Biomarkers in Drug Discovery and Development

A Handbook of Practice, Application, and Strategy

Ramin Rahbari, Jonathan Van Niewaal, Michael R. Bleavins, Ramin Rahbari, Jonathan Van Niewaal, Michael R. Bleavins

• Verlag: Wiley
• Jahr: 2020
• ISBN:
  9781119187523
• Auflage: 2
• Thema: Médecine
• Thema: Pharmacologie

This book continues the legacy of a well-established reference within the pharmaceutical industry – providing perspective, covering recent developments in technologies that have enabled the expanded use of biomarkers, and discussing biomarker characterization and validation and applications throughout drug discovery and development.

• Explains where proper use of biomarkers can substantively impact drug development timelines and costs, enable selection of better compounds and reduce late stage attrition, and facilitate personalized medicine
• Helps readers get a better understanding of biomarkers and how to use them, for example which are accepted by regulators and which still non-validated and exploratory
• Updates developments in genomic sequencing, and application of large data sets into pre-clinical and clinical testing; and adds new material on data mining, economics, and decision making, personal genetic tools, and wearable monitoring
• Includes case studies of biomarkers that have helped and hindered decision making
• Reviews of the first edition:
  "If you are interested in biomarkers, and it is difficult to imagine anyone reading this who wouldn't be, then this book is for you." ( ISSX ) and "...provides a good introduction for those new to the area, and yet it can also serve as a detailed reference manual for those practically involved in biomarker implementation." ( ChemMedChem )

Part I
Biomarkers and Their Role in Drug Development

1
Biomarkers Are Not New

Ian Dews

Envestia Ltd., Thame, Oxfordshire, UK

Introduction

The word biomarker in its medical context is a little over 40 years old. The first ever usage of this term was by Karpetsky, Humphrey, and Levy in the April 1977 edition of the Journal of the National Cancer Institute, where they reported that the “serum RNase level … was not a biomarker either for the presence or extent of the plasma cell tumor.” Few new words have proved so popular – a recent PubMed search lists more than 810, 676 publications that use it! Part of this success can undoubtedly be attributed to the fact that the word gave a long-overdue name to a phenomenon that has been around at least since the seventh century BC, when Sushustra, the “father of Ayurvedic surgery,” recorded that the urine of patients with diabetes attracted ants because of its sweetness. However, although the origins of biomarkers are indeed ancient, it is fair to point out that the pace of progress over the first 2500 years was somewhat less than frenetic.

Uroscopy

Because of its easy availability for inspection, urine was for many centuries the focus of attention. The foundation of the “science” of uroscopy is generally attributed to Hippocrates (460–355 BC) who hypothesized that urine was a filtrate of the “humors,” taken from the blood and filtered through the kidneys, a reasonably accurate description. One of his more astute observations was that bubbles on the surface of the urine (now known to be due to proteinuria) were a sign of long-term kidney disease. Galen (AD 129–200), the most influential of the ancient Greco-Roman physicians, sought to make uroscopy more specific but, in reality, added little to the subject beyond the weight of his reputation, which served to hinder further progress in this as in many other areas of medicine.

Five hundred years later, Theophilus Protospatharius, another Greek writer, took an important step towards the modern world when he investigated the effects of heating urine, thus developing the world's first medical laboratory test. He discovered that heating urine of patients with symptoms of kidney disease caused cloudiness (in fact, the precipitation of proteins). In the sixteenth century, Paracelsus (1493–1541) in Switzerland used vinegar to bring out the same cloudiness (acid, like heat, will precipitate proteins).

Events continued to move both farther north and closer to modernity when in 1695 Frederick Deckers of Leiden in the Netherlands identified this cloudiness as resulting from the presence of albumin. The loop was finally closed when Richard Bright (1789–1858), a physician at Guy's Hospital in London, made the association between proteinuria and autopsy findings of abnormal kidneys.

