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.

EurOP2E - the European Open Platform for Prescribing Education, a consensus study among clinical pharmacology and therapeutics teachers.

PURPOSE: Sharing and developing digital educational resources and open educational resources has been proposed as a way to harmonize and improve clinical pharmacology and therapeutics (CPT) education in European medical schools. Previous research, however, has shown that there are barriers to the adoption and implementation of open educational resources. The aim of this study was to determine perceived opportunities and barriers to the use and creation of open educational resources among European CPT teachers and possible solutions for these barriers. METHODS: CPT teachers of British and EU medical schools completed an online survey. Opportunities and challenges were identified by thematic analyses and subsequently discussed in an international consensus meeting. RESULTS: Data from 99 CPT teachers from 95 medical schools were analysed. Thirty teachers (30.3%) shared or collaboratively produced digital educational resources. All teachers foresaw opportunities in the more active use of open educational resources, including improving the quality of their teaching. The challenges reported were language barriers, local differences, lack of time, technological issues, difficulties with quality management, and copyright restrictions. Practical solutions for these challenges were discussed and include a peer review system, clear indexing, and use of copyright licenses that permit adaptation of resources. CONCLUSION: Key challenges to making greater use of CPT open educational resources are a limited applicability of such resources due to language and local differences and quality concerns. These challenges may be resolved by relatively simple measures, such as allowing adaptation and translation of resources and a peer review system.

WHO guide to good prescribing is 25 years old: quo vadis?

INTRODUCTION: Twenty-five years ago, the World Health Organization (WHO) published the Guide to Good Prescribing (GGP), followed by the accompanying Teacher's Guide to Good Prescribing (TGGP). The GGP is based on a normative 6-step model for therapeutic reasoning and prescribing, and provides a six-step guide for students to the process of rational prescribing. METHOD: We reviewed the need to update both WHO publications by evaluating their use and impact, including new (theoretical) insights and demands. Based on information from literature, Internet, and other (personal) sources, we draw the following conclusions. RESULTS: 1. An update of the GGP and TGGP, both in terms of content and form, is necessary because of the current need for these tools (irrational medicine use and unavailability of medicines), the lack of similar documents, and the lack of connection with recent developments, such as Internet and modern education; 2. The basic (6-step) model of the GGP is effective in terms of rational prescribing in the undergraduate situation and is still consistent with current theories about (context) learning, clinical decision-making, and clinical practice; 3. The dissemination and introduction of the GGP and TGGP in education has been successful so far, but is still not optimal because of lack of support and cooperation. CONCLUSIONS: On the basis of the evaluation results, a plan for the revision of the GGP and TGGP is presented.

Prior information for population pharmacokinetic and pharmacokinetic/pharmacodynamic analysis: overview and guidance with a focus on the NONMEM PRIOR subroutine.

Population pharmacokinetic analysis is used to estimate pharmacokinetic parameters and their variability from concentration data. Due to data sparseness issues, available datasets often do not allow the estimation of all parameters of the suitable model. The PRIOR subroutine in NONMEM supports the estimation of some or all parameters with values from previous models, as an alternative to fixing them or adding data to the dataset. From a literature review, the best practices were compiled to provide a practical guidance for the use of the PRIOR subroutine in NONMEM. Thirty-three articles reported the use of the PRIOR subroutine in NONMEM, mostly in special populations. This approach allowed fast, stable and satisfying modelling. The guidance provides general advice on how to select the most appropriate reference model when there are several previous models available, and to implement and weight the selected parameter values in the PRIOR function. On the model built with PRIOR, the similarity of estimates with the ones of the reference model and the sensitivity of the model to the PRIOR values should be checked. Covariates could be implemented a priori (from the reference model) or a posteriori, only on parameters estimated without prior (search for new covariates).

Sources of Variability and Accuracy of Performance Assessment in the Clinical Pharmacology Quality Assurance Proficiency Testing Program for Antiretrovirals.

BACKGROUND: The Clinical Pharmacology Quality Assurance (CPQA) program provides semiannual proficiency testing (PT) of antiretroviral analytes for 11 US and international clinical pharmacology laboratories (CPLs) to ensure interlaboratory comparability. In this article, we provide estimates of the main sources of variability and assess the accuracy of the algorithm for the assessment of performance. METHODS: Descriptive statistics are reported from 13 PT rounds from 2010 to 2016. Eight of the most common antiretroviral analytes were examined. Variance components analysis was used to rank the relative contributions of CPLs, antiretroviral analyte, and concentration category (low, medium, and high) to bias and variability using mixed models. Binary classification metrics of the PT assessment algorithm are calculated in comparison with a model using 95% prediction limits around estimated regression equations. RESULTS: CPLs provided 4109 reported concentrations of 65 unique samples for each of the 8 antiretroviral analytes across 13 PT rounds. Individual CPL accounted for the greatest amount of total variability (4.4%). Individual CPL and analyte combination (interaction) accounted for the greatest amount of bias (8.1%). Analyte alone accounted for 0.5% or less for total variability and bias. Overall, using a ±20% acceptance window around the final target, 97% of individual reported concentrations were scored acceptable, and 96% of antiretroviral/round scores were deemed satisfactory. Comparison with the regression model gave 100% sensitivity but only 34.47% specificity. Narrowing the acceptance window to ±15% improved specificity to 84.47% while maintaining a 99.17% sensitivity. CONCLUSIONS: The current CPQA PT scoring algorithm that use a ±20% acceptance window seems to suffer from a low specificity and may be too lenient. A stricter ±15% acceptance window would increase specificity and overall accuracy while lowering the overall pass rate by only 3%.

Clinical Pharmacology: A Comprehensive Drug Reference.

This column discusses the point-of-care tool Clinical Pharmacology. This review is primarily intended for newer health sciences librarians who are learning about drug references and clinical decision-making support systems or health sciences librarians making collection development decisions, although any librarian will find this review useful. A sample search will be provided to highlight the database's unique features as well as a comparison to other resources.

Peer review in Clinical Pharmacology using the 8-D Assessment.

The requirement for editors of clinical pharmacology journals to maintain an overview of the peer review process for manuscripts submitted can be facilitated by use of the 8-D Assessment. The 8-D Assessment comprises peer review criteria to determine if the:1. Design of the study, 2. Diagnoses employed, 3. Drug molecules involved, 4. