Bertil Abrahamsson

The gastrointestinal microbiota as a site for the biotransformation of drugs

There are 100 trillion microbes in the human gastrointestinal tract with numbers increasing distally. These microbiota secrete a diverse array of enzymes (primarily for carbohydrate and protein fermentation) giving them substantial metabolic potential which can have major implications for drug stability. At least thirty drugs which are, or have been, available commercially, were subsequently shown to be substrates for these bacterial enzymes, and with increasing numbers of new and existing drugs having the potential for contact with the distal gut (through modified release systems or poor solubility/permeability), many more are expected to be discovered. The major concern with bacterial drug degradation is the behaviour of the metabolite; is it more or less active than the parent compound, or has toxicity resulted? For example, there were eighteen deaths in 1993 due to a drug interaction in which a toxic drug metabolite was produced by bacterial fermentation. Thus, the objective of this review is the provision of a comprehensive overview of this area; the gastrointestinal microbiota, their drug substrates and metabolic mechanisms, and approaches to studying this further are discussed.

The Effects of Food on the Dissolution of Poorly Soluble Drugs in Human and in Model Small Intestinal Fluids

PurposeThis study was conducted to determine the effect of food on drug solubility and dissolution rate in simulated and real human intestinal fluids (HIF).MethodsDissolution rate obtained via the rotating disk method and saturation solubility studies were carried out in fed and fasted state HIF, fed dog (DIF), and simulated (FeSSIF) intestinal fluid for six aprotic low solubility drugs. The intestinal fluids were characterized with respect to physical–chemical characteristics and contents.ResultsFed HIF provided a 3.5- to 30-times higher solubility compared to fasted HIF and FeSSIF, whereas fed DIF corresponded well (difference of less than 30%) to fed HIF. The increased solubility of food could mainly be attributed to dietary lipids and bile acids. The dissolution rate was also 2 to 7 times higher in fed HIF than fasted HIF. This was well predicted by both DIF and FeSSIF (difference of less than 30%).ConclusionsIntestinal solubility is higher in fed state compared to fasted state. However, the dissolution rate does not increase to the same extent. Dog seems to be a good model for man with respect to dissolution in the small intestine after intake of a meal, whereas FeSSIF is a poorer means of determining intestinal saturation solubility in the fed state.

The use of biopharmaceutic classification of drugs in drug discovery and development: current status and future extension.

Bioavailability (BA) and bioequivalence (BE) play a central role in pharmaceutical product development and BE studies are presently being conducted for New Drug Applications (NDAs) of new compounds, in supplementary NDAs for new medical indications and product line extensions, in Abbreviated New Drug Applications (ANDAs) of generic products and in applications for scale‐up and post‐approval changes. The Biopharmaceutics Classification System (BCS) has been developed to provide a scientific approach for classifying drug compounds based on solubility as related to dose and intestinal permeability in combination with the dissolution properties of the oral immediate‐release (IR) dosage form. The aim of the BCS is to provide a regulatory tool for replacing certain BE studies by accurate in‐vitro dissolution tests. The aim of this review is to present the status of the BCS and discuss its future application in pharmaceutical product development. The future application of the BCS is most likely increasingly important when the present framework gains increased recognition, which will probably be the case if the BCS borders for certain class II and III drugs are extended. The future revision of the BCS guidelines by the regulatory agencies in communication with academic and industrial scientists is exciting and will hopefully result in an increased applicability in drug development. Finally, we emphasize the great use of the BCS as a simple tool in early drug development to determine the rate‐limiting step in the oral absorption process, which has facilitated the information between different experts involved in the overall drug development process. This increased awareness of a proper biopharmaceutical characterization of new drugs may in the future result in drug molecules with a sufficiently high permeability, solubility and dissolution rate, and that will automatically increase the importance of the BCS as a regulatory tool over time.

In vitro models for the prediction of in vivo performance of oral dosage forms.

