The scientific basis of rational prescribing. A guide to precision clinical pharmacology based on the WHO 6-step method.

BACKGROUND AND METHODS: This opinion paper expanded on the WHO "six-step approach to optimal pharmacotherapy," by detailed exploration of the underlying pharmacological and pathophysiological principles. This exercise led to the identification of a large number of domains of research that should be addressed to make clinical pharmacology progress toward "precision clinical pharmacology," as a prerequisite for precision medicine. RESULT: In order to improve clinical efficacy and safety in patient groups (to guide drug development) as well as in individuals (to guide therapeutic options and optimize clinical outcome), developments in clinical pharmacology should at least tackle the following: (1) molecular diagnostic assays to guide drug design and development and allow physicians to identify the optimal targets for therapy in the individual patient in a quick and precise manner (to guide selection of the right drug for the right patient); (2) the setting up and validation of biomarkers of target engagement and modification as predictors of clinical efficacy and safety; (3) integration of physiological PK/PD models and intermediate markers of pharmacological effects with the natural evolution of the disease to predict the drug dose that most effectively improves clinical outcome in patient groups and individuals, making use of advanced modeling technologies (building on deterministic models, machine-learning, and deep learning algorithms); (4) methodology to validate human or humanized in vitro, ex vivo, and in vivo models for their ability to predict clinical outcome with investigational therapies, including nucleic acids or recombinant genes together with vectors (including viruses or nanoparticles), cell therapy, or therapeutic vaccines; (5) methodological complements to the gold-standard, large Phase 3 randomized clinical trial to provide clinically relevant and reliable data on the efficacy and safety of all treatment options at the population level (pragmatic clinical trials), as well as in small groups of patients (as low as n = 1); (6) regulatory science, so as to optimize the ethical review process, documentation, and monitoring of clinical trials, improve efficiency, and reduce costs of clinical drug development; (7) interventions to effectively improve patient compliance and to rationalize polypharmacy for the reduction of adverse effects and the enhancement of therapeutic interactions; and (8) appraisal of the ecological and societal impact of drug use to safeguard against environmental hazards (following the "One Health" concept) and to reduce drug resistance. DISCUSSION AND CONCLUSION: As can be seen, precision clinical pharmacology aims at being highly translational, which will require very large panels of complementary skills. Interdisciplinary collaborations, including non-clinical pharmacologists, will be key to achieve such an ambitious program.

Opportunities for collaboration between pharmacists and clinical pharmacologists to support medicines optimisation in the UK.

Medicines optimisation is a clinician-driven, person-centred ongoing process. Pharmacists and clinical pharmacologists have medicines-related expertise to deliver medication review which optimises clinical and cost-effective use of medication, aligned with patient preferences, contributing to improved health outcomes. There is a large pharmacy workforce, directly accessible to patients, who can provide expert medicines-related care on the high street, and increasingly in general practice and care homes settings. There are a small number of clinical pharmacologists in practice, mainly working in a hospital setting. Potential opportunities for collaboration are extensive, including local initiatives in collaborative education, formulary/medicines management, electronic prescribing, service evaluation, research, direct clinical services as well as strategic planning through the Regional Medicines Optimisation Committees. Pharmacists and clinical pharmacologists have complementary skill sets and through acknowledging the differences in their approaches and valuing their unique skills, health services can ensure that patients are signposted to appropriate services.

The UK's Life Sciences Strategy: opportunities for clinical pharmacology.

The UK's Life Sciences Strategy provides UK clinical pharmacologists with a unique opportunity to enhance the impact of their discipline on patients and the NHS as well as the pharmaceutical industry. The full benefits of electronic prescribing systems, supported by artificial intelligence, will require clinical pharmacological expertise. Similarly, the Strategy's support for 'healthy ageing' will only be realized if clinical pharmacologists are able to use their expertise in promoting the safe and effective use of medicines in older people. Furthermore, their needs to be an active - and continuing - collaboration between clinical pharmacologists in the NHS and the pharmaceutical industry in general as well as with the discipline of pharmaceutical medicine.

Educational paper: do we need neonatal clinical pharmacologists?

