A quantification of gastric and duodenal fluid volumes in older adults using MRI.

Older adults are an inherently heterogeneous population with various underlying pathologies, medication use, and habits. In this study, the variability of this population was studied for the gastric and duodenal fluid volumes, as the amount of gastrointestinal volumes could play an essential role in the dissolution of drugs. The fluid volumes were retrospectively quantified by using magnetic resonance imaging (MRI). In 265 included fasted older individuals, the gastric fluid volume was 28.9 ± 21.1 mL (arithmetic mean ± standard deviation). No significant covariate-effect on stomach fluid volume was observed for various medication use, pathologies, and habits (e.g. hypertension, smoking, proton-pump inhibitors (PPIs), and aspirin). The gastric fluid volume remained constant with increasing age and had a high variability. The volumes and the variability were, however, not higher than the gastric values reported in healthy younger adults. The duodenal fluid volume was 16.6 ± 10.0 mL and a slight but statistically significant decrease with age was seen. In addition, cystic pancreas, obesity, diuretics, and PPI use demonstrated a moderate but significant correlation with the duodenal fluid volume. The findings of this study could be considered when developing and testing new drug candidates for the older adult population. For example, the volumes including their variability could be used as an input in physiologically based pharmacokinetic (PBPK) modelling approaches to predict drug exposure in this population.

Dissolution, phase behavior and mass transport of amorphous solid dispersions in aspirated human intestinal fluids.

Amorphous solid dispersions (ASDs) typically show improved dissolution and generate supersaturated solutions, enhancing the oral bioavailability of poorly soluble drugs. To gain insights into intraluminal ASD behavior, we utilized two poorly soluble drugs with different crystallization tendencies, atazanavir and posaconazole, prepared as ASDs at a 10% drug loading with hydroxypropyl methylcellulose acetyl succinate (HPMCAS). We evaluated their release in aspirated fasted-state human intestinal fluid (FaHIF), and multi-component fasted-state simulated intestinal fluid (composite-FaSSIF), characterizing the supersaturation profiles and drug-rich nanodroplets that formed. Complete release was observed for atazanavir ASDs over a 90 min period. Flux for dissolved atazanavir ASDs remained high over the experimental time period of 3 h. In contrast, posaconazole solution concentrations were initially high and then decreased. Likewise, flux was initially high and then decreased where these changes are attributed to crystallization of the drug. Generation of spherical nano-sized amorphous droplets of ∼100-150 nm was found to occur in ex vivo FaHIF media for both ASDs, maximizing the diffusive flux during the supersaturation window. Moreover, buffer capacity differences were postulated to influence release rates of ASDs in simulated vs aspirated fluids. Importantly, the solution phase phenomena observed during ASD release in simulated fluids, namely amorphous nanodroplet formation and drug crystallization, were also found to occur in aspirated luminal fluids.

The effect of sparkling water on the systemic pharmacokinetics of paracetamol in older adults.

Paracetamol absorption kinetics show considerable variability in older adults, complicating the development of effective dosing regimens in the advanced-age population. In previous research, sparkling water has been shown to influence absorption-related processes. This study aimed to apply these findings to older adults and investigate the impact of sparkling water on absorption-related variability and early exposure. To this end, fourteen volunteers, with a median age of 72.5, were enrolled in a small-scale, randomised, controlled clinical trial with a cross-over design. A single immediate-release 500 mg paracetamol tablet was administered with sparkling or still water. Venous blood samples were collected regularly over 8 hours and analysed using HPLC-UV. Reduced variability of absorption-related parameters and a trend towards higher early exposure were observed in the sparkling water group, as demonstrated by a 1.6-fold increased AUC0-30min, a 2-fold reduced geometric coefficient of variation (GCV) for AUC0-30min, and a reduced median [interquartile range] Tmax of 25.0 [20.0-30.0] min compared to 30.0 [25.0-45.0] min. Based on our findings, sparkling water as a real-life dosing condition might improve paracetamol absorption kinetics and early exposure in the advanced-age population.

Characterization of luminal contents from the fasted human proximal colon.

