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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.
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Acetaminofén , Analgésicos no Narcóticos , Estudios Cruzados , Agua , Humanos , Acetaminofén/farmacocinética , Acetaminofén/administración & dosificación , Acetaminofén/sangre , Anciano , Masculino , Femenino , Agua/química , Analgésicos no Narcóticos/farmacocinética , Analgésicos no Narcóticos/administración & dosificación , Analgésicos no Narcóticos/sangre , Anciano de 80 o más Años , Área Bajo la Curva , Persona de Mediana Edad , Comprimidos , Administración OralRESUMEN
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.
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Ácidos y Sales Biliares , Colon , Ayuno , Humanos , Femenino , Masculino , Adulto , Colon/metabolismo , Ayuno/metabolismo , Ácidos y Sales Biliares/metabolismo , Adulto Joven , Concentración de Iones de Hidrógeno , Fosfolípidos/metabolismo , Concentración Osmolar , Lípidos , Ácidos Grasos Volátiles/metabolismoRESUMEN
Chikungunya virus (CHIKV) is a mosquito-borne virus transmitted by Aedes mosquitoes. While there are no antiviral therapies currently available to treat CHIKV infections, several licensed oral drugs have shown significant anti-CHIKV activity in cells and in mouse models. However, the efficacy in mosquitoes has not yet been assessed. Such cross-species antiviral activity could be favorable, since virus inhibition in the mosquito vector might prevent further transmission to vertebrate hosts. Here, we explored the antiviral effect of ß-d-N4-hydroxycytidine (NHC, EIDD-1931), the active metabolite of molnupiravir, on CHIKV replication in Aedes aegypti mosquitoes. Antiviral assays in mosquito cells and in ex vivo cultured mosquito guts showed that NHC had significant antiviral activity against CHIKV. Exposure to a clinically relevant concentration of NHC did not affect Ae. aegypti lifespan when delivered via a bloodmeal, but it slightly reduced the number of eggs developed in the ovaries. When mosquitoes were exposed to a blood meal containing both CHIKV and NHC, the compound did not significantly reduce virus infection and dissemination in the mosquitoes. This was confirmed by modelling and could be explained by pharmacokinetic analysis, which revealed that by 6 h post-blood-feeding, 90% of NHC had been cleared from the mosquito bodies. Our data show that NHC inhibited CHIKV replication in mosquito cells and gut tissue, but not in vivo when mosquitoes were provided with a CHIKV-infectious bloodmeal spiked with NHC. The pipeline presented in this study offers a suitable approach to identify anti-arboviral drugs that may impede replication in mosquitoes.
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Aedes , Fiebre Chikungunya , Virus Chikungunya , Citidina/análogos & derivados , Animales , Ratones , Virus Chikungunya/fisiología , Replicación Viral , AntiviralesRESUMEN
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.
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Proteínas Portadoras , Imidazoles , Proteínas de Transporte de Membrana , Compuestos de Organosilicio , Adulto , Recién Nacido , Humanos , Niño , Proteínas de Transporte de Membrana/metabolismo , Intestino Delgado/metabolismo , Hígado/metabolismoRESUMEN
BACKGROUND AND PURPOSE: The pathophysiology of obesity has been the product of extensive research, revealing multiple interconnected mechanisms contributing to body weight regulation. The regulation of energy balance involves an intricate network, including the gut-neuroendocrine interplay. As a consequence, research on the gut-brain-microbiota axis in obesity has grown extensively. The physiology of the gastrointestinal tract, far from being underexplored, has significant implications for the development of specific complications in people living with obesity across the fields of gastroenterology, nutrition, and pharmacology. Clinical research indicates higher fasting bile acids serum levels, and blunted postprandial increases in bilious secretions in people living with obesity. Findings are less straightforward for the impact of obesity on gastric emptying with various studies reporting accelerated, normal, or delayed gastric emptying rates. Conversely, the effect of obesity on gastrointestinal pH, gastrointestinal transit, and gastric and pancreatic enzyme secretion is largely unknown. In this review, we explore the current evidence on the gastrointestinal physiology of obesity.
