On the processes limiting oral drug absorption when amorphous solid dispersions are administered after a high-calorie, high-fat meal: Sporanox® pellets.

OBJECTIVES: 1) Identify processes limiting the arrival of itraconazole at the intestinal epithelium when Sporanox® amorphous solid dispersion (ASD) pellets are transferred from the stomach through the upper small intestine, after a high-calorie, high-fat meal. 2) Evaluate whether itraconazole concentrations in the colloidal phase of aqueous contents of the upper small intestine are useful for the assessment of dose effects in the fed state and food effects on plasma levels. METHODS: Itraconazole concentrations, apparent viscosity, and solubilization capacity were measured in aspirates from the upper gastrointestinal lumen collected during a recently performed clinical study in healthy adults. Published itraconazole concentrations in plasma, after a high-calorie high-fat meal and Sporanox® ASD pellets, and in contents of the upper small intestine of healthy adults, after administration of Sporanox® ASD pellets in the fasted state, were used to achieve the second objective. RESULTS: When Sporanox® ASD pellets (up to 200 mg) are transferred from the stomach through the upper small intestine, after a high-calorie, high-fat meal, itraconazole concentrations in the colloidal phase or the micellar phase of aqueous contents of the upper small intestine are unsaturated, in most cases. During the first 3 h post-dosing after a high-calorie, high-fat meal, the impact of dose (200 mg vs. 100 mg) on itraconazole concentrations in the colloidal phase of aqueous contents of the upper small intestine seems to underestimate the impact of dose on plasma levels. When Sporanox® ASD pellets are administered after a high-calorie, high-fat meal at the 200 mg dose level, itraconazole concentrations in the colloidal phase of aqueous contents of the upper small intestine are, on average, lower than those achieved in fasted state. CONCLUSIONS: When Sporanox® ASD pellets are transferred from the stomach to the upper small intestine after a high-calorie, high-fat meal, itraconazole's arrival at the intestinal epithelium seems to be limited by its arrival at the colloidal phase of aqueous contents of the upper small intestine. The impact of dose (100 mg vs. 200 mg) on plasma levels after a high-calorie, high-fat meal and during the gastrointestinal transfer of Sporanox® pellets requires consideration of pre-systemic itraconazole metabolism. At the 200 mg dose level, after taking into consideration differences in the volume of the contents of the upper small intestine between the fasted and the fed state during the gastrointestinal transfer of Sporanox® ASD pellets, itraconazole concentrations in the colloidal phase of aqueous contents of the upper small intestine suggest a mild negative food effect on average plasma levels; published clinical data are inconclusive.

Understanding the Conditions Under Which Drugs are Transferred from the Stomach Through the Upper Small Intestine After a High-Calorie, High-Fat Meal.

Information on the conditions under which drugs are transferred from the stomach through the upper small intestine after a high-calorie, high-fat meal is very limited. To simulate the drug presence after disintegration and arrival in the antral region, paracetamol solution and Sporanox® amorphous solid dispersion pellets at two dose levels were administered to the antrum of 8 healthy adults 30 min after administration of a high-calorie, high-fat meal on a crossover basis. The overall median buffer capacity of antral contents was estimated to be 18.0 and 24.0 mmol/ml/ΔpH when titrating with NaOH and HCl, respectively. The corresponding values for the contents of upper the small intestine were 14.0 and 16.8 mmol/ml/ΔpH, respectively. The drug transfer process from the antrum through the upper small intestine occurred with apparent first-order kinetics. The best estimate for the antral emptying half-life was 39min and 45min for paracetamol and itraconazole, respectively, the apparent volume of contents of the upper small intestine was more than double compared with previously reported values in the fasted state, the half-life of drug elimination from the upper small intestine was similar to recent estimates for highly permeable drugs in the fasted state, and the apparent volume of antral contents during the first couple of hours post drug administration was 303mL. Information collected in this study could increase the reliability of in silico and/or in vitro modelling approaches applied in clinical drug development.

Drug Dissolution in Oral Drug Absorption: Workshop Report.

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.

Managing the clinical effects of drug-induced intestinal dysbiosis with a focus to antibiotics: Challenges and opportunities.

The term "intestinal dysbiosis" is used for indicating change(s) of the intestinal microbiota which have been associated with the development of diseases and the deterioration of disease treatments in humans. In this review, documented clinical effects of drug-induced intestinal dysbiosis are briefly presented, and methodologies which could be considered for the management of drug-induced intestinal dysbiosis based on clinical data are critically reviewed. Until relevant methodologies are optimized and/or their effectiveness to the general population is confirmed, and, since drug-induced intestinal dysbiosis refers predominantly to antibiotic-specific intestinal dysbiosis, a pharmacokinetically-based approach for mitigating the impact of antimicrobial therapy on intestinal dysbiosis is proposed.

