying of Drug Substances and Gastric Content Volume Based on Meal Characteristics.

Delayed gastric emptying is known to have a major impact on drug absorption. While the test meal recommended by the FDA and EMA to study food effects represents a worst-case scenario, it does not reflect the reality of the patients. Physiologically based pharmacokinetic (PBPK) models could bridge the gap between clinical settings of food effect studies and the diverse nonclinical situations by simulating the effect of meals with different compositions and volumes. A mathematical equation based on a stretched exponential function was reparameterized to describe the gastric emptying process of mixed solid meals. The model was fitted to literature data including the gastric emptying data of 23 meals from 15 studies. Using a multiple linear regression model, we were able to predict the two function parameters from the meal characteristics caloric content and the percentage of calories derived from fat. After implementation into the PBPK software PK-Sim, the model, together with a separate compartment for liquid gastric contents, was compared to commercially available software. The model is able to simulate the gastric emptying of mixed solid meals containing drugs based on specific meal characteristics. A second compartment allows for distribution between liquid and solid components and rapid gastric emptying along the Magenstrasse.

Importance of Gastric Secretion and the Rapid Gastric Emptying of Ingested Water along the Lesser Curvature ("Magenstraße") in Predicting the In Vivo Performance of Liquid Oral Dosage Forms in the Fed State Using a Modeling and Simulation.

The objective of the present study was to develop an in silico model of the stomach for predicting oral drug absorption in fed humans. We focused on a model capable of simulating dynamic fluid volume changes and included a simulated Magenstraße "stomach road," a route along the lesser curvature that often carries fluids rapidly to assess the gastric emptying of drugs. Two types of model liquid drug formulations, liquid-filled soft gelatin capsules (enzalutamide, cyclosporine, and nifedipine) and oral solutions (levofloxacin and fenfluramine), were used. An in silico model was assembled, and simulations were performed using Stella Professional software. The secretion rate of the gastric juice induced by food ingestion was assessed along with the gastric emptying of the ingested water via the Magenstraße in the fed state. The model for the fed state successfully described the in vivo performance of the model drug formulations. These results clearly indicate the importance of including gastric secretion and the kinetics of Magenstraße when predicting the in vivo performance of dosage forms using an in silico modeling and simulation of fed humans. This simulation model should be further optimized to allow for the different physiological mechanisms following the ingestion of different types of meals, as well as modifications for interindividual and intraindividual variabilities in gastrointestinal physiology in the fed state in the future.

Application of the GastroDuo as an in Vitro Dissolution Tool To Simulate the Gastric Emptying of the Postprandial Stomach.

In the postprandial stomach, processes such as secretion, digestion, and gastric emptying all occur simultaneously. Therefore, the system is highly heterogeneous and dynamically changing, for instance, in terms of various physicochemical parameters such as pH value or viscosity. Thus, the administration of a drug together with food can result in highly variable drug plasma concentrations, which may affect the efficacy and safety of the pharmacotherapy. In this work, the pharmacokinetic (PK) data obtained from two fed-state bioequivalence studies with the immediate release (IR) drug products Viagra (sildenafil) and Adenuric (febuxostat) have been analyzed. This evaluation revealed that basically three characteristic types of onset behaviors of drug plasma concentration can be distinguished. It was hypothesized that the different types of onset behaviors were mainly caused by the interplay between gastric drug dissolution and gastric emptying. To study this interplay in vitro, a biopredictive dissolution tool-GastroDuo-was developed and used for both drug products. Therefore, three different test programs have been applied to simulate certain aspects of the postprandial human stomach, which included dynamic pH changes, gastric peristalsis, and the kinetics of gastric emptying. Specifically, the behavior of noncaloric fluids by the so-called "Magenstrasse" was taken into deeper consideration. The experiments revealed that the dissolution and emptying behavior of the two drug products were affected in different ways by the three test programs. The in vitro data nicely explained the tendencies of the drug products for certain types of onset behaviors observed in the PK data. While Viagra was strongly affected by simulated peristalsis, Adenuric was more sensitive to the simulated emptying kinetics. This work clearly demonstrated the important role of gastric fluid emptying for the onset of drug plasma concentration after oral administration of IR formulations in the fed state. Moreover, this was the first study in which GastroDuo was applied as a biopredictive in vitro model which is able to simulate crucial parameters of the human stomach (e.g., pH profiles and gastric emptying) in a realistic manner.

Gastric Water Emptying under Fed State Clinical Trial Conditions Is as Fast as under Fasted Conditions.

