Biopharmaceutics and Clinical Pharmacokinetics

An Introduction, Fourth Edition,

Robert E. Notari

• Publisher: Routledge
• Year: 2017
• ISBN:
  9781351463843
• Edition: 4
• Topic: Physical Sciences
• Subtopic: Chemistry
• Index: Chemistry

For a decade and a half, Biopharmaceutics and Clinical Pharmacokinetics has been used in theclassrooms around the world as an introductory textbook on biophannaceutics and phannacokinetics. Now, the new Fourth Edition, Revised and Expanded further enhances the preceding editions'proven features, introducing significant advances in clinical pharmacokinetics, pharmacokineticdesign of drugs and dosage forms, and model-independent analyses. Still usable without prior knowledge of calculus or kinetics, this successfully implemented workbookmaintains a carefully graduated "building block" presentation, incorporating sample problemsand exercises throughout for a thorough understanding of the material.Biopharmaceutics and Clinical Pharmacokinetics features a growth-oriented format that systematicallydevelops and interrelates all subject matter... introduces basic theory and fields of application... emphasizes model-independent pharmacokinetic analyses... presents biopharmaceutical aspectsof product design and evaluation... offers a unique approach to teaching dosage regimen design andindividualization... and considers structural modification of drug molecules for problems associatedwith pharmacokinetics. As a comprehensive coverage of the basic principles and the recent achievements in the field, noother textbook does as much for students of pharmacy, pharmacology, medicinal chemistry, andmedicine, or for scientists who desire a simple but thorough introduction to theory and application.

1

Introduction

It is both an enlightening and astonishing experience to read the labels on so-called cure-alls and tonics on display in museums and occasionally found collecting dust in remote corners of storerooms in old established pharmacies. Since we are no longer obliged to take these medicines when we become ill, we may even see a great deal of humor in their claims. Therapeutic effectiveness was generally certified on the basis of testimonials or anecdotal evidence. Modesty was not a characteristic of promotional statements. Hamlin’s Wizard Oil, “The Great Medical Wonder,” recognized no limitations in stating, “There is no sore it will not heal. No pain it will not subdue.” Dr. King’s New Discovery was favorably compared with other recent inventions such as the steamship, steam engine, automobile, telephone, telegraph, and radio. According to the advertisement, it rated well as “The Greatest of All.” “No-To-Bac made a man of me,” another advertisement read, and, picturing a young man embracing a young woman, it noted that by use of this product he had “thrown away his pipe and tobacco and thereby won the love of this stunning girl.” A delightful review of that era can be found in the book One for a Man, Two for a Horse [1]. That title in itself shows that individualization of dosage regimens (discussed in Chap. 6 of this text) is not as innovative as one might think. As a final example of immodest claims and an unbelievable dosage regimen, consider the statement regarding Pond’s Extract and made by the popular fictional character Buster Brown: “From my own personal experiences, Pond’s Extract is the best remedy for all inflammations, hemorrhages, sprains, cuts, bruises, chill blains, burns, scalds, frostbite.” So much for the indications. Now for the clinical results: “It has made a better and healthier boy of me and is my best friend.” And finally the dosage regimen: “Used externally, internally, and eternally.”

How well did the products and claims of yesteryear measure up to the standards of today? One might use the following criteria:

1.  Contents

2.  Percent strength

3.  Purity

4.  Safety

5.  Clinical effectiveness

6.  Bioavailability

Not only did the contents of such products not appear on the label, but it is unlikely that the manufacturer knew the ingredients. If the contents are not known, the question of percent strength becomes meaningless. Plant sources sold for the production of drug products were often adulterated. Even if the plants used were pure, the active ingredients, if there were any, were not known. Chemical analyses were neither possible nor of great concern to a naive society. Some awareness of the danger in such a system probably evolved as a direct result of unfortunate experiences with products that not only failed to cure but also caused toxic effects which may have been worse than the malady. Initially, society responded with legislation aimed at ensuring that medicines were safe and free from adulterants. No doubt these seemingly simple goals presented tremendous problems, without adding concern for therapeutic effectiveness, which was generally certified on the basis of testimonials or anecdotal evidence.

The development of analytical chemistry brought about an acute awareness of the importance of controlling the contents of a product. That each drug should have an adequate purity rubric became the concern of those given the responsibility for setting standards for the protection of society. Tests for physical characteristics were introduced, and as analytical technology advanced, the sophistication of product tests increased. Trace analysis made limitations on allowable contamination practical. Chemical content and product purity advanced to a scientific level commensurate with the analytical technology of the day.

And so we can observe that since the turn of the century, product development has evolved from cure-all herb teas to stable, pure formations containing known amounts of chemicals that have been defined as drugs. It was quite natural that the scientific community and society at large had confidence in a product which adhered to its purity rubric. This philosophy dominated from 1938 (when the final drug safety amendments to the Federal Food, Drug, and Cosmetic Act were made) until relatively recent years. During that time it was widely assumed that all products containing equal doses of the same drug were equipotent when put to use by the clinician. The first four criteria in our list were regarded as sufficient. More recently we have come to the sometimes surprising realization that percentage chemical strength is not the sole criterion for clinical effectiveness. In fact, formulations were produced and marketed that satisfied all of the required legal standards but which were not therapeutically active. It became obvious that a dosage form must not only contain the correct amount of the labeled drug but must also release that drug upon administration to the patient. Clinical effectiveness and bioavailability were thus added to the criteria for effective drug product development. A drug should be not only safe but beneficial as well, and its therapeutic claims must be based upon sound clinical evidence. Furthermore, a drug which has been proven effective can be rendered ineffective owing to lack of bioavailability.