To treat colonic diseases more effectively, improved therapies are urgently needed. In this respect, delivering drugs locally to the colon is a key strategy to achieve higher local drug concentrations while minimizing systemic side effects. Understanding the luminal environment is crucial to efficiently develop such targeted therapies and to predict drug disposition in the colon. In this clinical study, we collected colonic contents from an undisturbed fasted proximal colon via colonoscopy and characterized their composition with regard to drug disposition. Colonic pH, osmolality, protein content, bile salts, lipids, phospholipids and short-chain fatty acids were investigated in 10 healthy volunteers (8 male and 2 female, age 19-25). The unique environment of the proximal colon was reflected in the composition of the sampled luminal fluids and the effect of the microbiota could be observed on the pH (median 6.55), the composition of bile salts (majority deconjugated and secondary), and the abundance of short-chain fatty acids. At the same time, an increase in phospholipid concentration, osmolality and total protein content compared to reported ileal values was seen, likely resulting from desiccation. Lipids could only be found in low quantities and mainly in the form of cholesterol and free fatty acids, showing almost complete digestion and absorption by the time luminal contents reach the colon. All characteristics also displayed the considerable intersubject variability found in different regions of the gastrointestinal tract. This study contributes to an improved understanding of the luminal conditions in the proximal colon and facilitates the development of new predictive tools to study colonic drug absorption.

Expression of intestinal drug transporter proteins and metabolic enzymes in neonatal and pediatric patients.

The development of pediatric oral drugs is hampered by a lack of predictive simulation tools. These tools, in turn, require data on the physiological variables that influence oral drug absorption, including the expression of drug transporter proteins (DTPs) and drug-metabolizing enzymes (DMEs) in the intestinal tract. The expression of hepatic DTPs and DMEs shows age-related changes, but there are few data on protein levels in the intestine of children. In this study, tissue was collected from different regions of the small and large intestine from neonates (i.e., surgically removed tissue) and from pediatric patients (i.e., gastroscopic duodenal biopsies). The protein expression of clinically relevant DTPs and DMEs was determined using a targeted mass spectrometry approach. The regional distribution of DTPs and DMEs was similar to adults. Most DTPs, with the exception of MRP3, MCT1, and OCT3, and all DMEs showed the highest protein expression in the proximal small intestine. Several proteins (i.e., P-gp, ASBT, CYP3A4, CYP3A5, CYP2C9, CYP2C19, and UGT1A1) showed an increase with age. Such increase appeared to be even more pronounced for DMEs. This exploratory study highlights the developmental changes in DTPs and DMEs in the intestinal tract of the pediatric population. Additional evaluation of protein function in this population would elucidate the implications of the presented changes in protein expression on absorption of orally administered drugs in neonates and pediatric patients.

Investigating Tacrolimus Disposition in Paediatric Patients with a Physiologically Based Pharmacokinetic Model Incorporating CYP3A4 Ontogeny, Mechanistic Absorption and Red Blood Cell Binding.

Tacrolimus is a crucial immunosuppressant for organ transplant patients, requiring therapeutic drug monitoring due to its variable exposure after oral intake. Physiologically based pharmacokinetic (PBPK) modelling has provided insights into tacrolimus disposition in adults but has limited application in paediatrics. This study investigated age dependency in tacrolimus exposure at the levels of absorption, metabolism, and distribution. Based on the literature data, a PBPK model was developed to predict tacrolimus exposure in adults after intravenous and oral administration. This model was then extrapolated to the paediatric population, using a unique reference dataset of kidney transplant patients. Selecting adequate ontogeny profiles for hepatic and intestinal CYP3A4 appeared critical to using the model in children. The best model performance was achieved by using the Upreti ontogeny in both the liver and intestines. To mechanistically evaluate the impact of absorption on tacrolimus exposure, biorelevant in vitro solubility and dissolution data were obtained. A relatively fast and complete release of tacrolimus from its amorphous formulation was observed when mimicking adult or paediatric dissolution conditions (dose, fluid volume). In both the adult and paediatric PBPK models, the in vitro dissolution profiles could be adequately substituted by diffusion-layer-based dissolution modelling. At the level of distribution, sensitivity analysis suggested that differences in blood plasma partitioning of tacrolimus may contribute to the variability in exposure in paediatric patients.