The Magenstrasse (stomach road) describes the fast emptying of ingested liquids from the postprandial stomach. The occurrence of the Magenstrasse has great importance for drugs administered together with food as it represents a shortcut through the fed stomach and allows rapid onset of plasma levels. In this study, we investigated the effect of different meals and their texture and fat content on the occurrence of the Magenstrasse. Since the administration of water is common 60 min after drug intake in clinical trials, we also investigated the effect of time point of water administration on the Magenstrasse by a second water administration. The texture of solid meals and a higher amount of solid food components turned out to favor the presence of the Magenstrasse. On the other hand, the effect of fat content of the meals was negligible. Additionally, the gastric emptying of water was comparable between the first and the second (60 min later) fluid administration, which could lead to an entrainment of drug substance. So far, the Magenstrasse is proven for water; an investigation of other liquid vehicles might be interesting for further mechanistic understanding and utilization. It turned out that the phenomenon of the Magenstrasse can also occur at later time points in clinical studies and may have great impact on the pharmacokinetic profiles obtained in these studies.

George Sclavunos (1869-1954): Anatomical Insights and His Contribution into the "Magenstrasse of Waldeyer".

The purpose of this article is to present a well-known physician and highlight his contribution into an essential, but neglected anatomical feature. George Sclavunos (1869-1954) was a 20th century Greek physician, whose scientific work was a significant milestone in global medical knowledge. In 1899 he became Professor of Anatomy and Head Director of the Department of Anatomy. In 1906 Sclavunos G. published the first volume of the three volume book "Human Anatomy" (1906-1926), which is characterized by its unparalleled illustrations. For more than a century it was the most important book of medical literature in Greece. In 1926 he became a Full Member of the Academy of Athens and was named Life Partner of the International Anatomical Society. His interests included Anatomy, Physiology, Histology, as well as Osteology and Syndesmology. In his book "Human Anatomy", he described for first time the "Sialine Groove of the Stomach", which was described by Waldeyer-Hartz almost at the same time as the "Magenstrasse", a German word that means "stomach road". It is a ribbon-like path that extends along the lesser curvature of the stomach from the gastric cardia to the antrum and releases the gastric content directly into the small intestine. Its importance is confirmed by its association not only with drug delivery, but also with anti-obesity surgical techniques. The old German term has come back into common medical usage in view of the commonly performed Magenstrasse and Mill procedure, a form of bariatric surgery. CONCLUSION: Sclavunos G. managed to observe an anatomical structure that has remained of great importance until today.

Impact of advanced age on the gastric emptying of water under fasted and fed state conditions.

Although older people are the main users of oral medications, few studies are reported on the influence of advanced age on gastric emptying rate of non-caloric liquids. This study aimed at evaluating the gastric emptying of 240 ml water in healthy older and young adults in fasted and fed state conditions using the established method of salivary caffeine kinetics. The gastric emptying of water was evaluated in 12 healthy older volunteers (mean age: 73 ± 6 years) and 12 healthy younger volunteers (mean age: 25 ± 2 years) with the ingestion of a rapid disintegrating tablet containing 20 mg of 13C3-caffeine. The gastric emptying of water was assessed indirectly by calculating the AUC ratios of salivary caffeine concentrations in specific time segments. Comparison of the AUC ratios showed no statistically significant difference between young and older volunteers in both fasted and fed state conditions (p > 0.05). Advanced age itself seems to have no relevant effect on gastric emptying of water in either fasted or fed state conditions and the phenomenon of Magenstrasse appears to follow a similar pattern in healthy older adults as in healthy younger adults.

Predicting gastric emptying of drug substances taken under postprandial conditions by combination of biorelevant dissolution and mechanistic in silico modeling.

Physiologically based pharmacokinetic (PBPK) models can help to understand the effects of gastric emptying on pharmacokinetics and in particular also provide a platform for understanding mechanisms of food effects, as well as extrapolation between different postprandial conditions, whether standardized clinical or patient-oriented, non-clinical conditions. By integrating biorelevant dissolution data from the GastroDuo dissolution model into a previously described mechanistic model of fed-state gastric emptying, we simulated the effects of a high-calorie high-fat meal on the pharmacokinetics of sildenafil, febuxostat, acetylsalicylic acid, theobromine and caffeine. The model was able to simulate the variability in Cmax and tmax caused by the presence of the stomach road. The main influences investigated to affect the gastric emptying process were drug solubility (theobromine and caffeine), tablet dissolution rate (acetylsalicylic acid) and sensitivity to gastric motility (sildenafil and febuxostat). Finally, we showed how PBPK models can be used to extrapolate pharmacokinetics between different prandial states using theobromine as an example with results from a clinical study being presented.