The progress from Hippocrates's bubbles to Bright's disease represents the successful side of uroscopy, but other aspects of the subject now strike us as a mixture of common sense and bizarre superstition. The technique of collecting urine was thought to be of paramount importance for accurate interpretation. In the eleventh century, Ismail of Jurjani insisted on a full 24-hour collection of urine in a vessel that was large and clean (very sensible) and shaped like a bladder, so that the urine would not lose its “form” (not at all sensible). His advice to keep the sample out of the sun and away from heat continues, however, to be wise counsel even today.

Gilles de Corbeil (1165–1213), physician to King Philip Augustus of France, recorded differences in sediment and color of urine which he related to 20 different bodily conditions. He also invented the matula, or jorden, a glass vessel through which the color, consistency, and clarity of the sample could be assessed. Shaped like a bladder rounded at the bottom and made of thin clear glass, the matula was to be held up in the right (not the left) hand for careful inspection against the light. De Corbeil taught that different areas of the body were represented by the urine in different parts of the matula. These connections, which became ever more complex, were recorded on uroscopy charts that were published only in Latin, thus ensuring that the knowledge and its well-rewarded use in treating wealthy patients were confined only to appropriately educated men. To further this education, de Corbeil, in his role as a professor at the Medical School of Salerno, set out his own ideas and those of the ancient Greek and Persian writers in a work called Poem on the Judgment of Urines, which was set to music such that medical students could memorize it more easily. It remained popular for several centuries.

Blood Pressure

One of the first deviations from the usage of urine in the search for markers of function and disease came in 1555 with the publication of a book called Sphygmicae artis iam mille ducentos annos perditae & desideratae Libri V by a physician named Józef Struś (better known by his Latinized name, Iosephus Struthius) from Poznán, Poland. In this 366-page work, Struthius described placing increasing weights on the skin over an artery until the pulse was no longer able to lift the load. The weight needed to achieve this gave a crude measure of what he called “the strength of the pulse” or, as we would call it today, blood pressure.

Early attempts at quantitative measurement of blood pressure had to be made on animals rather than on human subjects because of the invasiveness of the technique. The first recorded success with these techniques dates from 1733, when the Reverend Stephen Hales, a British veterinary surgeon, inserted a brass pipe into a horse's artery and connected the pipe to a glass tube. Hales observed the blood rising in the tube and concluded not only that the rise was due to the pressure of the blood in the artery but also that the height of the rise was a measure of that pressure.

By 1847, experimental technique had progressed to the point where it was feasible to measure blood pressure in humans, albeit still invasively. Carl Ludwig inserted brass cannulas directly into an artery and connected them via further brass pipework to a U-shaped manometer. An ivory float on the water in the manometer was arranged to move a quill against a rotating drum, and the instrument was known as a kymograph (“wave-writer” in Greek).

Meanwhile, in 1834, Jules Hérisson had described his sphygmomètre, which consisted of a steel cup containing mercury, covered by a thin membrane, with a calibrated glass tube projecting from it. The membrane was placed over the skin covering an artery, and the pressure in the artery could be gauged from the movements of the mercury into the glass tube.

Although minor improvements were suggested by a number of authors over the next few years, credit for the invention of the true sphygmomanometer goes to Samuel Siegfried Karl Ritter von Basch, whose original 1881 model used water in both the cuff and the manometer tube. Five years later, Scipione Riva-Rocci introduced an improved version in which an inflatable bag in the cuff was connected to a mercury manometer, but neither of these early machines attracted widespread interest. Only in 1901, when the famous American surgeon Harvey Cushing brought back one of Riva-Rocci's machines on his return from a trip to Italy did noninvasive blood pressure measurement really take off.

Sphygmomanometers of the late nineteenth century relied on palpation of the pulse and so could only be used to determine systolic blood pressure. Measurement of diastolic pressure only became possible when Nikolai Korotkoff observed in 1905 that characteristic sounds were made by the constriction of the artery at certain points in the inflation and deflation of the cuff. The greater accuracy allowed by auscultation of these Korotkoff sounds opened the way for the massive expansion in research works on blood pressure that characterized the twentieth century.

Imaging

To physicians keen to understand the hidden secrets of the human body, few ideas have been more appealing than the dream o...