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.

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.

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.

Combining biorelevant in vitro and in silico tools to investigate the in vivo performance of the amorphous solid dispersion formulation of etravirine in the fed state.

INTRODUCTION: In the development of bio-enabling formulations, innovative in vivo predictive tools to understand and predict the in vivo performance of such formulations are needed. Etravirine, a non-nucleoside reverse transcriptase inhibitor, is currently marketed as an amorphous solid dispersion (Intelence® tablets). The aims of this study were 1) to investigate and discuss the advantages of using biorelevant in vitro setups to simulate the in vivo performance of Intelence® 100 mg and 200 mg tablets in the fed state, 2) to build a Physiologically Based Pharmacokinetic (PBPK) model by combining experimental data and literature information with the commercially available in silico software Simcyp® Simulator V17.1 (Certara UK Ltd.), and 3) to discuss the challenges of predicting the in vivo performance of an amorphous solid dispersion and identify the parameters which influence the pharmacokinetics of etravirine most. METHODS: Solubility, dissolution and transfer experiments were performed in various biorelevant media simulating the fasted and fed state environment in the gastrointestinal tract. An in silico PBPK model for etravirine in healthy volunteers was developed in the Simcyp® Simulator, using in vitro results and data available from the literature as input. The impact of pre- and post-absorptive parameters on the pharmacokinetics of etravirine was investigated by simulating various scenarios. RESULTS: In vitro experiments indicated a large effect of naturally occurring solubilizing agents on the solubility of etravirine. Interestingly, supersaturated concentrations of etravirine were observed over the entire duration of dissolution experiments on Intelence® tablets. Coupling the in vitro results with the PBPK model provided the opportunity to investigate two possible absorption scenarios, i.e. with or without implementation of precipitation. The results from the simulations suggested that a scenario in which etravirine does not precipitate is more representative of the in vivo data. On the post-absorptive side, it appears that the concentration dependency of the unbound fraction of etravirine in plasma has a significant effect on etravirine pharmacokinetics. CONCLUSIONS: The present study underlines the importance of combining in vitro and in silico biopharmaceutical tools to advance our knowledge in the field of bio-enabling formulations. Future studies on other bio-enabling formulations can be used to further explore this approach to support rational formulation design as well as robust prediction of clinical outcomes.

Evaluation of Three Amorphous Drug Delivery Technologies to Improve the Oral Absorption of Flubendazole.

This study investigates 3 amorphous technologies to improve the dissolution rate and oral bioavailability of flubendazole (FLU). The selected approaches are (1) a standard spray-dried dispersion with hydroxypropylmethylcellulose (HPMC) E5 or polyvinylpyrrolidone-vinyl acetate 64, both with Vitamin E d-α-tocopheryl polyethylene glycol succinate; (2) a modified process spray-dried dispersion (MPSDD) with either HPMC E3 or hydroxypropylmethylcellulose acetate succinate (HPMCAS-M); and (3) confining FLU in ordered mesoporous silica (OMS). The physicochemical stability and in vitro release of optimized formulations were evaluated following 2 weeks of open conditions at 25°C/60% relative humidity (RH) and 40°C/75% RH. All formulations remained amorphous at 25°C/60% RH. Only the MPSDD formulation containing HPMCAS-M and 3/7 (wt./wt.) FLU/OMS did not crystallize following 40°C/75% RH exposure. The OMS and MPSDD formulations contained the lowest and highest amount of hydrolyzed degradant, respectively. All formulations were dosed to rats at 20 mg/kg in suspension. One FLU/OMS formulation was also dosed as a capsule blend. Plasma concentration profiles were determined following a single dose. In vivo findings show that the OMS capsule and suspension resulted in the overall highest area under the curve and Cmax values, respectively. These results cross-evaluate various amorphous formulations and provide a link to enhanced biopharmaceutical performance.

Optimisation of carbomer viscous eye drops: an in vitro experimental design approach using rheological techniques.

The optimisation of the in vitro interaction between several poly(acrylic acid) derivatives (Carbopol 1342P NF, Carbopol 974P and Carbopol 980 NF) and mucin was performed by an analysis technique combining oscillatory shear rheology and experimental design in order to improve the formulation of carbomer viscous eye drops.First, standard oscillation procedures were used to characterise the polyacrylic acid and mucin dispersions, and to investigate the influence of several polymer-related factors (concentration, preparation, type of polymer used) on the rheological properties. Second, an experimental plan design was developed to investigate the effect of polymer-related factors on the mucoadhesive indexes (MAI(G') and MAI(G")) which were calculated using the viscoelastic data obtained from polymer/mucin, polymer/tearfluid and mucin/tearfluid mixtures. Optimal mucoadhesive interactions were determined based on the experimental design results. Finally, the optima were fully characterised rheologically to further verify the mucoadhesive capacity. The main conclusion is that the factor influencing most explicitly the mucoadhesive interaction of the viscous eye drop is the mucin concentration and neither the type of polyacrylic acid, nor its concentration.

The use of xanthan gum in an ophthalmic liquid dosage form: rheological characterization of the interaction with mucin.

The development of an ocular dosage form containing xanthan gum and capable of interacting with mucin in the precorneal area is a challenge. The polymer concentration that can be applied is restricted because of the limited patient acceptability of highly viscous preparations. The precorneal mucin concentration is low and the high ionic strength of the lachrymal fluid forces xanthan gum in an ordered structure, less capable of interacting through heterotypic junctions. Intrinsic viscosity measurements and shear rheometry are used to investigate the effect of several factors (polymer concentration, additional boiling or sonication step to the preparation procedure) on the physicochemical properties of xanthan gum and the degree of interaction with a low (8%, w/v) and high (16.0%, w/v) concentrated mucin dispersion. Independent of the preparation procedure applied, a xanthan gum concentration of 1.0% (w/v) is required to obtain a measurable interaction with mucin. If an extra boiling or sonication step is added to the standard preparation procedure, the minimum mucin concentration necessary to achieve formation of heterotypic junctions is decreased. Only by sonication of the highly concentrated xanthan gum dispersion is the viscosity decreased to a level that is tolerable and comfortable to the patient. The findings of the present study clearly demonstrate that a significant interaction between a tolerable and comfortable ocular dosage form containing xanthan gum, and mucin 8% (w/v), is feasible after sonication of a highly concentrated polymer dispersion.