- Email: [email protected]
Polymers in medicine; a game of chess▾
discussion forum
DDT Vol. 8, No. 3 February 2003
protein activity and represent attractive potential binding sites for future drug candidates. Any candidates likely to suffer from low activity as a result of mutational change in the gene coding for the drug target can be removed early in the development process. The investment in this technology will need to be substantial: 3D protein structure is required and thus a new protein target or an existing target where none is available can not be evaluated. The technique might be difficult to apply to new drugs acting on new targets as the mutation frequency in the particular gene coding for the drug target might be too low to be detected without the initial selective pressure of the drug. Furthermore, amino acid changes in the mutant proteins must be correlated with changes in drug efficacy, so drug resistance would not be detected simply by sequencing the gene. Structural pharmacogenomics opens up new avenues for the development of both antiviral and antibacterial drugs where resistance emerges because of drug target alterations. Most antiviral drugs become less effective because of target modification, which often emerges quickly. However, it should be borne in mind that antibacterial resistance is not restricted to target modification: enzymatic inactivation or modification of the drug, drug efflux and changes in permeability also have important roles.
References 1 House of Lords Select Committee on Science and Technology (1998) Resistance to Antibiotics and Other Antimicrobial Agents, The Stationery Office 2 Livermore, DM (2000) Epidemiology of antibiotic resistance. Intensive Care Med. 26, S14–S21 3 Maggio, E. et al. (2002) Structural pharmacogenomics, drug resistance, and the rational design of anti-infective super-drugs. Drug Discovery Today 7, 1214–1220
Peter W. Taylor and Paul D. Stapleton The School of Pharmacy University of London 29-39 Brunswick Square London WC1N 1AX UK
Polymers in medicine; ▼ a game of chess▼ It is undeniable that the effective use of medicines has provided unparalleled benefit for the treatment of disease and infection. It is also recognized that nearly all medicines can cause harm. To attain the greatest benefit in large diverse populations, deleterious side effects and adverse interactions of medicines are continuously documented. Regulatory agencies and the pharmaceutical industry analyze voluminous amounts of often complex and incomplete information to determine the best practice for the clinical use of medicines. Clinicians require extensive training to best select and administer medicines, with close patient follow-up and treatment changes often being required. Considerable clinical experience is also essential to de-couple patient hopes and fears from the decision-making process that is required for the most effective use of medicines [1]. There is no acknowledgement in the recent article by Hunter and Moghimi [2] of the inherent complexity that typifies the development and widespread use of medicines. This is compounded by the use of not altogether appropriate comparisons and a less than representative inclusion of details about previous research. Collectively these limitations result in the loss of a balanced argument that detracts from the author’s central, and important, premise that research effort is required to determine the immunotoxicology of parenteral medicines derived from physiologically soluble polymers. It is widely accepted that constant vigilance and research are required to understand completely the toxicological implications of many chemicals used in society [3], including all the constituent components (e.g. actives and formulation excipients) of medicines. Polymers have long been widely used
update
in consumer and healthcare applications. This includes parenteral use where many toxicological issues are well documented [4,5]. To address the toxicological implications for the parenteral administration of physiologically soluble polymers, the authors compare disparate systems; for example, cationic vectors for non-viral gene delivery, PEG-grafted liposomes and drug solubilizing polymers. These systems are complex mixtures of molecules, both small and large molecular weight. The disentanglement of the toxicological properties, including immunological issues, of these different systems is being carefully determined by the comparative study of each type of system separately [6,7], rather than grouped together as done by the authors. Comparative toxicology is entirely dependent on well defined end-use specifications and physicochemical and biological characteristics that are related to composition, formulation and processing. Much toxicological research is predicated on knowing molecular structures before and after administration. Although the authors fittingly describe how the heterogeneities of polymer structure can obscure the determination of biological and toxicological properties, this has been well known for many years. Much remains to be done but, as the authors intimated, there has been significant progress to prepare biomedical polymers with more uniform structure [8,9]. The need for homogeneous structure and complete structure characterization has generally applied to all medicines and the author’s statement that ‘the absolute chemical characterization of small drug molecules is straightforward’ is simply not true, considering the real complexity of medicines; for example, stereoisomers, polymorphs, pseudopolymorphs, the changes in structure caused by generally unavoidable instabilities of drug
1359-6446/02/$ – see front matter ©2002 Elsevier Science Ltd. All rights reserved. PII: S1359-6446(02)02583-7
www.drugdiscoverytoday.com
111
update
discussion forum