Correction: Van der Veken et al. Gastrointestinal Fluid Volumes in Pediatrics: A Retrospective MRI Study. Pharmaceutics 2022, 14, 1935.

In the original publication [...].

Characterization of neonatal and infant enterostomy fluids - part II: Drug solubility.

Previous research revealed marked differences in the composition of intestinal fluids between infants and adults. To explore the impact on the solubilization of orally administered drugs, the present study assessed the solubility of five poorly water-soluble, lipophilic drugs in intestinal fluid pools from 19 infant enterostomy patients (infant HIF). For some but not all drugs, the average solubilizing capacity of infant HIF was similar to that of HIF obtained from adults (adult HIF) in fed conditions. Commonly used fed state simulated intestinal fluids (FeSSIF(-V2)) predicted fairly well drug solubility in the aqueous fraction of infant HIF, but did not account for the substantial solubilization by the lipid phase of infant HIF. Despite similarities in the average solubilities of some drugs in infant HIF and adult HIF or SIF, the underlying solubilization mechanisms likely differ, considering important compositional differences (e.g., low bile salt levels). Finally, the huge variability in composition of infant HIF pools resulted in a highly variable solubilizing capacity, potentially causing variations in drug bioavailability. The current study warrants future research focusing on (i) understanding the mechanisms underlying drug solubilization in infant HIF and (ii) evaluating the sensitivity of oral drug products to interpatient variations in drug solubilization.

Characterization of Aspirated Duodenal Fluids from Parkinson's Disease Patients.

Parkinson's disease, one of the most common neurodegenerative diseases, may not only affect the motor system, but also the physiology of the gastrointestinal tract. Delayed gastric emptying, impaired motility and altered intestinal bacteria are well-established consequences of the disease, which can have a pronounced effect on the absorption of orally administered drugs. In contrast, no studies have been performed into the composition of intestinal fluids. It is not unlikely that Parkinson's disease also affects the composition of intestinal fluids, a critical factor in the in vitro and in silico simulation of drug dissolution, solubilization and absorption. In the current study, duodenal fluids were aspirated from Parkinson's disease (PD) patients and age-matched healthy controls (healthy controls, HC) consecutively in fasted and fed conditions. The fluids were then characterized for pH, buffer capacity, osmolality, total protein, phospholipids, bile salts, cholesterol and lipids. In a fasted state, the intestinal fluid composition was highly similar in PD patients and healthy controls. In general, the same was true for fed-state fluids, apart from a slightly slower and less pronounced initial change in factors directly affected by the meal (i.e., buffer capacity, osmolality, total protein and lipids) in PD patients. The absence of a fast initial increase for these factors immediately after meal intake, as was observed in healthy controls, might result from slower gastric emptying in PD patients. Irrespective of the prandial state, a higher relative amount of secondary bile salts was observed in PD patients, potentially indicating altered intestinal bacterial metabolism. Overall, the data from this study indicate that only minor disease-specific adjustments in small intestinal fluid composition should be considered when simulating intestinal drug absorption in PD patients.

Characterization of neonatal and infant enterostomy fluids.

The composition of gastrointestinal (GI) fluids is crucial for the dissolution, solubilization, and absorption of orally administered drugs. Disease- or age-related changes in GI fluid composition could significantly affect the pharmacokinetics of oral drugs. However, limited studies have been conducted on the characteristics of GI fluids in neonates and infants due to practical and ethical challenges. The current study collected enterostomy fluids from 21 neonate and infant patients over an extended period of time and from different regions of the small intestine and colon. The fluids were characterized for pH, buffer capacity, osmolality, total protein, bile salts, phospholipids, cholesterol, and lipid digestion products. The study found a large variability in the fluid characteristics among the different patients, in line with the highly heterogeneous study population. Compared to adult intestinal fluids, the enterostomy fluids from neonates and infants had low bile salt concentrations, with an increasing trend as a function of age; no secondary bile salts were detected. In contrast, total protein and lipid concentrations were relatively high, even in the distal small intestine. These findings suggest marked differences in intestinal fluid composition between neonates and infants versus adults, which may affect the absorption of certain drugs.

The impact of inflammation on the expression of drug transporters and metabolic enzymes in colonic tissue from ulcerative colitis patients.

