Current Drug Safety - Volume 5, Issue 4, 2010

Biotherapeutics are a burgeoning class of drugs that encompass three main categories of biopharmaceuticals. The first group includes early biotherapeutics such as insulin as replacement therapy, and more recently protein molecules such as the interferons. These represent equivalents to endogenous proteins and may therefore to a large extent be regarded, and recognised, as normal protein and not as foreign protein. A second group which is becoming more prevalent in the biopharmaceutical sphere is that of biosimilars. These are generally recombinantly produced proteins that are made as generic products once patent lifetime for the original biotherapeutic has expired. Similarly, these do not in theory present as foreign protein, though in practice, issues do materialise in manufacture that must be carefully addressed. The third and perhaps the largest, most diverse and most rapidly expanding group of biotherapeutics comprises therapeutic antibodies. Therapeutic antibodies are generally seen by the patient's immune system as foreign protein, and thus present the most challenging issues in their development, manufacture and eventual clinical use. It is important to distinguish between drug effects that are related to mechanism of action and those that derive from certain physicochemical aspects of the drug protein structure. The former include drug-related adverse effects that result, for example, from non-exclusivity of target (lack of complete specificity). The latter include immunotoxicity and immunogenicity - immunogenicity being largely the focus of this collection of reviews. The following questions are proposed. 1) What is the magnitude of the problem clinically with respect to the immunogenicity of biotherapeutics and in particular therapeutic antibodies? 2) Can clinically significant immunogenicity be predicted pre-clinically? 3) How can the potential of a protein biological to give rise to immunogenicity be minimised? 4) Is there justification for a pharmaceutical industry/regulatory authority co-ordinated program to identify best practise for pre-clinical prediction and monitoring of actual immunogenicity for the development of biologicals such as monoclonal antibodies? The first of the articles in this hot topic issue provides a comprehensive overview of the most predominant class of biotherapeutic in development - monoclonal antibodies. These were seen as the proverbial “magic bullet” when first concepts of their clinical use emerged. In more recent times we have seen the reality that, just as with any other drug, they have multiple side effects. These may be related to their lack of absolute specificity and also their propensity to elicit secondary immune responses involving antibody-dependent cellular cytotoxicity (ADCC) and the recruitment of the complement system (complement-dependent cytotoxicity; CDC). Although, this sometimes has beneficial effects - see trastuzumab (Herceptin) [1, 2]. Niebecker and Kloft have managed thoroughly to describe these issues for the main therapeutic areas, currently the targets of monoclonal antibodies; chronic inflammatory disease and oncology/haematology. Immunogenicity of monoclonal antibodies features in a dedicated section and clearly sets out the problems that have arisen in monoclonal therapeutic antibody development from the original murine full-length antibodies to wholly human antibodies generated in specially engineered “humanised” (relative to antibody production) mice [3]. The questions I would put to the field are the following. a) How much of the drive towards fully human antibodies has been evidence based? b) To what extent is this a pharmaceutical industry trend that has placed an undeservedly high value on identifying and eliminating potential immunogenicity, in the face of the much more substantial and lifethreatening drug mechanism-of-action related adverse effects? There is a case for minimising the risk of immunogenicity. However, since the first chimeric human/murine antibodies became clinically validated (e.g. cetuximab (Erbitux), infliximab (Remicade), rituximab (Rituxan) and abciximab (ReoPro) [4-11]) it has surely been proven that the impact of immunogenicity, where murine variable regions may constitute 30% of a whole antibody, is of a much lesser significance than their wholly murine predecessors. The success of these chimeric molecules should indicate that development of entirely human antibodies, though perhaps theoretically ideal, ought not to be an absolute requirement in therapeutic antibody development. Indeed, it is clear from evidence, that even fully human antibodies suffer the risk of generating anti-antibody antibodies with the consequent potential loss of efficacy [12]. Other approaches for antibody humanization have also led to promising drug candidates [13, 14]. These have included changing murine variable regions (retaining murine complementarity-determining-regions (CDRs)) for human variable domains. However, this kind of humanization approach has potentially detrimental effects on function that sometimes can only be restored by re-murinization of certain amino acid sequences [15, 16]. From Niebecker and Kloft we can also conclude that prediction and effective monitoring of immunogenicity are reasonable aims and that management of immunogenicity of therapeutic antibodies once in humans (e.g. by altering dosing schedules and routes of administration) is of equal importance. The article by Büttel et al., though not expressing the views of the regulatory authorities, gives a flavour of the kind of approach being taking in relation to potential immunogenicity of drugs in development. This outlines very much a flexible approach, with clear emphasis on treatment of drug candidates on a case-by-case basis. This is helpful, as the risk of a more prescriptive system would be that many more promising molecules would be excluded from further development, based on no firm evidence that clinically significant immunogenicity might ever materialise. Although no-one would dispute the high prevalence of immunogenic responses to fully murine antibodies, a more prescriptive approach would most likely lead to only fully human antibodies being authorised for further development. This may in fact be the current industry trend, but once again Büttel et al. indicate that immunogenicity of fully human antibodies is not an unusual occurrence. The questions this raises in my view are: a) what pre-clinical assessment criteria could be used to predict immunogenicity once in humans? b) what methods can be used to distinguish between neutralising (effecting drug efficacy) and non-neutralising (perhaps clinically irrelevant, or at least clinically manageable) forms of immunogenicity?..................