Accurate prediction of the in vivo biopharmaceutical performance of oral drug formulations is critical to efficient drug development. Traditionally, in vitro evaluation of oral drug formulations has focused on disintegration and dissolution testing for quality control (QC) purposes. The connection with in vivo biopharmaceutical performance has often been ignored. More recently, the switch to assessing drug products in a more biorelevant and mechanistic manner has advanced the understanding of drug formulation behavior. Notwithstanding this evolution, predicting the in vivo biopharmaceutical performance of formulations that rely on complex intraluminal processes (e.g. solubilization, supersaturation, precipitation…) remains extremely challenging. Concomitantly, the increasing demand for complex formulations to overcome low drug solubility or to control drug release rates urges the development of new in vitro tools. Development and optimizing innovative, predictive Oral Biopharmaceutical Tools is the main target of the OrBiTo project within the Innovative Medicines Initiative (IMI) framework. A combination of physico-chemical measurements, in vitro tests, in vivo methods, and physiology-based pharmacokinetic modeling is expected to create a unique knowledge platform, enabling the bottlenecks in drug development to be removed and the whole process of drug development to become more efficient. As part of the basis for the OrBiTo project, this review summarizes the current status of predictive in vitro assessment tools for formulation behavior. Both pharmacopoeia-listed apparatus and more advanced tools are discussed. Special attention is paid to major issues limiting the predictive power of traditional tools, including the simulation of dynamic changes in gastrointestinal conditions, the adequate reproduction of gastrointestinal motility, the simulation of supersaturation and precipitation, and the implementation of the solubility-permeability interplay. It is anticipated that the innovative in vitro biopharmaceutical tools arising from the OrBiTo project will lead to improved predictions for in vivo behavior of drug formulations in the GI tract.

Gastric flow and mixing studied using computer simulation

The fed human stomach displays regular peristaltic contraction waves that originate in the proximal antrum and propagate to the pylorus. High–resolution concurrent manometry and magnetic resonance imaging (MRI) studies of the stomach suggest a primary function of antral contraction wave (ACW) activity unrelated to gastric emptying. Detailed evaluation is difficult, however, in vivo. Here we analyse the role of ACW activity on intragastric fluid motions, pressure, and mixing with computer simulation. A two–dimensional computer model of the stomach was developed with the ‘lattice–Boltzmann’ numerical method from the laws of physics, and stomach geometry modelled from MRI. Time changes in gastric volume were specified to match global physiological rates of nutrient liquid emptying. The simulations predicted two basic fluid motions: retrograde ‘jets’ through ACWs, and circulatory flow between ACWs, both of which contribute to mixing. A well–defined ‘zone of mixing’, confined to the antrum, was created by the ACWs, with mixing motions enhanced by multiple and narrower ACWs. The simulations also predicted contraction–induced peristaltic pressure waves in the distal antrum consistent with manometric measurements, but with a much lower pressure amplitude than manometric data, indicating that manometric pressure amplitudes reflect direct contact of the catheter with the gastric wall. We conclude that the ACWs are central to gastric mixing, and may also play an indirect role in gastric emptying through local alterations in common cavity pressure.

In vivo methods for drug absorption - comparative physiologies, model selection, correlations with in vitro methods (IVIVC), and applications for formulation/API/excipient characterization including food effects.

This review summarizes the current knowledge on anatomy and physiology of the human gastrointestinal tract in comparison with that of common laboratory animals (dog, pig, rat and mouse) with emphasis on in vivo methods for testing and prediction of oral dosage form performance. A wide range of factors and methods are considered in addition, such as imaging methods, perfusion models, models for predicting segmental/regional absorption, in vitro in vivo correlations as well as models to investigate the effects of excipients and the role of food on drug absorption. One goal of the authors was to clearly identify the gaps in todays knowledge in order to stimulate further work on refining the existing in vivo models and demonstrate their usefulness in drug formulation and product performance testing.

In silico predictions of gastrointestinal drug absorption in pharmaceutical product development : Application of the mechanistic absorption model GI-Sim

Oral drug delivery is the predominant administration route for a major part of the pharmaceutical products used worldwide. Further understanding and improvement of gastrointestinal drug absorption predictions is currently a highly prioritized area of research within the pharmaceutical industry. The fraction absorbed (fabs) of an oral dose after administration of a solid dosage form is a key parameter in the estimation of the in vivo performance of an orally administrated drug formulation. This study discloses an evaluation of the predictive performance of the mechanistic physiologically based absorption model GI-Sim. GI-Sim deploys a compartmental gastrointestinal absorption and transit model as well as algorithms describing permeability, dissolution rate, salt effects, partitioning into micelles, particle and micelle drifting in the aqueous boundary layer, particle growth and amorphous or crystalline precipitation. Twelve APIs with reported or expected absorption limitations in humans, due to permeability, dissolution and/or solubility, were investigated. Predictions of the intestinal absorption for different doses and formulations were performed based on physicochemical and biopharmaceutical properties, such as solubility in buffer and simulated intestinal fluid, molecular weight, pK(a), diffusivity and molecule density, measured or estimated human effective permeability and particle size distribution. The performance of GI-Sim was evaluated by comparing predicted plasma concentration-time profiles along with oral pharmacokinetic parameters originating from clinical studies in healthy individuals. The capability of GI-Sim to correctly predict impact of dose and particle size as well as the in vivo performance of nanoformulations was also investigated. The overall predictive performance of GI-Sim was good as >95% of the predicted pharmacokinetic parameters (C(max) and AUC) were within a 2-fold deviation from the clinical observations and the predicted plasma AUC was within one standard deviation of the observed mean plasma AUC in 74% of the simulations. GI-Sim was also able to correctly capture the trends in dose- and particle size dependent absorption for the study drugs with solubility and dissolution limited absorption, respectively. In addition, GI-Sim was also shown to be able to predict the increase in absorption and plasma exposure achieved with nanoformulations. Based on the results, the performance of GI-Sim was shown to be suitable for early risk assessment as well as to guide decision making in pharmaceutical formulation development.