Leveraging the use of in vitro and computational methods to support the development of enabling oral drug products: An InPharma commentary.

Due to the strong tendency towards poorly soluble drugs in modern development pipelines, enabling drug formulations such as amorphous solid dispersions, cyclodextrins, co-crystals and lipid-based formulations are frequently applied to solubilize or generate supersaturation in gastrointestinal fluids, thus enhancing oral drug absorption. Although many innovative in vitro and in silico tools have been introduced in recent years to aid development of enabling formulations, significant knowledge gaps still exist with respect to how best to implement them. As a result, the development strategy for enabling formulations varies considerably within the industry and many elements of empiricism remain. The InPharma network aims to advance a mechanistic, animal-free approach to the assessment of drug developability. This commentary focuses current status and next steps that will be taken in InPharma to identify and fully utilize 'best practice' in vitro and in silico tools for use in physiologically based biopharmaceutic models.

Usefulness of the Beagle Model in the Evaluation of Paracetamol and Ibuprofen Exposure after Oral Administration to Pediatric Populations: An Exploratory Study.

The present study aimed to explore the usefulness of beagle dogs in combination with physiologically based pharmacokinetic (PBPK) modeling in the evaluation of drug exposure after oral administration to pediatric populations at an early stage of pharmaceutical product development. An exploratory, single-dose, crossover bioavailability study in six beagles was performed. A paracetamol suspension and an ibuprofen suspension were coadministered in the fasted-state conditions, under reference-meal fed-state conditions, and under infant-formula fed-state conditions. PBPK models developed with GastroPlus v9.7 were used to inform the extrapolation of beagle data to human infants and children. Beagle-based simulation outcomes were compared with published human-adult-based simulations. For paracetamol, fasted-state conditions and reference-meal fed-state conditions in beagles appeared to provide adequate information for the applied scaling approach. Fasted-state and/or reference-meal fed-state conditions in beagles appeared suitable to simulate the performance of ibuprofen suspension in pediatric populations. Contrary to human-adult-based translations, extrapolations based on beagle data collected under infant-formula fed-state conditions appeared less useful for informing simulations of plasma levels in pediatric populations. Beagle data collected under fasted and/or reference-meal fed-state conditions appeared to be useful in the investigation of pediatric product performance of the two investigated highly permeable and highly soluble drugs in the upper small intestine. The suitability of the beagle as a preclinical model to understand pediatric drug product performance under different dosing conditions deserves further evaluation with a broader spectrum of drugs and drug products and comparisons with pediatric in vivo data.

The impact of advanced age on gastrointestinal characteristics that are relevant to oral drug absorption: An AGePOP review.

The purpose of this review is to summarize the current knowledge on three physiological determinants of oral drug absorption, i.e., gastric emptying, volumes and composition of luminal fluids, and intestinal permeability, in the advanced age population, so that potential knowledge gaps and directions for further research efforts are identified. Published data on gastric emptying rates in older people are conflicting. Also, there are significant knowledge gaps, especially on gastric motility and emptying rates of drugs and of non-caloric fluids. Compared with younger adults, volumes of luminal contents seem to be slightly smaller in older people. Our understanding on the impact of advanced age on luminal physicochemical characteristics is, at best, very limited, whereas the impact of (co)morbidities and geriatric syndromes in the advanced age population has not been addressed to date. The available literature on the effect of advanced age on intestinal permeability is limited, and should be approached with caution, primarily due to the limitations of the experimental methodologies used.

Screening for Differences in Early Exposure in the Fasted State with in Vitro Methodologies can be Challenging: Experience with the BioGIT System.