What is bioavailability? The simplest concept to consider is that of a bioavailable dose. This is the dose available to the patient, in contrast to the dose stated on the label. Only a drug that is completely absorbed into the bloodstream will have a bioavailable dose equal to that stated on the label. In the case of tablets or capsules administered orally, the bioavailable dose will generally be less than the administered dose. Bioavailability therefore deals with the transfer of drug from the site of administration into the body itself as evidenced by its appearance in the general circulation. Since a transfer process is involved, it may be characterized by both the rate of transfer and the total amount transferred. The bioavailable dose refers only to the total amount transferred. A complete description of the bioavailability of a drug from a dosage form must include both the rate and the amount. Methods for such characterizations are discussed in this book. Bioavailability has been defined in various ways [2, 3, 4, 5]. Those which ignore the rate of transfer [2,3] are inadequate to explain cases where products show differences in blood levels and/or clinical response due in total or in part to the rate of release of drug. A more acceptable definition for bioavailability is therefore [5] “a term used to indicate the rate and relative amount of the administered drug which reaches the general circulation intact.”

The measure of success in the use of any drug is the degree to which the results obtained agree with those expected. Therefore the degree of success achieved by the use of a drug product may be altered by factors which affect bioavailability, such as certain foods, other drugs, the dosage regimen, the route of administration, a less than optimum formulation, or the inappropriate use of a suitable formulation. Biopharmaceutics deals with such problems. It is concerned with obtaining the expected therapeutic effect from a drug product when it is in use by the patient. One such definition has been offered as follows [5]: “Biopharmaceutics is the study of the factors influencing the bioavailability of a drug in man and animals and the use of this information to optimize pharmacologic or therapeutic activity of drug products in clinical application.”

Since studies involving the rates of drug transfer employ kinetic methods, biopharmaceutics is closely linked to pharmacokinetics. Indeed, the terms have been interchanged often in the literature. In this book the following definition [5] will be used: “Pharmacokinetics is the study of the kinetics of absorption, distribution, metabolism, and excretion of drugs and their pharmacologic, therapeutic, or toxic response in animals and man.”

Finally, consider the term bioeguivalency. Like the others, it has been defined in various ways. We shall use the simplest interpretation. Two drug products containing equal doses of a drug will be said to be bioequivalent if they do not differ significantly in either their bioavailable dose or its rate of supply. Thus the time course for drug in the blood following the administration of either product would be identical. Bioequivalency therefore includes not only the amount of active ingredient available but also the rate at which it is available.

A corollary to the more recent concerns for product quality and effectiveness is the challenge to physicians and pharmacists to consider the impact of these sciences on clinical practice. For example, the clinician must be informed when the coadministration of other drugs or foods may influence the bioavailability of an active ingredient. As research defines the critical factors influencing the absorption of drugs, the information must be put to clinical use so that practitioners are aware of those situations that should be avoided.

This concept can be further extended into all areas of biomedical drug research. Let us consider pharmacology as a case in point. In a broader sense the concept of bioavailability cannot be circumvented by the choice of the route of administration. Regardless of where the experiment begins, the final observations are a function of the bioavailability of the drug to the site of action, and the factors influencing its arrival there are many. Since the movement of drug from the site of administration to the site of action requires time, the overall process may best be analyzed by pharmacokinetics. Thus the bioavailability time profile is again critical in the comparison of drugs or drug analogs. A pharmacological study is greatly enhanced by a knowledge of the amount of the drug that has reached the receptor as a function of time.

The concept of bioavailability in biomedical drug research, pharmaceutical product development, and the rational clinical use of formulations is the subject of this book.

REFERENCES

1.  G. Carson, One for a Man, Two for a Horse, Bramhall House, New York, 1961.

2.  National Formulary XVIII, American Pharmaceutical Association, Washington, D.C., 1970.

3.  Food and Drug Administration, Fed. Regist. 35.885–887 (1973).

4.  Guidelines for Biopharmaceutical Studies in Man, A.Ph.A. Academy of Pharmaceutical Sciences, Washington, D.C., February 1972.

5.  Pharmacokinetics and biopharmaceutics: A definition of terms, J. Pharmacokinet. Biopharm. 1:3 (1973).

2

Rates, Rate Constants, and Order

I. Order

II. Rales and Rate Constants

A. First-Order Rates

1. Hydrolysis

Sample Problem 1

Practice Problem 1

B. Zero-Order Rates

Sample Problem 2

C. Negative Tests

Sample Problem 3

Practice Problem 2

D. Competing First-Order Rates

Practice Problem 3

Practice Problem 4

I. ORDER

The concept of order and its application to rate processes originated in chemical kinetics. If the rate of decrease in the concentration, C, of reactant A to form product B,

$\text{reactant}A\to \text{product}B$

(1)

can be described as a function of time t by

$\frac{dC}{dt}=-k{C}^n$

(2)

then the reaction is nth order with respect to the concentration of reactant. This concept has been extended to p...

Table of contents

• Cover
• Half Title
• Title Page
• Copyright Page
• Table of Contents
• Preface to the Fourth Edition
• Preface to the Third Edition
• Preface to the Second Edition
• Preface to the First Edition
• Nomenclature
• 1. Introduction
• 2. Rates, Rate Constants, and Order
• 3. Active and Passive Transport
• 4. Pharmacokinetics
• 5. Biopharmaceutics
• 6. Dosage Regimens
• 7. Pharmacokinetic Aspects of Structural Modifications in Drug Design and Therapy
• 8. Pharmacokinetic Applications in Clinical Practice
• Appendix
• Index