From pharmacology to immunopharmacology

Imagine a clinical pharmacologist administering a new competitive antagonist at muscarinic receptors to a healthy volunteer. The effects are dramatic. Mydriasis and loss of accommodation, sedation, and hallucinations occur within minutes, a tachycardia develops with a shortened PR interval on the electrocardiogram, the skin becomes dry, and the body temperature rises; the volunteer complains of a very dry mouth. The clinical pharmacologist observes these effects with considerable interest but without concern.

Now imagine the same clinical pharmacologist giving MDX010, an antibody-based inhibitor of the CTLA-4 receptor on T lymphocytes [1–3]. This antibody inhibits the receptor sites that keep autoreactive T cells suppressed when activated. Inhibition produces (after some time for the autoreactive clones to proliferate) equally dramatic effects. A hypophysitis develops and some volunteers get severe diarrhea and skin rashes, in short the symptoms of a severe autoimmune disease. These events are considerably more worrying.

The question is why. After all, both occurrences are induced by an antagonist that binds to a receptor, which causes downstream effects on a cellular system. In the first case the effects are caused by anticholinergic actions in different tissues, in the second by cell proliferation and toxic effects of the cells on tissues. Both were predictable from previous knowledge of the roles of mediators in physiology and cell biology.

The most important reason for feeling comfortable about administering a muscarinic receptor antagonist is of course that we know so much about it. Sir Thomas Fraser (1841–1920) started this research in Edinburgh as a result of advances in the isolation of alkaloids made in around the 1820s, when atropine, cocaine, and physostigmine were isolated from plants in their pure forms. The discovery of these extraordinary potent molecules allowed the discipline of pharmacology to flourish. With increasing knowledge about physiology this led to extensive understanding of regulation of the autonomic nervous system and neurotransmission. Many great names appear in this story [4], and a clear trail can be drawn from Otto Loewi’s ‘Vagusstoff’, with its basis in autonomic neurotransmission, to James Black and beta-adrenoceptor antagonists and to ACE inhibitors. All pharmacologists and clinical pharmacologists would agree that this area is theirs. Pharmacology books often start with the autonomic nervous system and it is one of the first things that medical students learn when they do their course in general pharmacology (at least in the small minority of medical schools where it is still taught).

There is little doubt either about the momentous therapeutic innovations that were derived from this knowledge or about its value for patients with a range of diseases. This area of pharmacology is old and venerable.

Immunology is a discipline that also deals with receptors, agonists, antagonists, and highly complex and fascinating second messenger systems and genetic variations. Many more diseases are probably caused by deranged immunological systems than by abnormal autonomic regulation. However, we do not call this area pharmacology because the development of drugs that affect the immune system has largely followed development of knowledge about its physiology and biology. The same edition of Goodman and Gilman that devotes 156 pages to the pharmacology of the autonomic nervous system devotes only 24 pages to the immunological system and the medicines that affect it, and the same trend can be found in other standard pharmacology textbooks. And while clinical pharmacologists were instrumental in the development of a range of techniques for studying cardiovascular effects of drugs in humans [5], their role in the study of other organ systems may have (in retrospect) been underdeveloped.

While this imbalance is perhaps understandable on historical grounds, it does not prepare clinical pharmacologists for the future. Our current state of knowledge in immunology and biotechnology will ensure that large numbers of substances that affect the immune response will reach the clinic in the next decade. Colin Dollery has rightly described the clinical pharmacologist as the ultimate knowledge integrator [5] and the ideal scientist to manage the translational interface required for these novel therapeutic interventions.

This is not, however, how things have worked out. The 1980s and 1990s saw an unprecedented industrialization of clinical drug research in humans. The quality systems and operational complexity of Good Clinical Practice (GCP)-compliant trials produced the Contract Research Organization (CRO) as a specialized entity. Evaluation of data from complex preclinical experiments has increasingly been done by governmental bodies, hence diminishing knowledge about this among academic clinical pharmacologists, who have largely come to rely on the authorities and pharmacovigilance systems to advise them about the potential risks of new medicines.

Trials performed in academic institutions originally delivered academic knowledge and contributed to the training of a broadly based group of clinical pharmacologists, many of whom eventually ended up in pharmaceutical companies and regulatory authorities. As industrialization proceeded, more specialists developed, but the broadly trained clinician–clinical pharmacologists have started to disappear [6]. Research ethics committees previously often functioned as the final scientific stage gate – with considerable scientific integrating power – but in many countries (including the UK) these have now been allocated a more specialized job – just the ethics, not the science.

So, when genetics, immunology, and what used to be called the ‘new’ biology are starting to yield substances that have unprecedented effects on human biology [7] and pathophysiology, we have insufficient numbers of scientists with the right training and experience to deal with them. It does not matter whether we call them translational scientists or clinical pharmacologists; we need the ‘jack of all trades’ or knowledge integrator more than ever [5]. The clinical immunopharmacologist needs to be invented.

This is perhaps best illustrated by the widely publicized case of TGN1412 [8–13], a CD-28 receptor superagonist intended for the treatment of autoimmune diseases and leukemia, which was given to six healthy volunteers in March of this year. All of them developed a severe cytokine release syndrome after the first dose and only survived this experiment by advanced intensive care.

This molecule was the result of advanced research in a university. Its development was not possible without external capital provided by private investors. Production of the drug required a contract manufacturer and preclinical toxicology tests required a certified contract laboratory. The data were amalgamated by the company and supplied to drug regulatory authorities to evaluate the science and to an ethics committee to evaluate the ethics.