The Biorelevant Gastrointestinal Transfer (BioGIT) system is a useful screening tool for assessing the impact of dose and/or formulation on early exposure after administration of immediate release or enabling drug products with a glass of water in the fasted state. The objective of this study was to investigate potential limitations. BioGIT experiments were performed with five low solubility active pharmaceutical ingredients with weakly alkaline characteristics: mebendazole (tablet and chewable tablet), Compound E (aqueous solutions, three doses), pazopanib-HCl (Votrient™ tablet, crushed Votrient™ tablet and aqueous suspension), Compound B-diHCl (hard gelatin capsule, three doses) and Compound C (hard gelatin capsule containing nanosized drug and hard gelatin capsule containing micronized drug). For all formulation or dose comparisons the ratio of mean BioGIT AUC0-50 min values was not predictive of the ratio of mean plasma AUC0-60 min values which became available after completion of BioGIT experiments. BioGIT experimental conditions have not been designed to simulate the gastrointestinal drug transfer process after administration of chewable tablets or aqueous solutions, therefore, BioGIT may not be useful for the assessment of intraluminal performance early after administration of such drug products. Also, based on this study, BioGIT may not be useful in investigating the impact of dose and/or formulation on early exposure when the dose is not administered with a glass of water to fasted healthy individuals or when BioGIT data are highly variable. Finally, the rapid dissolution of nanocrystals after administration of low solubility weak bases may require adjustment of the pH in the gastric compartment of BioGIT to slightly higher pH values. Limitations identified in this study for the BioGIT system may be also relevant to other in vitro systems proposed for similar evaluations.

Usefulness of the BioGIT system in screening for differences in early exposure in the fasted state on an a priori basis.

The objective of the present study was to confirm the usefulness of BioGIT data in the evaluation of the impact of dose and/or formulation on early exposure after oral administration of immediate release or enabling products of low solubility active pharmaceutical ingredients (APIs) with a glass of water in the fasted state. BioGIT experiments were performed with four APIs: Compound Α (tablet, three dose levels), Compound E (capsule PiC1, capsule PiC2 and tablet), fenofibrate (Lipidil® capsule and Lipidil 145 ONE® tablet) and Compound F (HP-ß-CD aqueous solution and tablet). Based on mean plasma AUC0-60min values which became available after completion of the BioGIT experiments, mean BioGIT AUC0-50min values were useful for the evaluation of the impact of dose and/or formulation on early exposure. The log-transformed ratios of mean BioGIT AUC0-50min values for two doses and/or two formulations estimated in this study and in a recent study for two diclofenac potassium products (Cataflam® tablet and Voltfast® sachet, same dose) vs. the corresponding log-transformed ratios of mean plasma AUC0-60min values (n = 7 pairs of ratios), were included in a previously established correlation between log-transformed ratios of mean BioGIT AUC0-50min values and log-transformed ratios of plasma AUC0-60min values (n = 9 pairs of ratios). The correlation between log-transformed plasma AUC0-60min ratios vs. log-transformed BioGIT AUC0-50min ratios was confirmed (n = 16 pairs of ratios, R = 0.90). Compared with the previously established correlation the statistical characteristics were improved. Based on this study, the BioGIT system could be useful as a screening tool for assessing the impact of dose and/or formulation differences on early exposure, after administration of immediate release or enabling drug products of low solubility APIs with a glass of water in the fasted state, on an a priori basis.

Usefulness of Optimized Human Fecal Material in Simulating the Bacterial Degradation of Sulindac and Sulfinpyrazone in the Lower Intestine.

The first aim of this study was to evaluate the usefulness of optimized human fecal material in simulating sulforeductase activity in the lower intestine by assessing bacterial degradation of sulindac and sulfinpyrazone, two sulforeductase substrates. The second aim was to evaluate the usefulness of drug degradation half-life generated in simulated colonic bacteria (SCoB) in informing PBPK models. Degradation experiments of sulfinpyrazone and of sulindac in SCoB were performed under anaerobic conditions using recently described methods. For sulfinpyrazone, the abundance of clinical data allowed for construction of a physiologically based pharmacokinetic (PBPK) model and evaluation of luminal degradation clearance determined from SCoB data. For sulindac, the availability of sulindac sulfide and sulindac sulfone standards allowed for evaluating the formation of the main metabolite, sulindac sulfide, during the experiments in SCoB. Both model compounds degraded substantially in SCoB. The PBPK model was able to adequately capture exposure of sulfinpyrazone and its sulfide metabolite in healthy subjects, in ileostomy and/or colectomy subjects, and in healthy subjects pretreated with metoclopramide by implementing degradation half-lives in SCoB to calculate intrinsic colon clearance. Degradation rates of sulindac and formation rates of sulindac sulfide in SCoB were almost identical, in line with in vivo data suggesting the sulindac sulfide is the primary metabolite in the lower intestine. Experiments in SCoB were useful in simulating sulforeductase related bacterial degradation activity in the lower intestine. Degradation half-life calculated from experiments in SCoB is proven useful for informing a predictive PBPK model for sulfinpyrazone.