The intestinal tract forms an important barrier against xenobiotics while allowing nutrients to pass. In ulcerative colitis (UC), a chronic inflammatory bowel disease, this barrier function is impaired leading to an abnormal immune response and inflammation of the colonic mucosa. Transporter proteins and metabolic enzymes are an integral part of the protective barrier in the gut and play an important role in the disposition of nutrients, toxins and oral drugs. In this study, the protein expression of 13 transporters and 13 enzymes was determined in the sigmoid and rectum of UC patients in endoscopic remission and during active inflammation. In inflamed conditions (endoscopic Mayo sub-score 1, 2 or 3), a significant decrease (q < 0.05) was observed in the median expression of the transporters P-gp (0.046 vs 0.529 fmol/µg protein), MRP4 (0.003 vs 0.023 fmol/µg protein) and MCT1 (0.287 vs 1.090 fmol/µg protein), and the enzymes CYP3A5 (0.031 vs 0.046 fmol/µg protein) and UGT2B7 (0.083 vs 0.176 fmol/µg protein). Moreover, during severe inflammation, the decrease was even more pronounced. Expression levels of other proteins were not altered during inflammation (e.g., OATP2B1, CYP3A4, CYP2B6 and UGT2B15). The results suggest a decreased transport and metabolism of xenobiotics in the colon of UC patients during active inflammation potentially altering local drug concentrations and thus treatment outcome.

Gastrointestinal Fluid Volumes in Pediatrics: A Retrospective MRI Study.

The volume and distribution of fluids available in the gastrointestinal (GI) tract may substantially affect oral drug absorption. Magnetic resonance imaging (MRI) has been used in the past to quantify these fluid volumes in adults and its use is now being extended to the pediatric population. The present research pursued a retrospective, explorative analysis of existing clinical MRI data generated for pediatric patients. Images of 140 children from all pediatric subpopulations were analyzed for their resting GI fluid volumes in fasting conditions. In general, an increase in fluid volume as a function of age was observed for the stomach, duodenum, jejunum, and small intestine (SI) as a whole. No specific pattern was observed for the ileum and colon. Body mass index (BMI), body weight, body height, and SI length were evaluated as easy-to-measure clinical estimators of the gastric and SI fluid volumes. Although weight and height were identified as the best estimators, none performed ideally based on the coefficient of determination (R2). Data generated in this study can be used as physiologically relevant input for biorelevant in vitro tests and in silico models tailored to the pediatric population, thereby contributing to the efficient development of successful oral drug products for children.

Structured solubility behaviour in bioequivalent fasted simulated intestinal fluids.

Drug solubility in intestinal fluid is a key parameter controlling absorption after the administration of a solid oral dosage form. To measure solubility in vitro simulated intestinal fluids have been developed, but there are multiple recipes and the optimum is unknown. This situation creates difficulties during drug discovery and development research. A recent study characterised sampled fasted intestinal fluids using a multidimensional approach to derive nine bioequivalent fasted intestinal media that covered over 90% of the compositional variability. These media have been applied in this study to examine the equilibrium solubility of twenty one exemplar drugs (naproxen, indomethacin, phenytoin, zafirlukast, piroxicam, ibuprofen, mefenamic acid, furosemide, aprepitant, carvedilol, tadalafil, dipyridamole, posaconazole, atazanavir, fenofibrate, felodipine, griseofulvin, probucol, paracetamol, acyclovir and carbamazepine) to determine if consistent solubility behaviour was present. The bioequivalent media provide in the majority of cases structured solubility behaviour that is consistent with physicochemical properties and previous solubility studies. For the acidic drugs (pKa < 6.3) solubility is controlled by media pH, the profile is identical and consistent and the lowest and highest pH media identify the lowest and highest solubility in over 70% of cases. For weakly acidic (pKa > 8), basic and neutral drugs solubility is controlled by a combination of media pH and total amphiphile concentration (TAC), a consistent solubility behaviour is evident but with variation related to individual drug interactions within the media. The lowest and highest pH × TAC media identify the lowest and highest solubility in over 78% of cases. A subset of the latter category consisting of neutral and drugs non-ionised in the media pH range have been identified with a very narrow solubility range, indicating that the impact of the simulated intestinal media on their solubility is minimal. Two drugs probucol and atazanavir exhibit unusual behaviour. The study indicates that the use of two appropriate bioequivalent fasted intestinal media from the nine will identify in vitro the maximum and minimum solubility boundaries for drugs and due to the media derivation this is probably applicable in vivo. These media could be applied during discovery and development activities to provide a solubility range, which would assist placement of the drug within the BCS/DCS and rationalise drug and formulation decisions.