Eventually, the protocol (written by the company) was supplied to a CRO with all the necessary approvals, and the trial was executed with the now generally known disastrous results. The assessment of the risk of this trial was, in line with the current custom, divided across several parties, who dealt with the production, the preclinical studies, and the ethics. The available documentation appears to confirm that no integrative view was produced about the risk, and some of the assessments appear to have been less than critical [14]. One might wonder with hindsight what would have happened if a well-trained clinical pharmacologist/translational scientist or knowledge integrator had been required to take final overall responsibility. There is no doubt, however, that structured communication about the risks is an advantage for future compounds like this, and relevant proposals have been made [9, 14, 15]. No matter how much knowledge is obtained from animal or cell models, testing in the intact organism will always be necessary, and this may generate unexpected effects or risks. So there must be individuals who have training to take responsibility for these experiments in healthy or diseased humans. William Withering said it all in 1785 [16]:

“As the more obvious and sensible properties of plants such as colour, taste, and smell, have but little connexion with the diseases they are adapted to cure; so their peculiar qualities have no certain dependence upon their external configuration. Their chemical examination by fire, after an immense waste of time and labour, having been found useless, is now abandoned by general consent. Possibly other modes of analysis will be found out, which may turn to better account; but we have hitherto made only a very small progress in the chemistry of animal and vegetable substances. Their virtues must therefore be learnt, either from observing their effects upon insects and quadrupeds; from analogy, deduced from the already known powers of some of their congenera, or from the empirical usages and experience of the populace…”

To play a credible role in these fields clinical pharmacologists will have to extend their focus from the traditional fields of cardiovascular pharmacology and neuropharmacology to areas such as immunopharmacology. This theme issue of the Journal, dealing as it does with immunological topics, is therefore timely. The set of immunological papers in this issue mainly concern the application of standard pharmacokinetic techniques to drugs with effects on the immune system. This is all useful, although it lacks the mechanistic approach that is the main strength of clinical pharmacology [17].

For instance, Schirm et al. [18] have studied dosages of inhaled glucocorticoids in Dutch children and have found that they are not dosed according to standard guidelines. This is important information, but we are not told about how well the children fared. Assuming that Dutch doctors evaluate their patients, one is left to wonder if the guidelines are wrong when applied in a general population; the only way to tell is to look at the patients’ clinical status.

Accounts of the development of new methods are welcome in the Journal, and Lavorini et al. contribute to this in their description of a new simple and practical challenge model to compare direct-acting bronchodilators [19]. Perhaps this is not universally applicable, as they rightly conclude, but it should be useful in many circumstances.

Mortimer and colleagues have studied plasma drug concentrations after the administration of inhaled glucocorticoids and have found that the better pulmonary function is, the better these agents are absorbed systemically [20]. This gives rise to an interesting paradox. Is dose reduction necessary when symptoms are well controlled? This study may be of special relevance in children, in whom it should be repeated.

No drug-related journal is complete these days without some information about population pharmacokinetics. Dansirikul et al. have applied this technique to sirolimus [21] and Nestorov et al to etanercept [22]. The etanercept study involved 1300 patients with psoriasis. However, this elegant study leaves one wondering if there was any relation between the effects of the drug and the pharmacokinetics and the authors leave us on the edges of our seats by announcing that this is still to come; it is a pity that it was not published in the same paper and we look forward to seeing the data.

Elsewhere in this issue we also publish a range of papers on pharmacogenetics and drug–drug and food–drug interactions with immunological medicines. Nor is pharmacoepidemiology missing. Amy Downing suggests that angio-oedema occurs less often in users of COX-2 selective NSAIDs [23]. The difference between the relative risks of COX-2 inhibitors and regular NSAIDs is not large and we hope for a lively correspondence about unaccounted bias.

Finally, Michel Sibille draws attention to the register of French Phase I units and the adverse effects that occur during Phase I studies [24]. Whenever the risks of Phase I studies are discussed there is a lack of data, because of a dearth of high-quality registers in which data have been collected for sufficiently long periods of time. The French registry at least confirms that the risk of serious adverse effects in Phase I studies is very low, a valuable contribution. The authors of this paper have also suggested some approaches to risk minimization, including a recommendation not to study too many subjects at the same time. However, risk reduction in trials of new medicines in humans cannot be assured by operational measures. Careful planning before the trial is essential. If clinical pharmacologists want to reassert their role as knowledge integrators it is essential that the specialty extends its focus to the biology that will drive the medicines of the future.

We hope that this special immunology issue is only the beginning of a series of high-quality papers on immunopharmacology, with increasing attention to pharmacodynamics and pharmacokinetic–pharmacodynamic relationships.

The BJCP Prize

The British Pharmacological Society will award an annual prize of £1000 for the best paper published in the print version of the British Journal of Clinical Pharmacology during a calendar year. Those eligible will be Specialist Registrars in Clinical Pharmacology and Therapeutics registered for Higher Medical Training in the UK and the Republic of Ireland and those in comparable training schemes elsewhere.

On acceptance of a manuscript the authors will automatically, as part of the Manuscript Central system, be sent a reminder about the BJCP prize and will be invited to fill in an application form, giving information about the provenance of the work and the precise role played by the potential award winner. The judges will be the Editors of the Journal, but they may call for expert assistance in making their decision, which will be final.