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Tránsito Gastrointestinal , Obesidad , Humanos , Obesidad/complicaciones , Tránsito Gastrointestinal/fisiología , Peso Corporal , Ayuno , Estómago , Motilidad Gastrointestinal/fisiología , Vaciamiento Gástrico , Tracto GastrointestinalRESUMEN
Janus kinase (JAK) inhibitors are effective anti-inflammatory agents for treatment of ulcerative colitis (UC).1 According to drug regulatory agencies and international guidelines, JAK inhibitors should be avoided during pregnancy and lactation.2-4 The existing evidence on safety of JAK inhibitors during pregnancy is scarce and almost exclusively limited to tofacitinib.4-7.
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The aim of the current study was (1) to develop an automation-based protocol for in vitro assessment of enzymatic drug stability at fasted- and fed-state intestinal conditions, (2) to characterize the inter-individual variability of drug degradation in fasted- and fed-state human intestinal fluids, and (3) to compare the obtained in vitro results to drug degradation in human intestinal fluids by taking variability into account. In human intestinal fluids, drug degradation displayed large inter-individual variability, with coefficients of variance generally ranging between 30 and 70 %. The effect of food on the inter-individual variability was highly dependent on the type of drug. The increase of pH in the range between 5.0 and 7.0 significantly accelerated the degradation rate of the studied drugs both in the in vitro and ex vivo experiments. In contrast, the increase of bile salt and phospholipid concentrations in the in vitro screen decreased strongly the degradation rate of the hydrophobic drugs. The developed automated in vitro screen mimicked relatively well the ex vivo degradation of all drugs in the fasted state, whereas in the fed state the degradation of only one of the drugs was adequately reproduced.
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Profármacos , Humanos , Solubilidad , Intestinos/química , Intestino Delgado , Ayuno/metabolismoRESUMEN
The in-person workshop "Drug Dissolution in Oral Drug Absorption" was held on May 23-24, 2023, in Baltimore, MD, USA. The workshop was organized into lectures and breakout sessions. Three common topics that were re-visited by various lecturers were amorphous solid dispersions (ASDs), dissolution/permeation interplay, and in vitro methods to predict in vivo biopharmaceutics performance and risk. Topics that repeatedly surfaced across breakout sessions were the following: (1) meaning and assessment of "dissolved drug," particularly of poorly water soluble drug in colloidal environments (e.g., fed conditions, ASDs); (2) potential limitations of a test that employs sink conditions for a poorly water soluble drug; (3) non-compendial methods (e.g., two-stage or multi-stage method, dissolution/permeation methods); (4) non-compendial conditions (e.g., apex vessels, non-sink conditions); and (5) potential benefit of having both a quality control method for batch release and a biopredictive/biorelevant method for biowaiver or bridging scenarios. An identified obstacle to non-compendial methods is the uncertainty of global regulatory acceptance of such methods.
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Biofarmacia , Absorción Intestinal , Humanos , Liberación de Fármacos , Solubilidad , AguaRESUMEN
Drug permeation across the intestinal epithelium is a prerequisite for successful oral drug delivery. The increased interest in oral administration of peptides, as well as poorly soluble and poorly permeable compounds such as drugs for targeted protein degradation, have made permeability a key parameter in oral drug product development. This review describes the various in vitro, in silico and in vivo methodologies that are applied to determine drug permeability in the human gastrointestinal tract and identifies how they are applied in the different stages of drug development. The various methods used to predict, estimate or measure permeability values, ranging from in silico and in vitro methods all the way to studies in animals and humans, are discussed with regard to their advantages, limitations and applications. A special focus is put on novel techniques such as computational approaches, gut-on-chip models and human tissue-based models, where significant progress has been made in the last few years. In addition, the impact of permeability estimations on PK predictions in PBPK modeling, the degree to which excipients can affect drug permeability in clinical studies and the requirements for colonic drug absorption are addressed.