Toward an Increased Understanding of the Barriers to Colonic Drug Absorption in Humans: Implications for Early Controlled Release Candidate Assessment

The purpose of this study was to increase the understanding of in vivo colonic drug absorption in humans by summarizing and evaluating all regional in vivo human absorption data with focus on the interpretation of the colonic absorption data in relation to intestinal permeability and solubility. In addition, the usefulness of the Biopharmaceutics Classification System (BCS) in early assessment of the in vivo colonic absorption potential of controlled release drug candidates was investigated. Clinical regional absorption data (Cmax, Tmax, and AUC) of 42 drugs were collected from journal articles, abstracts, and internal reports, and the relative bioavailability in the colon (Frel(colon)) was obtained directly or calculated. Bioavailability, fraction dose absorbed, and information if the compounds were substrates for P-glycoprotein (P-gp) or cytochrome P450 3A (CYP3A) were also obtained. The BCS I drugs were well absorbed in the colon (Frel(colon) > 70%), although some drugs had lower values due to bacterial degradation in the colon. The low permeability drugs (BCS III/IV) had a lower degree of absorption in the colon (Frel(colon) < 50%). There was a clear correlation between in vitro Caco-2 permeability and Frel(colon), and atenolol and metoprolol may function as permeability markers for low and high colonic absorption, respectively. No obvious effect of P-gp on the colonic absorption of the drugs in this study was detected. There was insufficient data available to fully assess the impact of low solubility and slow dissolution rate. The estimated in vivo fractions dissolved of the only two compounds administered to the colon as both a solution and as solid particles were 55% and 92%, respectively. In conclusion, permeability and solubility are important barriers to colonic absorption in humans, and in vitro testing of these properties is recommended in early assessment of colonic absorption potential.

Clinical relevance of dissolution testing in quality by design.

Quality by design (QbD) has recently been introduced in pharmaceutical product development in a regulatory context and the process of implementing such concepts in the drug approval process is presently on-going. This has the potential to allow for a more flexible regulatory approach based on understanding and optimisation of how design of a product and its manufacturing process may affect product quality. Thus, adding restrictions to manufacturing beyond what can be motivated by clinical quality brings no benefits but only additional costs. This leads to a challenge for biopharmaceutical scientists to link clinical product performance to critical manufacturing attributes. In vitro dissolution testing is clearly a key tool for this purpose and the present bioequivalence guidelines and biopharmaceutical classification system (BCS) provides a platform for regulatory applications of in vitro dissolution as a marker for consistency in clinical outcomes. However, the application of these concepts might need to be further developed in the context of QbD to take advantage of the higher level of understanding that is implied and displayed in regulatory documentation utilising QbD concepts. Aspects that should be considered include identification of rate limiting steps in the absorption process that can be linked to pharmacokinetic variables and used for prediction of bioavailability variables, in vivo relevance of in vitro dissolution test conditions and performance/interpretation of specific bioavailability studies on critical formulation/process variables. This article will give some examples and suggestions how clinical relevance of dissolution testing can be achieved in the context of QbD derived from a specific case study for a BCS II compound.

Jejunal permeability and hepatic extraction of fluvastatin in humans

The primary objective was to investigate the effective permeability and the hepatic extraction of fluvastatin, a new 3‐hydroxy‐3‐methylglutaryl‐coenzyme A (HMG‐CoA) reductase inhibitor, during a jejunal perfusion in humans. The secondary objective was to investigate the relationship between human jejunal effective permeability values and physicochemical properties for four different drugs.