Introduction

The importance of a biomarker in drug development is based on the weight of evidence that changes in dose and/or drug concentration levels correlate strongly with the biomarker and the clinical outcome desired. The linkage between pharmacokinetics of a new chemical entity (NCE), the dynamics of a biomarker, and the ultimate clinical outcome should be based on robust theoretical considerations, prior therapeutic experience, well-understood pathophysiology, and knowledge of the drug's mechanism of action. The validation of biomarkers is therefore very important, particularly if one considers their relevance for decision- making and regulatory purposes. The elements described below are crucial for the integration of a biomarker in a drug development program.

1. Identification, quantitation, and validation ofbiomarker assays and drug concentrations. Reliable and selective assays should be validated under

Biomarkers in Drug Development: A Handbook of Practice, Application, and Strategy, Edited by Michael R. Bleavins, Claudio Carini, Malle Jurima-Romet, and Ramin Rahbari Copyright © 2010 John Wiley & Sons, Inc.

a good laboratory practices (GLP)--ike environment for quantitative methods for measuring both biomarker responses and drug concentrations. Most biomarkers are endogenous macromolecules that can be measured in biological fluids. As for drug assays, biomarker assays should provide acceptable sensitivity, specificity, precision, and accuracy. For example, intra- and intersubject variability of the biomarker should be minimal and well understood, biomarker stability and sample storage conditions should be controlled, and quantitative assay should be standardized and validated with adequate power to distinguish between treatment and control groups [1-3].

Assays should be validated to meet study objectives at various drug development stages and possess adequate performance to quantify biochemical responses specific to the target disease progression and drug intervention. In addition, biomarker measurement should be technically practical, so that measurement can be obtained by minimally invasive techniques and that the sampling of the biomarker is minimal or is taken at the same time as other physiological, safety, or efficacy measurements

2. PK/PD correlation and integration of model-based drug development. Biomarkers typically have different time courses from clinical endpoints and often are more directly related to the time course of drug concentrations. To evaluate potential correlations, adequate information should be available on the pharmacokinetics (PK) of the new chemical entity (NCE). Similarly, adequate information should be available on the pharmacodynamics (PD) (including PK) of the biomarker, with the expected effect on clinical outcome. Following the identification of correlations between the NCE and specific biomarkers, PK/PD modeling may be performed in early stages of drug development to gain greater insight into the effect of drug concentrations on the biomarker as a function of time. PK/PD modeling involves a set of techniques using mathematical and mechanistic (as opposed to empirical) models derived from quantitative pharmacology. Biomarkers, together with PK/PD modeling and simulation, provide a continuous process to link what has been learned from today's drug development cycle to the next generation of biomarkers, assays, and models [5-7].

3. Correlation between biomarkers and clinical endpoint. The availability of a validated biomarker for a specific clinical endpoint may greatly facilitate the development of compounds that act via well-understood mechanisms of action. For example, biomarkers for HIV and AIDS include viral load (the number of free virus particles in the blood) and the count of CD4+ immune system cells. Fasting blood sugar and hemoglobin A1c, a protein that indicates a patient 's blood sugar history, are established biomarkers for diabetes treatments. The relationship of the biomarker to the therapeutic endpoint should be validated in early phase II trials; and, when possible, as early as phase I [8,9] .

Many surrogate markers can be assessed in healthy volunteers and in the intended patient population. The ability to assess surrogate markers in healthy volunteers can bring the initial decision-making process into phase I rather than phase II or phase III of the NCE development process. This can be a significant competitive advantage to those who use the opportunity. Table 1 presents widely used biomarkers according to disease and indications. Biomarkers can be elevated to the status of a surrogate endpoint based on the

TABLE 1 Widely Used Biomarkers for Specific Disease or Indications

Biomarkers

Disease or Indication

Pulmonary function tests, forced expiratory volume (FEV)

PT (including INR), APTT, anti-Xa activity, fragment

1 + 2, plasminogen, plasmin inhibitor, D-dimer Leukotrienes, cytokines, and chemokines

Epidermal growth factor (EGF), fibroblast growth factor (FGF), human growth hormone (HGH), neopterin Viral load, CD4 count

Cortisol, estradiol, estrone, follicle - stimulating hormone, luteinizing hormone, progesterone, testosterone

Angiotensin - I, angiotensin - II, plasma renin, aldoste-rone, and angiotensin-converting enzyme (ACE) activity

Eicosanoids (prostaglandins and leukotrienes) Interferons, interleukins, tumor necrosis factor

(TNF), rheumatoid factor Cholesterol, fatty acids, HDL, LDL, phospholipids Cytidine deaminase activity, inosine, xanthine, hypoxanthine, uric acid 8-Hydroxy-dG, protein carbonyls, I-kB, NF-kB

Glucose, glucagon, fructosamine, glycosylated albumin, and hemoglobin A1c, insulin, C-peptide Stomach fullness, cholecystokinin, glucagon - like peptide 1, bombesin, somatostatin, ghrelin, leptin, glucose, insulin, diet-induced thermogenesis, temperature, ventilatory parameters ProMMP - 1, ProMMP - 3, tissue inhibitory of MMP - 1

Asthma

Coagulation and fibrinolysis

Chronic obstructive pulmonary disease Growth modulation

Project Management Made Easy

Project Management Made Easy

What you need to know about… Project Management Made Easy! Project management consists of more than just a large building project and can encompass small projects as well. No matter what the size of your project, you need to have some sort of project management. How you manage your project has everything to do with its outcome.

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