Investigating the Mechanisms behind the Positive Food Effect of Abiraterone Acetate: In Vitro and Rat In Situ Studies.

The anticancer agent abiraterone suffers from an extensive positive food effect after oral intake of the prodrug abiraterone acetate (Zytiga). The underlying processes determining postprandial abiraterone absorption were investigated in this study. The impact of lipids and lipid digestion products on (i) the solubility of abiraterone acetate and abiraterone, (ii) the conversion of abiraterone acetate to abiraterone, and (iii) the passive permeation of abiraterone was determined in vitro. The interaction of abiraterone acetate and abiraterone with vesicles and colloidal structures in the simulated fed state media containing undigested lipids and lipid digestion products enhanced the solubility of both compounds but limited the esterase-mediated hydrolysis of abiraterone acetate and the potential of abiraterone to permeate. Rat in situ intestinal perfusion experiments with a suspension of abiraterone acetate in static fed state simulated media identified abiraterone concentrations in the perfusate as the main driving force for absorption. However, experiments with ongoing lipolysis in the perfusate highlighted the importance of including lipid digestion as a dynamic process when studying postprandial abiraterone absorption. Future research may employ the in situ perfusion model to study postprandial drug absorption from a dynamic lipolysis-mediated intestinal environment to provide reference data for the optimisation of relevant in vitro models to evaluate food effects.

Orlistat disposition in the human jejunum and the effect of lipolysis inhibition on bile salt concentrations and composition.

The lipolysis-mediated postprandial small intestinal environment is known to influence the solubilisation and subsequent absorption of lipophilic drugs. In a previously performed small-scale clinical study in healthy volunteers, co-administration of the lipase inhibitor orlistat increased jejunal solubilisation and systemic absorption of fenofibrate after intake of the lipid-based formulation Fenogal. In the present study, the jejunal disposition of the locally acting orlistat was assessed and linked to fenofibrate solubilisation. In addition, the effect of orlistat-induced lipolysis inhibition on bile salt concentrations and composition was evaluated. Orlistat was distributed predominantly in the lipid layer, as indicated by a 5- to 14-fold higher AUC0-320 min in the total jejunal samples as compared to the micellar layers. No effect of orally administered orlistat on bile salt composition or total concentrations (ranging from 1.5 to 24.8 mM and 1.8 to 33.2 mM with and without orlistat co-administration, respectively) could be observed. The intraluminal presence of orlistat in the total jejunal samples correlated with the increased fenofibrate solubilisation in the jejunum (r = 0.9344) and enhanced absorption (r = 0.8184), highlighting the importance of the intraluminal lipid phase in lipophilic drug absorption.

The effect of esomeprazole on the upper GI tract release and systemic absorption of mesalazine from colon targeted formulations.

The aim of the present study was to investigate the effect of coadministration of the proton pump inhibitor (PPI) esomeprazole on the upper GI tract behavior and systemic exposure of mesalazine from two mechanistically different colon targeted delivery systems: Claversal (pH-dependent release) and Pentasa (prolonged release). To this end, gastric, jejunal and systemic concentrations of mesalazine and its metabolite N-acetyl mesalazine were monitored in 5 healthy volunteers following oral intake of Pentasa or Claversal with or without PPI pre-treatment (cross-over study). Our exploratory study demonstrated that pre-treatment with a PPI may affect the release and absorption of mesalazine from formulations with different modified release mechanisms. Upon intake of Claversal, the onset of mesalazine absorption was accelerated substantially by PPI pre-treatment. While the PPI-induced increase in pH initiated the disintegration process already in the upper GI tract, the release of mesalazine started beyond the proximal jejunum. Upon intake of Pentasa, PPI pre-treatment seemed to increase the systemic exposure, even though the underlying mechanism could not be revealed yet. The faster release of mesalazine in the GI tract and/or the increased systemic absorption following PPI pre-treatment may reduce the ability of mesalazine to reach the colon. Future research assessing mesalazine disposition in the lower GI tract is warranted.