Effective and safe drug administration in young infants should be based on integrated knowledge concerning the evolving physiological characteristics of the infant who will receive the drug and the pharmacokinetic and pharmacodynamic characteristics of a given drug. Consequently, clinical pharmacology in neonates is as dynamic and diverse as the neonates we are entitled to take care of. Even more than median estimates, covariates of variability within the population are of clinical relevance. We aim to illustrate the complexity and the need for neonatal clinical pharmacology based on the gap between current and likely best clinical practice for two commonly administered compounds (aminoglycosides for infection and ibuprofen for patent ductus arteriosus) and one new compound (bevacizumab, to treat threshold retinopathy of prematurity). Progression has been made to render pharmacokinetic studies child size, e.g., low volume samples, optimal study design, and population pharmacokinetics. Challenges to further improve clinical pharmacology in neonates include, when appropriate, the validation of off-patent drug dosing regimens and of infant-tailored formulations. Knowledge integration, i.e., the use of available data to improve current drug use and to predict pharmacokinetics/pharmacodynamics for similar compounds is needed. Development of clinical research networks is helpful to achieve these goals.

Development and delivery of clinical pharmacology in regulatory agencies.

Medicines regulation is based on a foundation of science, policy and judgement. It operates within several frameworks (scientific, legal and public health), which are interdependent. While safety, quality and efficacy remain the criteria by which medicines are assessed, the benefit-to-harm balance for any medicine or medical device is of paramount importance. While the regulator was hitherto the gatekeeper who allowed a medicine on to the market, payers now require, in addition, assessment of cost and clinical effectiveness before use. As regulatory frameworks develop, several changes will occur, as follows: (i) formal benefit-harm assessment will become an integral part of submission for marketing authorizations; (ii) there will be greater use of surveillance for adverse reactions to new medicines using methods other than voluntary reporting; (iii) risk management plans will become benefit-risk management plans; (iv) life-saving medicines will be approved earlier; and (v) regulation and health technology assessment will take place simultaneously. Clinical pharmacologists will play important roles in these developments.

Developing and delivering clinical toxicology in the UK National Health Service.

Clinical toxicology concerns the investigation, diagnosis and management of suspected poisoning. It is an important discipline because of the frequency of suspected poisoning, including drug overdose. In the UK, most episodes are managed by nonspecialists, with support provided online or by telephone from the National Poisons Information Service. Leadership and clinical support for this is provided by a small number of clinical toxicologists, who are almost invariably accredited specialists in clinical pharmacology and therapeutics. Priorities for maintaining and enhancing clinical toxicology as a subspeciality in the UK include: 1 Maintaining funding for poisons centres. This is essential in spite of current budgetary pressures. 2 Formal training in the discipline. The 1 year optional training module in clinical toxicology approved in 2011 as part of the clinical pharmacology and therapeutics curriculum represents important progress, but funding for appropriate programmes and accreditation for trainees from other relevant disciplines is needed. Arrangements for registration and revalidation are also required. 3 An improved evidence base for management of poisoning. Priority areas include continued surveillance of the epidemiology and outcomes of poisoning, including syndromic surveillance, more rapid characterization of the human toxicity of newly introduced medicines and better clinical evidence on use of antidotes and other treatments; for example, acetylcysteine and lipid emulsion therapy.

Developing and delivering clinical pharmacology in pharmaceutical companies.

The challenges of developing new medicines are well known. Effective application of clinical pharmacology expertise is vital to the successful evaluation of potential new medicines. In drug development, this depends on effective integration of diverse skills. Many of these are currently in short supply, but through innovative partnerships between industry and academia there is an opportunity to reinvigorate the discipline by nurturing these key skills to the benefit of both partners. Specific areas of focus should be experimental medicine, modelling and simulation, and translational skills.

The roles of clinical pharmacologists in UK universities.

Clinical pharmacologists in universities play major roles in research and teaching and provide important contributions to National Health Service (NHS) activities, such as work for research ethics, drug and therapeutics, and clinical governance committees. Their research extends from preclinical studies using drugs to understand physiology and the mechanisms of disease to large-scale clinical trials and population studies. This work is truly translational, with a focus on drugs and medicines and an emphasis on efficacy and safety. The lack of an organ base has allowed clinical pharmacologists to follow their interests wherever they lead, but their visibility has been hampered by successive earlier versions of the General Medical Council's Tomorrow's Doctors document, which undermined some of the necessary scientific underpinning of medical practice and reduced the time clinical pharmacologists had to interact with medical students and recently qualified doctors at the point of choosing their careers. Additional problems have arisen from the stifling effect of the European Union Clinical Trials Directive, and its UK interpretation, on clinical research. For future success, clinical pharmacologists need to embrace translational research, use recent changes to Tomorrow's Doctors, linked to the creation of safe prescribing skills, to spend more face-to-face time with their students, fight for a simplification and proportionate regulation of research, and persuade doctors, health service planners and the government of the importance of clinical pharmacology for UK clinical research, the NHS, patient safety and creation of health and wealth.

