Biopharmaceutics. Группа авторов

This office is responsible for the generation, implementation and review of biopharmaceutics‐related guidance, policies and practices. There are several biopharmaceutics specific FDA regulatory guidance papers issues that are critical to the approval of new drugs. Similar to the USA there are many global regulatory bodies where biopharmaceutics guidance has been issued including the EMA (European Medicines Agency) and the Japanese Food and Drug Administration. Recently the ICH M9 guidance has sought to align these where possible for the BCS classification.

Biopharmaceutics interfaces with several other scientific disciplines, this book aims to provide a background to biopharmaceutics and to showcase how knowledge can be applied to the efficient development of drug products. The level of detail in terms of biopharmaceutics knowledge of a drug and a drug product will increase during the drug development process. This is shown schematically in Figure 1.4.

      Biopharmaceutics is an important scientific discipline, particularly for those developing new drugs. An understanding of biopharmaceutics aids in the design of appropriate drug candidates (Chapter 7) as well as optimised drug products (Chapter 8) to ensure that the drug is well absorbed from the site of administration. Clinical testing of drugs, from phase 1 to phase 4 clinical trials is expensive and time‐consuming. Biopharmaceutics tests and knowledge are critical to de‐risk changes in the clinical performance as a result of minor changes in the product and process used to manufacture the drug product used within these clinical trials. There is a strong relationship between biopharmaceutics and regulatory science during the development of drug products.

Figure 1.4 Overview of biopharmaceutics input in the drug development pathway.

1.5 Conclusions

      Biopharmaceutics is a relatively new science that brings together knowledge on anatomy and physiology to understand the biological environment where drugs are absorbed with materials science to appreciate the drug and excipient related effects on these processes. This book brings together the knowledge required to better understand biopharmaceutics and to apply this knowledge in the development of drug products.

References

      1 [1] Levy, G. and Nelson, E. (1961). Pharmaceutical formulation and therapeutic efficacy. JAMA 177 (10): 689–691.

      2 [2] Zathurecký, L. (1977). Progress in developing a standard terminology in biopharmaceutics and pharmacokinetics. Drug. Intell. Clin. Pharm. 11 (5): 281–296.

      3 [3] Wagner, J.G. (1961). Biopharmaceutics: absorption aspects. J. Pharm. Sci. 50: 359–387.

      4 [4] Sedo, T.K. (2020). 2019 Global drug delivery & formulation report part 1 a review of 2019 product approvals. Drug Develop. Deliv. 20 (2): 18–23.

      5 [5] Amidon, G.L., Lennernäs, H., Shah, V.P., and Crison, J.R. (1995). A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm. Res. 12 (3): 413–420.

      6 [6] Butler, J.M. and Dressman, J.B. (2010). The developability classification system: application of biopharmaceutics concepts to formulation development. J. Pharm. Sci. 99 (12): 4940–4954.

2 Basic Pharmacokinetics

       Hamid A. Merchant

       Department of Pharmacy, School of Applied Sciences, University of Huddersfield, Huddersfield, United Kingdom

2.1 Introduction

      This chapter aims to introduce basic pharmacokinetic terminologies and principles underpinning a drug's life cycle in the body, from administration to elimination. The chapter will help readers to understand a typical pharmacokinetic profile following drug administration via absorptive versus non‐absorptive routes.

      The understanding of the critical role of absorption processes in pharmacokinetics will help in understanding how biopharmaceutics principles and strategies can modulate the pharmacokinetic profile of a drug and in turn affect the therapeutics.

2.2 What is ‘Pharmacokinetics’?

      The term pharmacokinetics refers to the principles underpinning the absorption, distribution, metabolism and elimination of a drug following its administration into the body. The drug can be administered via a range of routes; many require absorption of the drug from the site of administration to get into the blood circulation, whereas drug can also be administered directly into the blood circulation (intravenously) bypassing the absorption process.

The clinical efficacy of a drug relies on the delivery of a drug to the receptor site at the required concentration to produce a therapeutic effect. A drug, therefore, must bypass the barriers at the absorptive site and the metabolic challenges for successful delivery to the target site. The life cycle of a drug typically means that it goes ‘into’ the body, goes ‘around’ the body, exerts its pharmacological effects and comes ‘out’ of the body (Figure 2.1).

Figure 2.1 Illustration showing a typical life cycle of a drug in the body (RBCs = red blood cells).

      When a drug is administered into the body, it is absorbed from the tissues where it was administered (e.g., muscles, gastrointestinal tract under the skin, etc.) to get into blood circulation. It is then distributed across the body once it is in the systemic circulation where a fraction of the drug arrives at the target sites, binds the receptors and produces a therapeutic effect. The drug is also metabolised by various tissues (mainly liver and gut) into other forms (mainly inactive) during its voyage into the body and then it is excreted out of the body, mainly via urine. The ‘pharmacokinetics’ is the study of the processes governing the ‘absorption’, ‘distribution’, ‘metabolism’ and ‘excretion’ of a drug, often referred to as ADME.

2.3 Pharmacokinetic Profile

A typical pharmacokinetic profile represents a drug concentration in blood (or plasma or serum) over a period of time usually measured post drug administration until most of the drug is eliminated from the body. The shape of the plasma drug concentration–time profile depends on the route of administration of the drug. If the drug was administered intravenously, it becomes available in the systemic circulation instantly and the drug concentration is hypothetically at its maximum following its administration; this will gradually decline with time as the drug is eliminated from the body (Figure 2.2).

      When the drug is administered into the tissues, for example, muscles (intramuscular injection) or taken orally (tablets, capsules, etc.), it has to go through a complex absorption process before it appears in the blood. Hence, there is a significant lag time to see the therapeutic effect of the drug compared to intravenous administration. This is one reason when the intravenous route