On the usefulness of four in vitro methods in assessing the intraluminal performance of poorly soluble, ionisable compounds in the fasted state.

A small-scale two-stage biphasic system, a small-scale two-stage dissolution-permeation system, the Erweka mini-paddle apparatus, and the BioGIT system were evaluated for their usefulness in assessing the intraluminal performance of two low solubility drugs in the fasted state, one with weakly acidic properties (tested in a salt form, diclofenac potassium) and one with weakly alkaline properties [ritonavir, tested as an amorphous solid dispersion (ASD) formulation]. In all in vitro methods, an immediate-release tablet and a powder formulation of diclofenac potassium were both rapidly dissolved in Level II biorelevant media simulating the conditions in the upper small intestine. Physiologically based biopharmaceutics (PBB) modelling for the tablet formulation resulted in a successful simulation of the average plasma profile in adults, whereas for the powder formulation modelling indicated that gastric emptying and transport through the intestinal epithelium limit the absorption rates. Detailed information on the behaviour of the ritonavir ASD formulation under both simulated gastric and upper small intestinal conditions were crucial for understanding the luminal performance. PBB modelling showed that the dissolution and precipitation parameters, estimated from the Erweka mini-paddle apparatus data and the small-scale two-stage biphasic system data, respectively, were necessary to adequately simulate the average plasma profile after administration of the ritonavir ASD formulation. Simulation of the gastrointestinal transfer process from the stomach to the small intestine was necessary to evaluate the effects of hypochlorhydric conditions on the luminal performance of the ritonavir ASD formulation. Based on this study, the selection of the appropriate in vitro method for evaluating the intraluminal performance of ionisable lipophilic drugs depends on the characteristics of the drug substance. The results suggest that for (salts of) acidic drugs (e.g., diclofenac potassium) it is only an issue of availability and ease of operation of the apparatus. For weakly alkaline substances (e.g., ritonavir), the results indicate that the dynamic dissolution process needs to be simulated, with the type of requested information (e.g., dissolution parameters, precipitation parameters, luminal concentrations) being key for selecting the most appropriate method. Regardless of the ionisation characteristics, early in the drug development process the use of small-scale systems may be inevitable, due to the limited quantities of drug substance available.

In Vitro Simulation of the Environment in the Upper Gastrointestinal Lumen After Drug Administration in the Fed State Using the TIM-1 System and Comparison With Luminal Data in Adults.

We evaluated the environment in TIM-1 luminal compartments using paracetamol and danazol solutions and suspensions and the fed state configuration. Data were compared with recently published data in healthy adults. TIM-1 experiments were performed with a 3-fold downscale. Volumes of secretions in gastric and duodenal compartments adequately reflected the luminal data in adults up to 3 h post drug dosing. pH values in duodenal and jejunal compartments adequately reflected average pH values in adults. In gastric compartment pH values where initially higher than average values in adults and reached baseline levels earlier than in adults. The environment in the TIM-1 gastric compartment and jejunal compartment adequately reflected the average total paracetamol and danazol amounts per volume of contents in the adult stomach and upper small intestine, respectively. Total bile acids concentrations in the micellar phase of contents in duodenal and jejunal compartments overestimated micellar concentrations in the upper small intestine of adults. Adjustments in gastric emptying/acid secretion rates and bile acids identities in the duodenal and jejunal compartments, and application of dynamic bile acids secretion rates are expected to further improve the relevance of luminal conditions in TIM-1 compartments with those in adults.

Integration of advanced methods and models to study drug absorption and related processes: An UNGAP perspective.

