Читать книгу Biopharmaceutics - Группа авторов - Страница 15

There is a strong link between biopharmaceutics and pharmacokinetics. Pharmacokinetics measures the concentration of drug at a site in the body versus time. Understanding the biopharmaceutics will influence the pharmacokinetic profile observed. In particular, biopharmaceutics has a focus on the absorption phase of a drug as this is the phase where the dosage form design has influence over the pharmacokinetic profile. The metabolism and subsequent elimination and excretion are driven by the drug properties rather than those of the formulation used to administer the drug.

Pharmacokinetic studies provide information on drug concentrations (typically in plasma or blood) versus time; these studies can be used to demonstrate safety and efficacy of a drug as well as compare the relative performance of alternative dosage forms (for further details see Chapter 2). This performance can be by design, for example, to develop a sustained release product to alter dosing frequency. Generation of statistically similar pharmacokinetic profiles for alternative drug products provides reassurance that these medicines can be interchanged with limited effects on clinical efficacy. These statistically similar pharmacokinetic profiles show bioequivalence between drug products, this bioequivalence is discussed more in the chapter on regulatory biopharmaceutics (Chapter 10). This is of great importance for generic medicine development to ensure that medicines can be interchanged with not clinical impact to the patient.

Figure 1.3 Overview of the biopharmaceutics timeline of key events.

Pharmacokinetic data can be analysed to demonstrate what fraction of the drug administered orally was measured within the system; this fraction is termed the bioavailable dose. It is recognised that not all drug administered will reach the site of measurement as some will be lost due to: localised degradation; failure to permeate membranes to reach the site of measurement; metabolism between site of absorption and site of measurement. Calculation of the bioavailability of a drug is important in dosage form design as it will influence the dose to be administered as well as the likelihood of reaching the target concentration at the site of measurement (and site of action). This can also be termed the bioperformance of a product.

The processes that influence the bioavailable dose are key to the science of biopharmaceutics. There is emphasis on the fraction of drug absorbed as this relates to the inherent drug properties and how they link with the dosage form as well 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.