Practical and operational considerations related to paediatric oral drug formulation: An industry survey.

For over 15 years, US and EU regulations ensure that medicines developed for children are explicitly authorised for such use with age-appropriate forms and formulations, implying dedicated research. To shed light on how these regulations have been adopted by pharmaceutical companies and how various aspects of paediatric oral drug formulation development are currently handled, an exploratory survey was conducted. Topics included: general company policy, regulatory aspects, dosage form selection, in-vitro, in-silico and (non-)clinical in-vivo methods, and food effects assessment. The survey results clearly underline the positive impact of the paediatric regulations and their overall uptake across the pharmaceutical industry. Even though significant improvements have been made in paediatric product development, major challenges remain. In this respect, dosage form selection faces a discrepancy between the youngest age groups (liquid products preference) and older subpopulations (adult formulation preference). Additionally, concerted research is needed in the development and validation of in-vitro tools and physiology based pharmacokinetic models tailored to the paediatric population, and in estimating the effect of non-standard and paediatric relevant foods. The current momentum in paediatric drug development and research should allow for an evolution in standardised methodology and guidance to develop paediatric formulations, which would benefit pharmaceutical industry and regulators.

The Influence of Fed State Lipolysis Inhibition on the Intraluminal Behaviour and Absorption of Fenofibrate from a Lipid-Based Formulation.

The bioavailability of lipophilic drugs may or may not be increased when administered with food due to increased solubilisation in fed state gastrointestinal (GI) fluids. The in vivo interplay between drug solubilisation, lipid phase digestion and drug absorption is complex and remains poorly understood. This study aimed to investigate the role of fed state GI lipolysis on the intraluminal behaviour and absorption of fenofibrate, formulated as the lipid-based formulation Fenogal. Therefore, a crossover study was performed in healthy volunteers using orlistat as lipase inhibitor. Fenofibrate concentrations were determined in the proximal jejunum and linked to simultaneously assessed systemic fenofibric acid concentrations. Inhibition of lipolysis by orlistat resulted in a faster onset of absorption in 4 out of 6 volunteers, reflected by a decrease in systemic Tmax between 20 and 140 min. In addition, the increase of undigested lipids present in the small intestine upon orlistat co-administration sustained drug solubilisation for a longer period, resulting in higher fenofibrate concentrations in the jejunum and improved absorption in 5 out of 6 volunteers (median AUC0-8h 8377 vs. 5832 µM.min). Sustaining drug solubilisation in the lipid phase may thus contribute to the absorption of lipophilic drugs. More research into the different mechanisms underlying lipophilic drug absorption from fed state media at different levels of digestion is warranted.

Best practices in current models mimicking drug permeability in the gastrointestinal tract - An UNGAP review.

The absorption of orally administered drug products is a complex, dynamic process, dependant on a range of biopharmaceutical properties; notably the aqueous solubility of a molecule, stability within the gastrointestinal tract (GIT) and permeability. From a regulatory perspective, the concept of high intestinal permeability is intrinsically linked to the fraction of the oral dose absorbed. The relationship between permeability and the extent of absorption means that experimental models of permeability have regularly been used as a surrogate measure to estimate the fraction absorbed. Accurate assessment of a molecule's intestinal permeability is of critical importance during the pharmaceutical development process of oral drug products, and the current review provides a critique of in vivo, in vitro and ex vivo approaches. The usefulness of in silico models to predict drug permeability is also discussed and an overview of solvent systems used in permeability assessments is provided. Studies of drug absorption in humans are an indirect indicator of intestinal permeability, but both in vitro and ex vivo tools provide initial screening approaches and are important tools for assessment of permeability in drug development. Continued refinement of the accuracy of in silico approaches and their validation with human in vivo data will facilitate more efficient characterisation of permeability earlier in the drug development process and will provide useful inputs for integrated, end-to-end absorption modelling.