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The rate and extent of colon absorption are important determinants of the in vivo performance of extended-release (ER) drug products. The ability to appropriately predict this at different stages of development using mechanistic physiologically based biopharmaceutic modeling (PBBM) is highly desirable. This investigation aimed to evaluate the prediction performance of three different approaches to account for colon absorption in predictions of the in vivo performance of ER drug product variants with different in vitro release profiles. This was done by mechanistic predictions of the absorption and plasma exposure of the ER drug products using GastroPlus and GI-Sim for five drugs with different degrees of colon absorption limitations in humans. Colon absorption was accounted for in the predictions using three different approaches: (1) by an a priori approach using the default colon models, (2) by fitting the colon absorption scaling factors to the observed plasma concentration-time profiles after direct administration to the colon in humans, or (3) from the ER drug product variant with the slowest in vitro release profile. The prediction performance was evaluated based on the percentage prediction error and the average absolute prediction error (AAPE). Two levels of acceptance criteria corresponding to highly accurate (AAPE ≤ 20%) and accurate (AAPE 20-50%) predictions were defined prior to the evaluation. For the a priori approach, the relative bioavailability (Frel), AUC0-t, and Cmax of the ER drug product variants for the low to medium colon absorption limitation risk drugs was accurately predicted with an AAPE range of 11-53 and 8-59% for GastroPlus and GI-Sim, respectively. However, the prediction performance was poor for the high colon absorption limitation risk drugs. Moreover, accounting for the human regional colon absorption data in the models did not improve the prediction performance. In contrast, using the colon absorption scaling factors derived from the slowest ER variant significantly improved the prediction performance regardless of colon absorption limitation, with a majority of the predictions meeting the high accuracy criteria. For the slowest ER approach, the AAPE ranges were 5-24 and 5-32% for GastroPlus and GI-Sim, respectively, excluding the low permeability drug. In conclusion, the a priori PBBM can be used during candidate selection and early product design to predict the in vivo performance of ER drug products for low to medium colon absorption limitation risk drugs with sufficient accuracy. The results also indicate a limited value in performing human regional absorption studies in which the drug is administered to the colon as a bolus to support PBBM development for ER drug products. Instead, by performing an early streamlined relative bioavailability study with the slowest relevant ER in vitro release profile, a highly accurate PBBM suitable for ER predictions for commercial and regulatory applications can be developed, except for permeability-limited drugs.
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Biofarmacia , Absorción Intestinal , Humanos , Biofarmacia/métodos , Absorción Intestinal/fisiología , Preparaciones Farmacéuticas/metabolismo , Disponibilidad Biológica , Colon/metabolismo , Modelos Biológicos , Solubilidad , Administración OralRESUMEN
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.
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In the original publication [...].
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This study aimed at developing the Diamod® as a dynamic gastrointestinal transfer model with physically interconnected permeation. The Diamod® was validated by studying the impact of the intraluminal dilution of a cyclodextrin-based itraconazole solution and the negative food effect for indinavir sulfate for which clinical data are available demonstrating that the systemic exposure was strongly mediated by interconnected solubility, precipitation, and permeation processes. The Diamod® accurately simulated the impact of water intake on the gastrointestinal behavior of a Sporanox® solution. Water intake significantly decreased the duodenal solute concentrations of itraconazole as compared to no intake of water. Despite this duodenal behavior the amount of permeated itraconazole was not affected by water intake as observed in vivo. Next to this, the Diamod® accurately simulated the negative food effect for indinavir sulfate. Different fasted and fed state experiments demonstrated that this negative food effect was mediated by an increased stomach pH, entrapment of indinavir in colloidal structures and the slower gastric emptying of indinavir under fed state conditions. Therefore, it can be concluded that the Diamod® is a useful in vitro model to mechanistically study the gastrointestinal performance of drugs.
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The older population consisting of persons aged 65 years or older is the fastest-growing population group and also the major consumer of pharmaceutical products. Due to the heterogenous ageing process, this age group shows high interindividual variability in the dose-exposure-response relationship and, thus, a prediction of drug safety and efficacy is challenging. Although physiologically based pharmacokinetic (PBPK) modelling is a well-established tool to inform and confirm drug dosing strategies during drug development for special population groups, age-related changes in absorption are poorly accounted for in current PBPK models. The purpose of this review is to summarise the current state-of-knowledge in terms of physiological changes with increasing age that can influence the oral absorption of dosage forms. The capacity of common PBPK platforms to incorporate these changes and describe the older population is also discussed, as well as the implications of extrinsic factors such as drug-drug interactions associated with polypharmacy on the model development process. The future potential of this field will rely on addressing the gaps identified in this article, which can subsequently supplement in-vitro and in-vivo data for more robust decision-making on the adequacy of the formulation for use in older adults and inform pharmacotherapy.