formulations, trace impurities during manufacture and batch-to-batch variation. Paradigms in medicine development are evolving with new and, often more, complex products being developed for specific patient populations [10]. Therapeutic proteins and antibodies are obvious examples and their polymerconjugated variants have been shown to minimize many toxic effects that include reduced immunogenicity. Likewise, the appropriate conjugation of doxorubicin to a soluble polymer results in a dramatic reduction of the toxicity that limits the efficacy of this widely used drug for the treatment of cancer [11,12]. A co-polymer developed by Teva (http://www.teva.co.il) has recently been approved in the USA and EC for daily subcutaneous self-injection to treat multiple sclerosis [13]. This medicine is a polymer, derived from tyrosine, alanine, glutamic acid and lysine, that is designed to mimic the myelin basic protein. Although orally administered, the polymeric medicines developed by Geltex (http://www.geltex.com) exemplify the potential for beneficially exploiting the biological properties of large molecules [14]. These examples are structurally heterogeneous and, like any medicine, can have adverse side effects and interactions, but they do display benefit to risk ratios that justify their clinical use. The authors made little or no use of the extent literature regarding these or similar examples. Several broad assertions and claims are made in the article, which include ‘many products are failing because of neglect of the fundamental science surrounding the architectural control of the molecules present, their behaviour following in vivo administration and host response’. Another assertion is ‘adverse events following parenteral administration of approved synthetic polymer-based systems have resulted in unpredictable and fatal responses in a significant number of individuals.’ The authors repeatedly state there is ‘neglect’ in research associated
112
www.drugdiscoverytoday.com
DDT Vol. 8, No. 3 February 2003
with determining the ‘biological and pharmacological activity, immunotoxicity and cytotoxicity’ of parenteral medicines derived in some way from polymers. What products are failing and in what proportion is this to the total that have been clinically evaluated? Is this any different to that generally observed for all medicines? What is the precise meaning of ‘many products’, ‘significant number’ and ‘neglect’ in the complicated context of developing and using medicines? Can the polymer-based products already being used in the clinic really have been approved or have been selected for clinical evaluation if these assertions were on balance generally correct? Clearly not. Overall, the authors make the point that the complete toxicological evaluation of parenteral medicines derived from polymers is fundamentally important. This important concept is not new and there will be continued effort to seek a better understanding of the toxicology of substances produced for human use or consumption, including parenteral medicines derived from polymers. References 1 Carruba, M. and Pulazzini, A. (2001) Lipobay and the media. Scrip 36–37 2 Hunter, A.C. and Moghimi, S.M. (2002) Therapeutic synthetic polymers: a game of Russian roulette? Drug Discov. Today 7, 998–1001 3 Akingbemi, B. and Hardy, M. (2001) Oestrogenic and antiandrogenic chemicals in the environment : effects on male reproductive health. Ann. Med. 33, 391–403
4 Dukes, M. and Aronson, J. (2000) Meyler’s Side Effects of Drugs (14 Edn), pp. 1140–1170, Elsevier 5 Christensen, M. et al. (1978) Storage of polyvinypyrrolidone (PVP) in tissues following long-term treatment with a PVP-containing vasopressin preparation. Acta. Med. Scand. 204, 295–298 6 Hwang, S. and Davis, M. (2001) Cationic polymers for gene delivery: designs for overcoming barriers to systemic administration. Curr. Opin. Mol. Ther. 3, 183–191 7 Mayer, L. et al. (2000) Designing liposomal anticancer drug formulations for specific therapeutic applications. J. Liposome Res. 10, 99–115 8 van Hest, JC.M. and Tirrell, DA. (2001) Protein-based materials, toward a new level of structural control. Chem. Comm. 19, 1897–1904 9 Godwin, A. et al. (2001) Narrow molecular weight distribution precursors for polymerdrug conjugates. Angew. Chem. Int. Ed. Engl. 40, 614–617 10 Scrip Magazine (2002) Pharma must move to new business model. Scrip 20 November 2002, 14 11 Vasey, P. et al. (1999) Phase I clinical and pharmacokinetic study of PKI (HPMA copolymer doxorubicin): first member of a new class of chemotherapeutic agents : drugpolymer conjugates. Clin. Cancer Res. 5, 83–94 12 Muggia, F. (1999) Doxorubicin-polymer conjugates: further demonstration of the concept of enhanced permeability and retention. Clin. Cancer Res. 5, 7–8 13 Lobel, E. et al. (1996) Copolymer-1. Drugs of the Future 21, 131–134 14 Holmes-Farley, S.R. (1999) Novel polymeric pharmaceuticals: from startup to market. Polymer. Mater. Sci. Eng. 80, 246–247
Steve Brocchini Biomedical Polymer Group Department of Pharmaceutics School of Pharmacy, University of London 29-39 Brunswick Square London WC1N 1AX UK
Reproduce material from Drug Discovery Today? This publication and the contributions it contains are protected by the copyright of Elsevier Science. Except as outlined in the terms and conditions (see p. VI), no part of this journal can be reproduced without written permission from Elsevier Science Ltd, PO Box 800, Oxford, UK OX5 1DX
DDT Vol. 8, No. 3 February 2003
protein activity and represent attractive potential binding sites for future drug candidates. Any candidates likely to suffer from low activity as a result of mutational change in the gene coding for the drug target can be removed early in the development process. The investment in this technology will need to be substantial: 3D protein structure is required and thus a new protein target or an existing target where none is available can not be evaluated. The technique might be difficult to apply to new drugs acting on new targets as the mutation frequency in the particular gene coding for the drug target might be too low to be detected without the initial selective pressure of the drug. Furthermore, amino acid changes in the mutant proteins must be correlated with changes in drug efficacy, so drug resistance would not be detected simply by sequencing the gene. Structural pharmacogenomics opens up new avenues for the development of both antiviral and antibacterial drugs where resistance emerges because of drug target alterations. Most antiviral drugs become less effective because of target modification, which often emerges quickly. However, it should be borne in mind that antibacterial resistance is not restricted to target modification: enzymatic inactivation or modification of the drug, drug efflux and changes in permeability also have important roles.