Therapeutic monoclonal antibodies (mAbs) including antibody fusion proteins and antibody conjugates present an innovative class of (bio-)pharmaceuticals with increasing clinical importance. MAbs were initially perceived as comparatively safe drugs. As more mAbs appear on the market, characteristics of their safety profiles become apparent, including immunogenicity, i.e. the potential induced formation of human anti-drug antibodies (HADAs) in patients. European Public Assessment Reports were reviewed to provide an overview about main safety concerns and the immunogenicity of mAbs in chronic inflammatory diseases and oncology/haematology, including strategies for their prevention and clinical management. In total, both mechanism-related and non-specific adverse drug reactions (ADRs) have been reported, with infectious complications and administration-related reactions observed across the majority of mAbs. Most ADRs were predictable and manageable, although some have emerged unexpectedly. Immunogenicity occurred with almost all mAbs, with widely differing extent. Adverse consequences of HADAs were only identified for few mAbs. In conclusion, mAbs are generally safe but as they may be associated with significant ADRs, the individual risks need to be weighed against the expected therapeutic benefit. As several of the recently introduced mAbs are directed against new targets, and considering the limited understanding of immunogenicity, special caution and patient monitoring is highly recommended.

Antibody formation is an intended physiological reaction to a “non-self” protein intentionally triggered in the case of vaccines. However, an unwanted immune response to a therapeutic protein may lead to a loss of efficacy and/or to severe side effects. The Committee for Medicinal Products for Human Use (CHMP) at the European Medicines Agency (EMA) issued a multidisciplinary guideline providing general recommendations from a marketing authorisation perspective on how to systematically assess an unwanted immune response following the administration of a biological drug. In this article, we discuss key aspects of this guideline and its concept, with a particular focus on the impact of immunogenicity on benefit/risk estimation of a therapeutic protein.

The biopharmaceutical market has grown steadily since the early 1980s and today over 150 protein biopharmaceuticals have been approved for clinical use. These products often exhibit forms of immunotoxicity that often only come to light during clinical studies. The predictive value of animal studies and traditional in vitro screens is questionable, with few existing methods able to predict immunotoxicity in a way that is useful for estimating risk for entire patient populations for a specific, and often unique, product. Here, the relative merits of rational design and alternative strategies for immunotoxicity testing are considered with reference to the outcomes of preclinical and clinical studies on biopharmaceuticals. Specific reference is made to the prediction of immunogenicity using organotypic models, transgenic models of autoimmunity and immunogenicity as well as rodent models of hypersensitivity, immunosuppression and immunostimulation. The role played by human cell-based assays and in silico prediction models that have been developed and validated for the assessment of chemical classes is also appraised.

Protein therapeutics offer distinct advantages over other classes of drugs largely due to the high level of target specificity and generally low toxicity. Problems have, however, been encountered with some protein therapeutics inducing undesirable immune responses in patients. This immunogenicity can produce pleiotropic effects including the development of a high affinity B cell-mediated humoral response that is often directed against the therapeutic. Opinions are divided as to the principal causes of clinical immunogenicity and, as a result, this area has been the subject of much research. One thing that has emerged as a result of this intense activity is the development of pre-clinical models that can provide a level of prediction of the immunogenic potential of novel protein therapeutics before administration in man.

