Biopharmaceutics. Группа авторов

as the site where absorption occurs. Formulation scientists can design dosage forms for a range of sites for administration and understanding how the fraction absorbed varies by site of administration is important for systemically acting drugs. Absorption can be complex and is not a single‐step process; there are often several membranes or other barriers that lie between the site of administration and the site of measurement (or action) for a drug. The permeability (Chapter 5) of the drug across each of these barriers will dictate the fraction that can traverse the membrane. Measuring the fraction absorbed at each membrane is not possible and often there is a single point for administration and a single point for measurement which can complicate accurate determination of the fraction absorbed. This is exemplified in oral absorption of drugs. Drugs will enter the gastro‐intestinal system where some of the drug will be solubilised and will traverse the intestinal membrane; however, there may be some metabolism at the intestinal wall meaning that not all the drug absorbed reaches the systemic circulation. Furthermore, the portal vein drains from the intestine directly into the liver where further metabolism is likely to occur again reducing the quantity of drug present in the systemic circulation. The site of measurement; typically a blood or plasma sample taken peripherally will only show the drug that successfully traversed the intestinal wall AND was not metabolised within the liver; therefore this is lower than the actual fraction of drug absorbed.

      First pass metabolism is the term used to describe the fraction of drug lost between entering the portal vein directly from the intestine and existing the liver. This describes the fraction of drug lost during the first pass through the liver, prior to reaching the sampling site.

      The oral route is the most common route of drug administration and as such much of this book will focus on oral biopharmaceutics; however there are chapters on alternative routes of administration (Chapter 14: Inhaled Biopharmaceutics; Chapter 15: Biopharmaceutics of Injectable Formulations and Chapter 16: Topical Bioavailability).

A key factor that influences the absorption of drug from the gastro‐intestinal tract is the solubility (Chapter 4) of the drug within the intestinal fluids. The intestinal fluids are complex, affected by food and many other factors associated with ethnicity, disease and gender (Chapter 13: Special Populations). Understanding the composition of intestinal fluids and replication of this for in vitro models is of huge interest to those working within biopharmaceutics. Due to the transit time within the intestinal tract, it is not just the solubility that is important but the rate of drug dissolution (Chapter 6) within the fluids present that will influence the rate and extent of drug absorption.

      The biopharmaceutics classification system (BCS) (Chapter 9), introduced in 1995 by Gordon Amidon [5], sought to classify drugs based on their dissolution and permeability as these factors are fundamental in controlling the rate and extent of oral absorption. This system is still in use in regulatory science and has been extended to also look at the developability of drugs [6]. The BCS can also justify a biowaiver; this is a situation where the in vitro solubility and permeability data can negate the need for a clinical study to demonstrate bioequivalence, resulting in a large cost saving for those involved in development.

      The major emphasis of research in biopharmaceutics is the development of in vitro and in silico model that predict how a drug will be absorbed in vivo. Thus the use of biorelevant models that replicate the physiology, anatomy and local environment within the gastro‐intestinal tract (or other site of administration) are important. In particular, the use of physiologically based pharmacokinetic (PBPK) models (Chapter 12) that not only replicate the body but also provide indications on the population‐based variability in drug absorption.

1.4 The Role of Biopharmaceutics in Drug Development

      Drug development is a complex process that involves many scientists, a lot of money and at least 10 years. The process starts with target identification where chemicals are manufactured to ‘fit’ the receptor of interest and they are typically ranked by potency for that receptor. At this stage, there is little biopharmaceutics input. The next step is to evaluate the lead chemicals using preclinical models; this can be cell lines or animal models to determine whether the chemical is as potent in vivo. At this stage, some biopharmaceutics input is crucial as the drug may need to be formulated for administration to the animal model and may even be administered orally so the fraction absorbed can be measured. This often relates to the ‘drugability’ of the lead candidates; defined as the technical evaluation of whether a compound will be a commercially successful drug. Drugability here relates to the likelihood for sufficient and non‐variable pharmacokinetic exposure.

Success in preclinical models will trigger clinical evaluation in humans. There are three phases of clinical trial prior to launch of a product: phase 1 will measure safety and efficacy of a compound in healthy volunteers where possible; at this stage the bioavailable dose will be assessed. Phase 2 studies explore the safety and efficacy of the drug in patients with the disease of interest. The product used for phases 1 and 2 is often different to the final commercial product as the dose is still to be defined. Thus there may be differences in the bioavailable fraction of each formulation administered that needs to be accounted for when interpreting the data and determining the dose. The term bridging is used to describe how any differences between formulations used in preclinical and clinical testing are managed during the clinical testing. Phase 3 studies evaluate the efficacy and safety in a large patient population. Where possible the final commercial formulation will be used in phase 3 studies as these are pivotal to underpinning the evidence to justify the introduction of a new product. Biopharmaceutics is integral to the phases of clinical testing as predictive models to understand absorption and consequences of bridging are critical to the success of the interpretation of clinical data.

      In parallel to the clinical evaluation (phase 1, 2 and 3 studies) work will be ongoing to ensure that the chemistry manufacturing and controls (CMC) activities are on track. These CMC activities ensure that the product and manufacturing process meet the stringent regulatory requirements ensuring that a safe and high‐quality product is available to the patient population. Any changes to the product or manufacturing process need to be understood, particularly if there are likely to be consequences to the patient; thus biorelevant predictive tests are of value in de‐risking the development process. In addition to biorelevant tests, often discriminatory dissolution testing is required; this is a method that links to clinical data and shows where changes in the product (as a result of composition or manufacturing changes) are likely to have an effect on the clinical performance. These discriminatory dissolution tests are generated by links to in vivo clinical data; either using an in vitro in vivo relationship (IVIVR) or using the principles of quality by design (QbD).

      Regulatory approval of new products is essential. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) brings together the regulatory authorities and pharmaceutical industry to discuss scientific and technical aspects of drug registration. ICH guidelines include information on biopharmaceutics that are essential for the approval of medicines. Two guidelines are focussed on biopharmaceutics specifically: ICH M9 Biopharmaceutics classification system based biowaivers and M13 Bioequivalence for Immediate release solid oral dosage forms. Within the US the major regulatory agency is the FDA (Food and Drug Administration); the FDA have a Biopharmaceutics