This collection of contributions from the European Network on Understanding Gastrointestinal Absorption-related Processes (UNGAP) community assembly aims to provide information on some of the current and newer methods employed to study the behaviour of medicines. It is the product of interactions in the immediate pre-Covid period when UNGAP members were able to meet and set up workshops and to discuss progress across the disciplines. UNGAP activities are divided into work packages that cover special treatment populations, absorption processes in different regions of the gut, the development of advanced formulations and the integration of food and pharmaceutical scientists in the food-drug interface. This involves both new and established technical approaches in which we have attempted to define best practice and highlight areas where further research is needed. Over the last months we have been able to reflect on some of the key innovative approaches which we were tasked with mapping, including theoretical, in silico, in vitro, in vivo and ex vivo, preclinical and clinical approaches. This is the product of some of us in a snapshot of where UNGAP has travelled and what aspects of innovative technologies are important. It is not a comprehensive review of all methods used in research to study drug dissolution and absorption, but provides an ample panorama of current and advanced methods generally and potentially useful in this area. This collection starts from a consideration of advances in a priori approaches: an understanding of the molecular properties of the compound to predict biological characteristics relevant to absorption. The next four sections discuss a major activity in the UNGAP initiative, the pursuit of more representative conditions to study lumenal dissolution of drug formulations developed independently by academic teams. They are important because they illustrate examples of in vitro simulation systems that have begun to provide a useful understanding of formulation behaviour in the upper GI tract for industry. The Leuven team highlights the importance of the physiology of the digestive tract, as they describe the relevance of gastric and intestinal fluids on the behaviour of drugs along the tract. This provides the introduction to microdosing as an early tool to study drug disposition. Microdosing in oncology is starting to use gamma-emitting tracers, which provides a link through SPECT to the next section on nuclear medicine. The last two papers link the modelling approaches used by the pharmaceutical industry, in silico to Pop-PK linking to Darwich and Aarons, who provide discussion on pharmacometric modelling, completing the loop of molecule to man.

Oral biopharmaceutics tools: recent progress from partnership through the Pharmaceutical Education and Research with Regulatory Links collaboration.

OBJECTIVES: To summarise key contributions of the Pharmaceutical Education and Research with Regulatory Links (PEARRL) project (2016-2020) to the optimisation of existing and the development of new biopharmaceutics tools for evaluating the in vivo performance of oral drug products during the development of new drugs and at the regulatory level. KEY FINDINGS: Optimised biopharmaceutics tools: Based on new clinical data, the composition of biorelevant media for simulating the fed state conditions in the stomach was simplified. Strategies on how to incorporate biorelevant in vitro data of bio-enabling drug products into physiologically based pharmacokinetic (PBPK) modelling were proposed. Novel in vitro biopharmaceutics tools: Small-scale two-stage biphasic dissolution and dissolution-permeation setups were developed to facilitate understanding of the supersaturation effects and precipitation risks of orally administered drugs. A porcine fasted state simulated intestinal fluid was developed to improve predictions and interpretation of preclinical results using in vitro dissolution studies. Based on new clinical data, recommendations on the design of in vitro methodologies for evaluating the GI drug transfer process in the fed state were suggested. The optimized design of in vivo studies for investigating food effects: A food effect study protocol in the pig model was established which successfully predicted the food-dependent bioavailability of two model compounds. The effect of simulated infant fed state conditions in healthy adults on the oral absorption of model drugs was evaluated versus the fasted state and the fed state conditions, as defined by regulatory agencies for adults. Using PBPK modelling, the extrapolated fasted and infant fed conditions data appeared to be more useful to describe early drug exposure in infants, while extrapolation of data collected under fed state conditions, as defined by regulators for adults, failed to capture in vivo infant drug absorption. SUMMARY: Substantial progress has been made in developing an advanced suite of biopharmaceutics tools for streamlining drug formulation screening and supporting regulatory applications. These advances in biopharmaceutics were achieved through networking opportunities and research collaborations provided under the H2020 funded PEARRL project.

Impact of gastrointestinal tract variability on oral drug absorption and pharmacokinetics: An UNGAP review.

The absorption of oral drugs is frequently plagued by significant variability with potentially serious therapeutic consequences. The source of variability can be traced back to interindividual variability in physiology, differences in special populations (age- and disease-dependent), drug and formulation properties, or food-drug interactions. Clinical evidence for the impact of some of these factors on drug pharmacokinetic variability is mounting: e.g. gastric pH and emptying time, small intestinal fluid properties, differences in pediatrics and the elderly, and surgical changes in gastrointestinal anatomy. However, the link of colonic factors variability (transit time, fluid composition, microbiome), sex differences (male vs. female) and gut-related diseases (chronic constipation, anorexia and cachexia) to drug absorption variability has not been firmly established yet. At the same time, a way to decrease oral drug pharmacokinetic variability is provided by the pharmaceutical industry: clinical evidence suggests that formulation approaches employed during drug development can decrease the variability in oral exposure. This review outlines the main drivers of oral drug exposure variability and potential approaches to overcome them, while highlighting existing knowledge gaps and guiding future studies in this area.

Current challenges and future perspectives in oral absorption research: An opinion of the UNGAP network.