During the last few decades we have witnessed to a progressive deregulation of drug use and drug advertising. A good example of this process is the impressive number of medications which have been shifted from ‘prescription only’ to ‘over the counter’ status. Beyond economic interests on this status change (e.g. from pharmaceutical industry or health insurers) other less controversial motivations have been risen as arguments for self-medication. Among these are, wider and faster accessibility to drugs for patients and best use of physicians’ busy agendas. In a deregulated scenario, hard pressed physicians are freed from prescribing medications for minor, easily diagnosed ailments and pharmacists’ skills are better exploited. There is indeed a strong ethical basis for recognizing patients’ undeniable right to take part in medical decisions related to their own health and develop self-management abilities. Wider accessibility to medical information through modern communication technologies seems to have made these changes towards participatory models of health more pronounced. Nevertheless, there are still some risks and difficulties related to patients’ empowerment. True empowerment and true democratization of medical resources do not depend merely on ease of access to medications. Access to drugs is, at most, a necessary but not sufficient condition. As emphasized by all the articles in this issue, in an information era, for a patient to make a rational, safe use of the profuse, readily available medical resources (whether we think of drugs or medical information) access to quality, balanced information and education of the patient to search and appraise health-related info should be given priority. However, a number of studies prove that drug advertising often provides biased, unbalanced or vague information, frequently with a strong emotional content. What's more, the quality of online health information is highly variable and at present patients rely more and more on lay referral networks (instead of health professionals) for medical decisions. I fail to see the advantage of wider access to medications without a consequent wider access to lay education on safe health practices and appraisal of medical information and wider accessibility to quality encounters with health professionals (i.e. physicians and pharmacists): medications are one of the many tools in healthcare management and self-care practices are not meant to replace the encounter with the health professional but actually to complement it. The construction of risk perception around consumption of medications is another issue that deserves attention. The aforementioned unbalanced drug advertising together with the profusion of lifestyle drugs that defy our definitions of health and disease, the emergence of drug sale spots without health professional's surveillance and the very way in which drugs are commercialized at the pharmacies are some of the factors that bend the patients' perspective on drugs towards the belief that (at least some) medications should be treated as common, and completely safe, trade items. Drugs are no longer perceived as goods of rare, exceptional use that should always be consumed with certain precautions, but as usual part of our daily routine and landscape. We are far from being in position of guaranteeing access to quality, safe information on health to the patients and we are far from a general sensible, equilibrated use of the abundant modern medical resources. Return to a highly regulated scenario seems quite unlikely to happen, and an absolutely rational (and general) use of medicines appears as a distant, uncertain reality. Health professionals should accept this reality and adopt a new -not leading- role in health management, helping the patients to make the best possible use of the possibilities of this new, complex scenario. In the last decades, many universities and health institutions worldwide realized this reality, and physicians and pharmacists' formation have gained in courses on communication and clinical practice skills. The current, special theme issue on self-medication of Current Drug Safety opens with an interesting review from Ruiz, which analyzes current literature on risks of self-medication practices, with emphasis on drug-drug interactions, abuse and/or dependence and misdiagnosis and inappropriate choice of treatment. Pfaffenbach et al. examine the under-studied phenomena of self-medication in children and adolescents. Grigoryan et al. review current studies on the urgent, Public Health issue of self-medication with antibiotics, focusing on the consumption patterns in Europe. Consolini and Ragone review the most common herbal drugs used in self-medication in Buenos Aires province (Argentina) and their possible adverse reactions. Finally, Talevi analyzes the reasons behind the so-called “expert patient” and their influence on the self-medication practices and the patient/healthcare provider relationship.

Self-medication is defined as the selection and use of medicines by individuals (or a member of the individuals' family) to treat self-recognized or self-diagnosed conditions or symptoms. Several benefits have been linked to appropriate self-medication, among them: increased access to medication and relief for the patient, the active role of the patient in his or her own health care, better use of physicians and pharmacists skills and reduced (or at least optimized) burden of governments due to health expenditure linked to the treatment of minor health conditions However, self-medication is far from being a completely safe practice, in particular in the case of non-responsible self-medication. Potential risks of self-medication practices include: incorrect self-diagnosis, delays in seeking medical advice when needed, infrequent but severe adverse reactions, dangerous drug interactions, incorrect manner of administration, incorrect dosage, incorrect choice of therapy, masking of a severe disease and risk of dependence and abuse. In this short review the author analyzes recent literature on some of the most important dangers related to self-medication practices, particularly: polypharmacy and drug interactions, medications abuse or dependence, misdiagnosis and incorrect choice of treatment. The author also proposes measures that could be adopted in order to solve or improve these issues.