References 1 House of Lords Select Committee on Science and Technology (1998) Resistance to Antibiotics and Other Antimicrobial Agents, The Stationery Office 2 Livermore, DM (2000) Epidemiology of antibiotic resistance. Intensive Care Med. 26, S14–S21 3 Maggio, E. et al. (2002) Structural pharmacogenomics, drug resistance, and the rational design of anti-infective super-drugs. Drug Discovery Today 7, 1214–1220
Peter W. Taylor and Paul D. Stapleton The School of Pharmacy University of London 29-39 Brunswick Square London WC1N 1AX UK
Polymers in medicine; ▼ a game of chess▼ It is undeniable that the effective use of medicines has provided unparalleled benefit for the treatment of disease and infection. It is also recognized that nearly all medicines can cause harm. To attain the greatest benefit in large diverse populations, deleterious side effects and adverse interactions of medicines are continuously documented. Regulatory agencies and the pharmaceutical industry analyze voluminous amounts of often complex and incomplete information to determine the best practice for the clinical use of medicines. Clinicians require extensive training to best select and administer medicines, with close patient follow-up and treatment changes often being required. Considerable clinical experience is also essential to de-couple patient hopes and fears from the decision-making process that is required for the most effective use of medicines [1]. There is no acknowledgement in the recent article by Hunter and Moghimi [2] of the inherent complexity that typifies the development and widespread use of medicines. This is compounded by the use of not altogether appropriate comparisons and a less than representative inclusion of details about previous research. Collectively these limitations result in the loss of a balanced argument that detracts from the author’s central, and important, premise that research effort is required to determine the immunotoxicology of parenteral medicines derived from physiologically soluble polymers. It is widely accepted that constant vigilance and research are required to understand completely the toxicological implications of many chemicals used in society [3], including all the constituent components (e.g. actives and formulation excipients) of medicines. Polymers have long been widely used
update
in consumer and healthcare applications. This includes parenteral use where many toxicological issues are well documented [4,5]. To address the toxicological implications for the parenteral administration of physiologically soluble polymers, the authors compare disparate systems; for example, cationic vectors for non-viral gene delivery, PEG-grafted liposomes and drug solubilizing polymers. These systems are complex mixtures of molecules, both small and large molecular weight. The disentanglement of the toxicological properties, including immunological issues, of these different systems is being carefully determined by the comparative study of each type of system separately [6,7], rather than grouped together as done by the authors. Comparative toxicology is entirely dependent on well defined end-use specifications and physicochemical and biological characteristics that are related to composition, formulation and processing. Much toxicological research is predicated on knowing molecular structures before and after administration. Although the authors fittingly describe how the heterogeneities of polymer structure can obscure the determination of biological and toxicological properties, this has been well known for many years. Much remains to be done but, as the authors intimated, there has been significant progress to prepare biomedical polymers with more uniform structure [8,9]. The need for homogeneous structure and complete structure characterization has generally applied to all medicines and the author’s statement that ‘the absolute chemical characterization of small drug molecules is straightforward’ is simply not true, considering the real complexity of medicines; for example, stereoisomers, polymorphs, pseudopolymorphs, the changes in structure caused by generally unavoidable instabilities of drug
1359-6446/02/$ – see front matter ©2002 Elsevier Science Ltd. All rights reserved. PII: S1359-6446(02)02583-7
www.drugdiscoverytoday.com
111
update
discussion forum
