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An Introduction to Biopharmaceutics

Hannah Batchelor

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom

1.1 Introduction

The aim of this chapter is to introduce biopharmaceutics and to define some key terms used within biopharmaceutics. It will also briefly introduce where biopharmaceutics sits in the drug development process.

1.2 History of Biopharmaceutics

The term biopharmaceutics was introduced in the 1960s by Levy [1]. The word originates from the combination of bio- from the Greek meaning relating to living organisms or tissue and pharmaceutics defined as the science of pharmaceutical formulations; in this case the living organism is the person (or animal being treated). In modern parlance, the term biopharmaceutics encompasses the science associated with the physical/chemical properties of the drug product (including all components therein) and the interactions of this product with parameters linked to the route of administration that affect the rate and extent of drug uptake or presence at the site for local action. It combines knowledge of materials science; physiology; anatomy and physical sciences.

In more simple terms it is everything that controls the availability of the drug: that is how the drug exits the dosage form and travels to the systemic circulation (for systemically acting drugs) or to the local site of action for locally acting agents. It provides a link between the formulation and the clinical performance of a drug; a mechanistic understanding of biopharmaceutics ensures that the formulation is optimised in terms of exposure. This is shown schematically in Figure 1.1 where biopharmaceutics is focussed on absorption.

Figure 1.1 Schematic of the fate of drugs once administered orally; biopharmaceutics relates to the absorption aspect of this image.

The term biopharmaceutics can cause confusion; particularly with the advent of biopharmaceutical drug products. There is evidence in confusion in terminology back in the 1970s where efforts were made to standardise the terminology used [2]; these efforts defined biopharmaceutics in several ways according to the experts at the time of publication. The most widely used definition is, 'The study of the influence of formulation on the therapeutic activity of a drug product. Alternatively, it may be defined as a study of the relationship of the physical and chemical properties of the drug and its dosage form to the biological effects observed following the administration of the drug in its various dosage forms' [3].

An analysis of new drug approvals in 2019 (US, EU and Japan) showed that oral products represented the majority of approvals (50%) with tablets and capsules as the dominant oral dosage forms [4]. Thus biopharmaceutics has tended to focus on oral more than alternative routes of administration.

Historically biopharmaceutics was part of clinical pharmacology and pharmaceutical chemistry, only becoming its own scientific discipline in the 1970s. In scientific terms, the MeSH definition (MeSH [Medical Subject Headings] is the United States National Library of Medicine controlled vocabulary thesaurus used for indexing articles for PubMed) of biopharmaceutics (introduced in 1970) is, 'The study of the physical and chemical properties of a drug and its dosage form as related to the onset, duration and intensity of its action'. The MeSH term 'biopharmaceutics' being introduced in the 1970s provides an insight into the history of the topic; the scientific discipline existed long before but was previously listed in scientific data based under a bigger heading of pharmacology as:

Figure 1.2 Frequency of biopharmaceutics as a MESH terms in publications versus time.

Source: Data from Pubmed.gov, November 2020.

• Chemistry, Pharmaceutical (1966-1969)
• Drug Compounding (1966-1969)
• Drugs (1966-1969)
• Pharmacology (1966-1969)

A search in PubMed of 'Biopharmaceutics' [Mesh] conducted in November 2020 resulted in 2725 retrieved documents with a peak in the early 1970s as the science of biopharmaceutics developed. There has also been a general trend of increased use of the term biopharmaceutics since the year 2000. This is shown in Figure 1.2.

There have been a number of key events in the history of biopharmaceutics and these are highlighted in Figure 1.3.

1.3 Key Concepts and Definitions Used Within Biopharmaceutics

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...