Self-medication includes several forms through which the individual him/herself or the ones responsible for him/her decide, without medical evaluation, which drug they will use and in which way for the symptomatic relief and “cure” of a condition. It involves sharing drugs with other members of the family and social group, using leftovers from previous prescriptions or disrespecting the medical prescription either by prolonging or interrupting the dosage and the administration period prescribed. Although few researches have studied aspects of self-medication in children and adolescents, some authors have reported a high prevalence of self-medication in this age group. Similar to adults, the highest consumption of drugs involves the use of analgesics, antipyretics and anti-inflammatory drugs followed by antibiotics. This review describes the global pattern of self-medication in children and adolescents, and discusses public policies aiming to promote health interventions and strategies to prevent self-medication.

Unlike most other drugs that only affect individual patients if used incorrectly for self-medication, misused antibiotics add to the global risk of increased spread of bacterial resistance. This review focuses on self-medication with antibiotics in Europe and its determinants. High prevalence of self-medication with antibiotics has been repeatedly found in Southern and Eastern European countries that also report high levels of antibiotic resistance. Despite being illegal, over the counter dispensation of systemic antibiotics occurs in several European Union Member States. A second major source of self-medication is the availability of “leftover” antibiotics which results from either patient non-compliance or dispensation of a larger number of tablets than needed for one single course. The potentially modifiable factors associated with self-medication are: availability of antibiotics without prescription, pack-based antibiotic dispensing system, misconceptions of the general public about the efficacy of antibiotics for minor illnesses and prescribing of antibiotics for minor ailments by physicians. Measures that may reduce and prevent self-medication include dispensation of exact tablet quantities in pharmacies as already implemented e.g. in the UK, Netherlands, the Czech Republic and the United States, and enforcement of existing laws prohibiting over-the-counter sales of antibiotics. Such measures should be embedded in a general policy to change the culture of antibiotic use by improving awareness of the general public and professionals about antibiotics and the risks associated with their use as well as reducing misconceptions about the need for antibiotics for minor ailments.

Medicinal plants are useful as a natural therapy to treat minor illnesses, as gastrointestinal disorders or as topic antiinflammatories. Also, they have been increasingly used as a coadjuvant in cronic diseases as hypertension, diabetes or hyperlipidemias. Nevertheless, many of the plants have active principles which are contraindicated or need precaution in certain illnesses as coagulation disorders or in certain states as pregnancy or breastfeeding. In this review we had compiled the side-effects, precautions and interactions with other medicines of many plants which are used in self-medication in our region. A previous population study gave us information on the consumption of medicinal plants in 73 pharmacies of the Buenos Aires province, in Argentina. During a period of one year, there were 37102 self-medicated plants, while only 1532 were prescribed by the physician. Among the most frequently selfmedicated plants are Malva sylvestris L., Matricaria chamomile L., and Quassia amara. Among the most frequently prescribed are also “malva” and “chamomile”, Tilia cordata Mill. and Valeriana officinalis. Based in the most consumed medicinal plants in our region, we reviewed the risks of such plants and the precautions that should be taken for a rational use. Also, we detected 15 adverse-reactions reported by the pharmacists through a pharmaceutical vigilance program, which are described and analyzed here. The results of the study and other reports suggest that adverse reactions of herbal medicines could be avoided if preventing self-medication, and taking into consideration possible contraindications and interactions.

Due to a wide range of factors, such as increasing access to health information and government policies to promote self-care during the past 20-30 years, the “new patient” or ‘expert patient’ has become information strong, information seeking, increasingly demanding (or even aggressive) and skeptical of expert knowledge. This evolution in the patients’ profile has deeply changed the relationship between the patient and the health-care professional and the patients’ self-medication practices. As a result, the classical paternalistic model of health-care professional/patient relationship has shown its limitations, and new models have been proposed and adopted in the health-care community. In this paper, we have carefully analyzed the causes behind the changes in the patients´ behavior and their consequences on the self-medication phenomena, and discuss which of the known models of patient/health-care professional relationship (from the paternalistic to the deliberative model) should be adopted in order to move forward to responsible self-medication conducts.