Early Development of Therapeutic Biologics - Pharmacokinetics

Research Laboratories, Schering AG, Berlin, Germany.
Current Drug Metabolism (Impact Factor: 2.98). 02/2006; 7(1):15-21. DOI: 10.2174/138920006774832604
Source: PubMed


Modern biologics are biotechnology-derived pharmaceuticals. They are mostly used for diagnosis, prevention and treatment of serious and chronic diseases. Today, therapeutic biologics range from traditional biologics like blood and blood components, fractionated blood products, and antitoxins to modern biologics such as monoclonal antibodies, cytokines (e.g. interferon, interleukine), tissue growth factors, vaccines directed against non-infectious disease targets, and gene transfer products. Chemical as well as pre-clinical development are major challenges for biologics due to their different physicochemical properties (mostly protein structure) compared to small molecules. They demonstrate much more complex pharmacokinetic behaviour, which strongly influences their pre-clinical testing strategy. Biologics are often highly species-specific in action and immunogenic in test animal species and humans. Immunogenicity of therapeutic biologics may influence their pharmacokinetic behaviour as well as pharmacodynamics and toxicity. Biologics are frequently regulated by different procedures compared to small molecules. New guidances are evolving which reflect the rapid development of new technologies in this field. Bioanalytical method development and validation is a prerequisite not exclusively for pharmacokinetic studies but for the whole pre-clinical and clinical development. Due to their unique properties, different kinds of bioanalytical assays (mass assays, activity assays, immunogenicity assays) are necessary in early development of biologics.

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    • "Biopharmaceuticals frequently exhibit unique and unpredictable pharmacokinetic profiles which reflect their differential susceptibility to proteolysis, renal clearance, interaction with the host's immune system and many other factors (Lin 2009). Analytical methods have always been critically important for obtaining valid pharmacokinetics data, but until recently immunoassays and bioactivity assays were the two mainstays of the analytical support of pharmacokinetics of protein drugs, while MS-based methods were used only for a limited range of niche applications (Baumann 2006). However, the explosive growth of proteomics in recent years, and the central role played by MS in this field (Fenselau 2007) have resulted in a dramatic expansion of the scope of MS-based protein quantitation methods in pharmacokinetic studies of protein drugs(Ezan et al. 2009). "
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    ABSTRACT: Biopharmaceuticals are a unique class of medicines due to their extreme structural complexity. The structure of these therapeutic proteins is critically important for their efficacy and safety, and the ability to characterize it at various levels (from sequence to conformation) is critical not only at the quality control stage, but also throughout the discovery and design stages. Biological mass spectrometry (MS) offers a variety of approaches to study structure and behavior of complex protein drugs and has already become a default tool for characterizing the covalent structure of protein therapeutics, including sequence and post-translational modifications. Recently, MS-based methods have also begun enjoying a dramatic growth in popularity as a means to provide information on higher order structure and dynamics of biotechnology products. In particular, hydrogen/deuterium exchange MS and charge state distribution analysis of protein ions in electrospray ionization (ESI) MS offer a convenient way to assess the integrity of protein conformation. Native ESI MS also allows the interactions of protein drugs with their therapeutic targets and other physiological partners to be monitored using simple model systems. MS-based methods are also applied to study pharmacokinetics of biopharmaceutical products, where they begin to rival traditional immunoassays. MS already provides valuable support to all stages of development of biopharmaceuticals, from discovery to post-approval monitoring, and its impact on the field of biopharmaceutical analysis will undoubtedly continue to grow.
    Biotechnology advances 05/2011; 30(1):210-22. DOI:10.1016/j.biotechadv.2011.05.006 · 9.02 Impact Factor
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    ABSTRACT: It has long been recognized that living organisms have an astonishing ability to develop biochemical survival strategies [1]. One example for such a strategy is the mammalian immune system — an adaptive response to evolutionary challenges by microorganisms. In the past, numerous attempts have been made to exploit these endogenous “biological” survival strategies for medicine. One of the first successful attempts to employ a “biological” in this regard was the introduction of the variola vaccine by Jenner in 1796, at a time when the armamentarium of traditional chemical drugs had been notoriously poor. In the beginning of the 20th century, however, a revolution in chemistry and pharmacology overshadowed the “biological” by a “xenobiotic” concept and led to an explosion of our therapeutic options by providing the more than 10,000 traditional chemicals that we employ in medical practice today. Although our 100 years of experience with traditional chemicals have proven extremely successful, major challenges to our current drug development strategies have arisen by concerns about side effect profiles of many drugs and a perceived reduction in research productivity [1, 2]. Since the dawn of the 21st century we have witnessed the long expected and increasingly successful implementation of biotechnology derived pharmaceuticals (“biologicals”) in the medical practice. The term “biotechnology” was allegedly coined by Karl Ereky, a hungarian engineer in 1919 and related to techniques that had been employed by mankind for thousands of years to produce improved food products e.g. beer by the Sumerians as early as 6000 B.C. In contrast to the more traditional small molecular chemicals, biologicals are derived from living organisms like bacteria, yeast or even larger animals like goat or cow. Biologicals comprise a heterogenous group of pharmaceutical products, notably blood products, recombinant proteins, gene therapeutic products and cellular products. Due to their specific characteristics, biologicals introduce major challenges to our traditional concepts of drug development and routine practice of therapeutic medicine. Biologicals can be distinguished from traditional chemicals by a number of unique features, e.g. molecule size, low thermostability, species specificity and mode of administration. Therefore, biologicals do not only constitute novel pharmaceutical agents but represent an entirely different class of drugs which, unlike chemicals, do not follow well established paths, both in development and in practical use.
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