Is there a fast track ("Darmstrasse") for fluids in the small intestine? Evidence from magnetic resonance imaging.

BACKGROUND: The transit and distribution pattern of fluids in the small intestine is a key parameter for the dissolution and absorption of drugs. Although some information is known about the small intestinal water content after administration of fluid volumes and meals, the intestinal transit of orally ingested fluids and solutions has been barely investigated. The aim of this three-arm, cross-over, 9-subject human study was to investigate the transit of orally ingested water in the small intestine under fasting and postprandial conditions using MRI. To identify the ingested water, manganese gluconate, which can be identified with T1-weighted MRI sequences, was added as a marker. Using Horos (DICOM software), quantification of the distribution of Mn2+ ions in the gastrointestinal tract in fasted versus fed state (standard meal by FDA guidance and a light meal) was possible. The distribution and approximate wetted intestinal length was very similar in the fasting and postprandial states, suggesting rapid transport of water ingested after a meal through the chyme-filled small intestine in continuation of the "Magenstrasse" (stomach road). In some subjects, manganese gluconate reached deeper parts of the small intestine even more quickly in the postprandial state than in the fasting arm of the study. A deeper understanding of the behaviour of solutes in the gastrointestinal tract is fundamental to a mechanistic explanation for the kinetic interaction between food and drug intake (food effects).

Mixing and emptying of gastric contents in human-stomach: A numerical study.

Stomach is one of the most important organs in human gastro-track. To better understand the operation of human-stomach, the process of mixing and emptying of gastric contents is simulated using a numerical method. The numerical results confirm that a fast pathway is located close to the lesser curvature of the stomach when water is emptied. However, this fast pathway doesn't exist when the gastric contents are composed of water and food boluses with different properties. The muscle contractions enhance the mixing of light food boluses and water, while they have limited effects on heavy food boluses. As a result, the foods are distributed in layers; heavy food boluses are located in the bottom layer. Besides the gastric motility and high viscosity of foods, the food matrix made of heavy food particles is also important to the formation of the Magenstrasse (stomach road). The food matrix and the zone of wrinkles behave like a porous medium which has higher flow resistance to the light food particles than to the water, leading to faster emptying of water. The water is emptied along the stomach wall since the flow resistance in the stomach wrinkles is smaller than the one in the food matrix. This mechanism is supported by the numerical results, while it might interpret the phenomena observed in the experiments.

The biorelevant simulation of gastric emptying and its impact on model drug dissolution and absorption kinetics.

The highly variable physiological conditions within the gastrointestinal tract can cause variable drug release and absorption from the orally administrated dosage forms. The emptying of the gastric content is one of the most critical physiological processes, dictating the amount of the active ingredient available for absorption into the systemic circulation. In this study, we prepared two water gastric emptying regimes on advanced gastric simulator (AGS) with programmable "pyloric" valve. Gastric emptying regimes were designed in such a way to capture the main findings of the MRI (magnetic resonance imaging) in vivo studies, conducted under fasted conditions according to the EMA and FDA guidelines for bioavailability and bioequivalence studies. Four immediate release formulations containing a model drug of BCS class III were tested. Comparative dissolution tests were also performed with the USP2 apparatus. In vitro release profiles were compared to the in vivo data in order to evaluate the importance of gastric emptying for subsequent absorption of the active substance from the tested formulations. Our bio-relevant in vitro dissolution model showed good discriminatory power for all of the tested formulations. Moreover, a better relation to in vivo data was achieved with AGS with respect to the tested conventional dissolution method.

Application of the GastroDuo to study the interplay of drug release and gastric emptying in case of immediate release Aspirin formulations.