An Australian perspective.

Discussing the future of UK clinical pharmacology, eight Australasian clinical pharmacologists emphasized the need to make the discipline 'indispensable' in key areas. The visibility of clinical pharmacology in Australasia has been improved by working with the Consumers' Health Forum in Australia in the construction of the national Policy on Quality Use of Medicines and, later, of the formal National Medicines Policy. Our expertise in clinical pharmacology, combined with the Health Forum's political skills, proved a potent force for launching these policies. A second example was the construction of the national prescribing curriculum in partnership with the National Prescribing Service. This is being used in all medical schools with senior students. At a local level we found that taking over clinical toxicology services (that other clinicians wanted to jettison) provided a stimulus to clinical research and later the formation of a productive subgroup to study the special problems of envenomation. Fourthly, we note that no clinical pharmacology unit in UK is designated as a WHO collaborating centre. Considerable difference can be made to national problems with medicines by clinical pharmacologists willing to work for periods within developing countries. This has given a greater profile to several groups in Australia. The principle of stepping out of conventional settings and actively seeking collaboration with other groups beyond our discipline has enhanced the profile of the discipline in Australasia and could do the same in the UK.

Developing and delivering clinical pharmacology in the UK National Health Service.

Clinical pharmacologists are active in the delivery of general and specialist medical services across the UK. They also make major contributions, both locally and nationally, to medicines management and appraisal in the National Health Service. Most are also heavily involved in the organization and delivery of teaching and training of a range of healthcare professionals, both undergraduates and postgraduates. In the past, these contributions may not have been fully recognized, perhaps in part because the discipline is small. However, the British Pharmacological Society, particularly through its Clinical Section, is committed to initiatives to ensure that all clinical pharmacologists (whatever their background, training or subsequent working environment) can work together to improve patient care, nationally and internationally. Effective engagement with universities, the National Health Service and pharmaceutical companies will be vital if these initiatives are to have sustained benefits and improve health outcomes for patients.

International Union of Basic and Clinical Pharmacology. LXXIII. Nomenclature for the formyl peptide receptor (FPR) family.

Formyl peptide receptors (FPRs) are a small group of seven-transmembrane domain, G protein-coupled receptors that are expressed mainly by mammalian phagocytic leukocytes and are known to be important in host defense and inflammation. The three human FPRs (FPR1, FPR2/ALX, and FPR3) share significant sequence homology and are encoded by clustered genes. Collectively, these receptors bind an extraordinarily numerous and structurally diverse group of agonistic ligands, including N-formyl and nonformyl peptides of different composition, that chemoattract and activate phagocytes. N-formyl peptides, which are encoded in nature only by bacterial and mitochondrial genes and result from obligatory initiation of bacterial and mitochondrial protein synthesis with N-formylmethionine, is the only ligand class common to all three human receptors. Surprisingly, the endogenous anti-inflammatory peptide annexin 1 and its N-terminal fragments also bind human FPR1 and FPR2/ALX, and the anti-inflammatory eicosanoid lipoxin A4 is an agonist at FPR2/ALX. In comparison, fewer agonists have been identified for FPR3, the third member in this receptor family. Structural and functional studies of the FPRs have produced important information for understanding the general pharmacological principles governing all leukocyte chemoattractant receptors. This article aims to provide an overview of the discovery and pharmacological characterization of FPRs, to introduce an International Union of Basic and Clinical Pharmacology (IUPHAR)-recommended nomenclature, and to discuss unmet challenges, including the mechanisms used by these receptors to bind diverse ligands and mediate different biological functions.

Collaborations between Clinical Pharmacologists in Japan and in the United States - Report from the IQ CPLG and JPMA CPTF Meeting in Tokyo, Japan.

The International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) Clinical Pharmacology Leadership Group (CPLG) held its first meeting of Japan-based representatives at Astellas Pharma headquarters in Tokyo on October 1, 2019. The meeting was also attended by Japan Pharmaceutical Manufactures Association (JPMA) Clinical Pharmacology Task Force (CPTF) members. Overall, nearly 30 clinical pharmacologists representing 14 companies attended the event. The meeting met its goal of enhancing mutual understanding of each organization's activities. In a number of break-out sessions, participants identified scientific topics for potential future collaboration between JPMA CPTF and IQ CPLG.

Evaluating Patients With Impaired Renal Function During Drug Development: Highlights From the 2019 US FDA Pharmaceutical Science and Clinical Pharmacology Advisory Committee Meeting.