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Suplementos Dietéticos , Desarrollo de Medicamentos , Modelos Biológicos , Simulación por ComputadorRESUMEN
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.
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Líquidos Corporales , Enterostomía , Adulto , Recién Nacido , Humanos , Lactante , Solubilidad , Ayuno , Intestinos , Disponibilidad Biológica , Preparaciones Farmacéuticas , Absorción IntestinalRESUMEN
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.
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Background and objectives: To investigate the effect of carbohydrate intake before laparoscopic Roux-en-Y gastric bypass (LRYGB) on body weight, body composition and glycaemic status after surgery. Methods: In a tertiary centre cohort study, dietary habits, body composition and glycaemic status were evaluated before and 3, 6 and 12 months after LRYGB. Detailed dietary food records were processed by specialized dietitians on the basis of a standard protocol. The study population was subdivided according to relative carbohydrate intake before surgery. Results: Before surgery, 30 patients had a moderate relative carbohydrate intake (26%-45%, M-CHO), a mean body mass index (BMI) of 40.4 ± 3.9â kg/m² and a mean glycated haemoglobin A1c (A1C) of 6.5 ± 1.2% compared to 20 patients with a high relative carbohydrate intake (> 45%, H-CHO), mean BMI of 40.9 ± 3.7â kg/m² (non-significant, NS) and a mean A1C of 6.2% (NS). One year after surgery, body weight, body composition and glycaemic status were similar in the M-CHO (n = 25) and H-CHO groups (n = 16), despite less caloric intake in the H-CHO group (1317 ± 285â g vs. 1646 ± 345â g in M-CHO, p < 0.01). Their relative carbohydrate intake converged to 46% in both groups, but the H-CHO group reduced the absolute total carbohydrate consumption more than the M-CHO group (190 ± 50â g in M-CHO vs. 153 ± 39â g in H-CHO, p < 0.05), and this was especially pronounced for the mono- and disaccharides (86 ± 30â g in M-CHO vs. 65 ± 27â g in H-CHO, p < 0.05). Conclusion: A high relative carbohydrate intake before LRYGB, did not influence the change in body composition or diabetes status after surgery, despite a significantly lower total energy intake and less mono- and disaccharide consumption after surgery.
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Colon absorption is a key determinant for successful development of extended release and colon targeted drug products. This is the first systematic evaluation of the ability to predict in vivo regional differences in absorption and the extent of colon absorption in humans using mechanistic physiologically based biopharmaceutics modeling (PBBM). A new dataset, consisting of 19 drugs with a wide range of biopharmaceutics properties and extent of colon absorption in humans, was established. Mechanistic predictions of the extent of absorption and plasma exposure after oral, or jejunal and direct colon administration were performed in GastroPlus and GI-Sim using an a priori approach. Two new colon models developed in GI-Sim, were also evaluated to assess if the prediction performance could be improved. Both GastroPlus and GI-Sim met the pre-defined criteria for accurate predictions of regional and colon absorption for high permeability drugs irrespective of formulation type, while the prediction performance was poor for low permeability drugs. For solutions, the two new GI-Sim colon models improved the colon absorption prediction performance for the low permeability drugs while maintaining the accurate prediction performance for the high permeability drugs. In contrast, the prediction performance decreased for non-solutions using the two new colon models. In conclusion, PBBM can be used with sufficient accuracy to predict regional and colon absorption in humans for high permeability drugs in candidate selection as well as early design and development of extended release or colon targeted drug products. The prediction performance of the current models needs to be improved to allow high accuracy predictions for commercial drug product applications including highly accurate predictions of the entire plasma concentration-time profiles as well as for low permeability drugs.