The process of gastric emptying is of major importance for the in vivo performance of immediate release dosage forms. In the fed state, this process consists of two phases: the rapid emptying of water along the "Magenstrasse" and the continuous emptying of the chyme. The relevance of these phases for the pharmacokinetic (PK) profile of a drug depends on the release behavior from its dosage form. It was the aim of this study to investigate the role of gastric emptying for the pharmacokinetics of a fast disintegrating and dissolving Aspirin® tablet (FDDT). For this purpose, a three way pharmacokinetic study with 30 healthy volunteers was performed to investigate the performance of the FDDT under fasted and fed conditions and compare it to a regular Aspirin® tablet (RT) administered in the fed state. Plasma samples were taken at predetermined time points and analyzed by LC MS/MS. In the second part of this work, both products were tested in a biorelevant dissolution test device - the GastroDuo. To simulate the occurrence of the Magenstrasse at different time points, two test programs have been applied. The results of the PK study clearly demonstrated the superiority of the FDDT over the RT. We observed an earlier tmax (0.39 h vs. 2.00 h) and a higher Cmax (6.33 ± 2.37 µg/mL vs. 3.23 ± 1.28 µg/mL), whereas the AUC was only slightly different between both formulations. The administration of the FDDT together with food had no marked effect on tmax (0.34 h vs. 0.39 h), but caused a decrease in Cmax compared to fasted intake (14.76 ± 4.81 µg/mL vs. 6.33 ± 2.37 µg/mL). This effect could be explained by the in vitro data collected with the GastroDuo. The FDDT showed a faster drug release and improved emptying kinetics in the GastroDuo. In contrast, the RT showed incomplete emptying in both test programs. Thus, the early tmax observed for the FDDT under fed conditions could be related to the presence of the Magenstrasse. In contrast, drug release from the RT was insufficient to allow gastric emptying via the Magenstrasse, which resulted in later tmax. This study highlighted the importance of gastric emptying for immediate release dosage forms and illustrated that the application of suitable formulation techniques provides a strategy to generate a fast and reliable onset of drug plasma concentrations even in the fed state.

Laparoscopic Magenstrasse and Mill Gastroplasty (M&M): Midterm Results.

BACKGROUND: The Magenstrasse and Mill gastroplasty (M&M) is a gastric restrictive procedure without band or stomach resection. Short-term evaluation of the laparoscopic procedure showed low morbidity and satisfactory results on weight loss. Evidence of the validity of the technique in the longer term is scarce. METHODS: Data from patients who underwent M&M procedure from May 2012 to September 2015 were retrospectively reviewed. Preoperative clinical characteristics and data up to 4 years after operation were analyzed. RESULTS: A total of 132 patients were included in this study with a mean age of 46 ± 13.4 years. The mean body mass index (BMI) at the time of procedure was 43 ± 4.5 kg/m2. Mean percentage of excess weight loss (%EWL) was 67, 67, 58, and 57% at 1, 2, 3, and 4 years, respectively. The remission rate for diabetes was 36%. About half of the insulin-dependent patients could stop their insulin treatment. Hypertension was resolved in 33.8% of the patients after 4 years. Incidence of vitamin and mineral deficiency was low throughout the study period, less than or equal to 3% for vitamin B12 and 1% for ferritin. Incidence of gastroesophageal reflux did not exceed 15% during the study. Over 75% of the patients reported a good or very good quality of life following the surgery. CONCLUSION: These results confirm the validity of M&M as a bariatric procedure. The low incidence of vitamin deficiencies and gastroesophageal reflux might be the important asset of M&M over other existing techniques.

A Vertically Placed Clip for Weight Loss: a 39-Month Pilot Study.

BACKGROUND: Morbid obesity remains one of society's significant medical dilemmas. It is rapidly worsening and expected to affect 35% of the US population by the year 2020. Common current bariatric procedures exist and include, but not limited to, the adjustable gastric band, gastric bypass, and the sleeve gastrectomy. Although beneficial to morbidly obese patients, they also alter the patient's anatomy and involve resections, or require maintenance. The goal of the trial is to show a new minimally invasive vertical gastric clip technique that produces significant weight loss but requires no resection, no change in anatomy, and is reversible. METHODS: From November 2012 to February 2016, prospective collected data from 117 patients was included in the gastric clip trial. The clip consists of a silicone-covered titanium backbone with an inferior hinged opening that separates a medial lumen from an excluded lateral gastric pouch. The inferior opening allows the gastric juices to empty from the fundus and the body of the stomach into the distal antrum. RESULTS: Weight loss and comorbidities were evaluated among 117 patients over a 39-month period. 66.7% excess weight loss was seen with minimal adverse events. Average length of surgery was 69 min. Average length of stay was 1.3 days. Fifteen of the originally implanted clips were electively removed based on the original protocol, and the other two were removed for displacement of the device. CONCLUSION: The vertical, gastric clip trial has shown that excellent weight loss can be achieved without some of the complications seen with historical bariatric procedures. This clip is placed without requiring stapling, resection, malabsorption, change in anatomy, or maintenance. It is also easily reversible.