Patients with multiple chronic conditions, including more advanced chronic kidney disease (CKD), are often excluded from clinical trials, creating challenges in deriving appropriate dosing information and labeling. This article summarizes the May 7, 2019, US Food and Drug Administration Pharmaceutical Science and Clinical Pharmacology Advisory Committee Meeting, which solicited expert opinions on how to enroll patients with more advanced CKD into clinical trials as well as the assumptions behind and different approaches of exposure-matching.

Asia-inclusive global development of pevonedistat: Clinical pharmacology and translational research enabling a phase 3 multiregional clinical trial.

The investigational NEDD8-activating enzyme inhibitor pevonedistat is being evaluated in combination with azacitidine versus single-agent azacitidine in patients with higher-risk myelodysplastic syndrome (higher-risk MDS), higher-risk chronic myelomonocytic leukemia (higher-risk CMML), or low-blast acute myeloid leukemia (AML) in a Phase 3 trial PANTHER. To support Asia-inclusive global development, we applied multiregional clinical trial (MRCT) principles of the International Conference on Harmonisation E17 guidelines by evaluating similarity in drug-related and disease-related intrinsic and extrinsic factors. A PubMed literature review (January 2000-November 2019) supported similarity in epidemiology of higher-risk MDS, AML, and CMML in Western and East Asian populations. Furthermore, the treatment of MDS/AML was similar in both East Asian and Western regions, with the same dose of azacitidine being the standard of care. Median overall survival in MDS following azacitidine treatment was generally comparable across regions, and the types and frequencies of molecular alterations in AML and MDS were comparable. Dose-escalation studies established the same maximum tolerated dose of pevonedistat in combination with azacitidine in Western and East Asian populations. Pevonedistat clearance was similar across races. Taken together, conservation of drug-related and disease-related intrinsic and extrinsic factors supported design of an Asia-inclusive Phase 3 trial and a pooled East Asian region. A sample size of ~ 30 East Asian patients (of ~ 450 randomized) was estimated as needed to demonstrate consistency in efficacy relative to the global population. This analysis is presented as an exemplar to illustrate application of clinical pharmacology and translational science principles in designing Asia-inclusive MRCTs. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Azacitidine is the standard of care for myelodysplastic syndromes/low-blast acute myeloid leukemia (AML) across Western and East Asian patients. The first-in-class small-molecule inhibitor of NEDD8-activating enzyme, pevonedistat, has been investigated as a single agent in multiple studies of hematologic and nonhematologic malignancies and in combination with azacitidine in elderly patients with untreated AML. WHAT QUESTION DID THIS STUDY ADDRESS? By applying clinical pharmacology and translational science and International Conference on Harmonisation E17 principles, this study designed an East Asian-inclusive global pivotal Phase 3 trial of pevonedistat, taking into consideration drug-related and disease-related intrinsic and extrinsic factors. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? These analyses provide scientific rationale for Asia-inclusive globalization of the pivotal, Phase 3 PANTHER trial and for pooling clinical data across the East Asian region for assessing consistency in efficacy. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? We developed a framework to facilitate efficient global clinical development of investigational therapies for rare cancers and orphan diseases in Asia-inclusive multiregional clinical trials.

A manifesto for clinical pharmacology from principles to practice.

1. This is a manifesto for UK clinical pharmacology. 2. A clinical pharmacologist is a medically qualified practitioner who teaches, does research, frames policy, and gives information and advice about the actions and proper uses of medicines in humans and implements that knowledge in clinical practice. Those without medical qualifications who practise some aspect of clinical pharmacology could be described as, say, 'applied pharmacologists'. 3. Clinical pharmacology is operationally defined as a translational discipline in terms of the basic tools of human pharmacology (e.g. receptor pharmacology) and applied pharmacology (e.g. pharmacokinetics) and how they are used in drug discovery and development and in solving practical therapeutic problems in individuals and populations. 4. Clinical pharmacologists are employed by universities, health-care services, private organizations (such as drug companies), and regulatory agencies. They are mentors and teachers, teaching laboratory science, clinical science, and all aspects of practical drug therapy as underpinned by the science of pharmacology; they write and edit didactic and reference texts; researchers, covering research described by the operational definition; clinicians, practising general medicine, clinical toxicology, other medical specialties, and general practice; policy makers, framing local, national, and international medicines policy, including formularies, licensing of medicines and prescribing policies. 5. The future of clinical pharmacology depends on the expansion and maintenance of a central core of practitioners (employed by universities or health-care services), training clinical pharmacologists to practise in universities, health-care services, private organizations, and regulatory agencies, and training other clinicians in the principles and practice of clinical pharmacology.