formulations, trace impurities during manufacture and batch-to-batch variation. Paradigms in medicine development are evolving with new and, often more, complex products being developed for specific patient populations [10]. Therapeutic proteins and antibodies are obvious examples and their polymerconjugated variants have been shown to minimize many toxic effects that include reduced immunogenicity. Likewise, the appropriate conjugation of doxorubicin to a soluble polymer results in a dramatic reduction of the toxicity that limits the efficacy of this widely used drug for the treatment of cancer [11,12]. A co-polymer developed by Teva (http://www.teva.co.il) has recently been approved in the USA and EC for daily subcutaneous self-injection to treat multiple sclerosis [13]. This medicine is a polymer, derived from tyrosine, alanine, glutamic acid and lysine, that is designed to mimic the myelin basic protein. Although orally administered, the polymeric medicines developed by Geltex (http://www.geltex.com) exemplify the potential for beneficially exploiting the biological properties of large molecules [14]. These examples are structurally heterogeneous and, like any medicine, can have adverse side effects and interactions, but they do display benefit to risk ratios that justify their clinical use. The authors made little or no use of the extent literature regarding these or similar examples. Several broad assertions and claims are made in the article, which include ‘many products are failing because of neglect of the fundamental science surrounding the architectural control of the molecules present, their behaviour following in vivo administration and host response’. Another assertion is ‘adverse events following parenteral administration of approved synthetic polymer-based systems have resulted in unpredictable and fatal responses in a significant number of individuals.’ The authors repeatedly state there is ‘neglect’ in research associated
112
www.drugdiscoverytoday.com
DDT Vol. 8, No. 3 February 2003
with determining the ‘biological and pharmacological activity, immunotoxicity and cytotoxicity’ of parenteral medicines derived in some way from polymers. What products are failing and in what proportion is this to the total that have been clinically evaluated? Is this any different to that generally observed for all medicines? What is the precise meaning of ‘many products’, ‘significant number’ and ‘neglect’ in the complicated context of developing and using medicines? Can the polymer-based products already being used in the clinic really have been approved or have been selected for clinical evaluation if these assertions were on balance generally correct? Clearly not. Overall, the authors make the point that the complete toxicological evaluation of parenteral medicines derived from polymers is fundamentally important. This important concept is not new and there will be continued effort to seek a better understanding of the toxicology of substances produced for human use or consumption, including parenteral medicines derived from polymers. References 1 Carruba, M. and Pulazzini, A. (2001) Lipobay and the media. Scrip 36–37 2 Hunter, A.C. and Moghimi, S.M. (2002) Therapeutic synthetic polymers: a game of Russian roulette? Drug Discov. Today 7, 998–1001 3 Akingbemi, B. and Hardy, M. (2001) Oestrogenic and antiandrogenic chemicals in the environment : effects on male reproductive health. Ann. Med. 33, 391–403
4 Dukes, M. and Aronson, J. (2000) Meyler’s Side Effects of Drugs (14 Edn), pp. 1140–1170, Elsevier 5 Christensen, M. et al. (1978) Storage of polyvinypyrrolidone (PVP) in tissues following long-term treatment with a PVP-containing vasopressin preparation. Acta. Med. Scand. 204, 295–298 6 Hwang, S. and Davis, M. (2001) Cationic polymers for gene delivery: designs for overcoming barriers to systemic administration. Curr. Opin. Mol. Ther. 3, 183–191 7 Mayer, L. et al. (2000) Designing liposomal anticancer drug formulations for specific therapeutic applications. J. Liposome Res. 10, 99–115 8 van Hest, JC.M. and Tirrell, DA. (2001) Protein-based materials, toward a new level of structural control. Chem. Comm. 19, 1897–1904 9 Godwin, A. et al. (2001) Narrow molecular weight distribution precursors for polymerdrug conjugates. Angew. Chem. Int. Ed. Engl. 40, 614–617 10 Scrip Magazine (2002) Pharma must move to new business model. Scrip 20 November 2002, 14 11 Vasey, P. et al. (1999) Phase I clinical and pharmacokinetic study of PKI (HPMA copolymer doxorubicin): first member of a new class of chemotherapeutic agents : drugpolymer conjugates. Clin. Cancer Res. 5, 83–94 12 Muggia, F. (1999) Doxorubicin-polymer conjugates: further demonstration of the concept of enhanced permeability and retention. Clin. Cancer Res. 5, 7–8 13 Lobel, E. et al. (1996) Copolymer-1. Drugs of the Future 21, 131–134 14 Holmes-Farley, S.R. (1999) Novel polymeric pharmaceuticals: from startup to market. Polymer. Mater. Sci. Eng. 80, 246–247
Steve Brocchini Biomedical Polymer Group Department of Pharmaceutics School of Pharmacy, University of London 29-39 Brunswick Square London WC1N 1AX UK
Reproduce material from Drug Discovery Today? This publication and the contributions it contains are protected by the copyright of Elsevier Science. Except as outlined in the terms and conditions (see p. VI), no part of this journal can be reproduced without written permission from Elsevier Science Ltd, PO Box 800, Oxford, UK OX5 1DX