Although oral drug delivery is the preferred administration route and has been used for centuries, modern drug discovery and development pipelines challenge conventional formulation approaches and highlight the insufficient mechanistic understanding of processes critical to oral drug absorption. This review presents the opinion of UNGAP scientists on four key themes across the oral absorption landscape: (1) specific patient populations, (2) regional differences in the gastrointestinal tract, (3) advanced formulations and (4) food-drug interactions. The differences of oral absorption in pediatric and geriatric populations, the specific issues in colonic absorption, the formulation approaches for poorly water-soluble (small molecules) and poorly permeable (peptides, RNA etc.) drugs, as well as the vast realm of food effects, are some of the topics discussed in detail. The identified controversies and gaps in the current understanding of gastrointestinal absorption-related processes are used to create a roadmap for the future of oral drug absorption research.

Characteristics of Contents of Lower intestine in the 65-74 Years of Age Range Could Impact the Performance of Safe and Efficacious Modified Release Products.

We characterized the contents of distal ileum and proximal colon of older people from a pharmaceutical product performance perspective, under two extreme situations, i.e. 5 h after a glass of water to fasted volunteers (fasted state) and 5 h after a high-calorie, high-fat meal to fasted volunteers (fed state). Five males and three females (65-70 y) participated in a two-phase crossover study. Contents were collected via colonoscopy. In distal ileum, luminal pH was lower and buffer capacity was higher than in young adults; differences reached significance for pH in the fed state. In proximal colon, differences reached significance for pH/fasted state and for buffer capacity/both fasted and fed states. Aqueous fraction of contents contained more short chain fatty acids than previously observed in young adults. In distal ileum, osmolality was significantly higher than in young adults. In proximal colon, aqueous fraction in the fasted state was significantly lower and long chain fatty acids 5 h after meal was significantly higher than in young adults. Characteristics of contents of lower intestine that are relevant to the performance of certain modified release products differ between individuals 65-74 years old and young adults, the typical age group employed in safety and efficacy studies of oral drug products.

Factors Affecting Successful Extrapolation of Ibuprofen Exposure from Adults to Pediatric Populations After Oral Administration of a Pediatric Aqueous Suspension.

The importance of physiologically based pharmacokinetic (PBPK) model refinement with data acquired in adults using a pediatric formulation under age-relevant dosing conditions in order to extrapolate drug exposure to infants was recently demonstrated for paracetamol. In the present investigation, the aim was to evaluate the importance of similar PBPK model refinement for a low-solubility weak acid, ibuprofen, to simulate exposure across pediatric populations, i.e., infants, young children, and schoolchildren. After developing and evaluating adult disposition and oral absorption models for the aqueous suspension of ibuprofen, ibuprofen performance was extrapolated to pediatrics simulating exposure as a function of different prandial and dosing conditions: fasted conditions, reference-meal fed conditions (solid-liquid meal), and infant-formula fed conditions (homogeneous liquid). Successful predictions were achieved when employing the refined model for fasted state conditions or for fed state conditions relevant to specific age groups, i.e., infant formula for infants and reference meal for children. The present study suggested that ibuprofen performance was primarily guided by gastric emptying and showed sensitivity towards formulation characteristics and pH changes in the small intestine. Better understanding of luminal conditions in pediatrics and age-dependent ibuprofen post-absorptive processes could improve modeling confidence for ibuprofen, as well as other drugs with similar characteristics.

Successful Extrapolation of Paracetamol Exposure from Adults to Infants After Oral Administration of a Pediatric Aqueous Suspension Is Highly Dependent on the Study Dosing Conditions.

Extending licensed drug use to the pediatric population has become an essential part of the drug development process. Nonetheless, ethical concerns limit clinical testing in pediatric populations and data collected from oral bioavailability and food effect studies in adults are often extrapolated to the target pediatric (sub)populations. However, based on published information, food effects on drug absorption in infants may not be adequately evaluated by data collected in adults. In the present study, a physiologically based pharmacokinetic (PBPK) approach for modeling paracetamol suspension data collected in adults was proposed with the ultimate aim to investigate whether extrapolation to infants is substantially affected by the dosing conditions applied to adults. The development of the PBPK model for adults was performed using GastroPlus™ V9.7, and after scaling to infants considering physiological, anatomical, and drug clearance changes, extrapolation of the different dosing conditions was performed by applying dosing conditions dependent on changes on the paracetamol gastric emptying process. Successful simulations of previously observed plasma concentration levels in infants were achieved when extrapolating from fasted and infant formula-fed conditions data. Data collected following the reference meal appeared less useful for simulating paracetamol suspension performance in infants. The proposed methodology deserves further evaluation using high-quality clinical data both in adults and in infants.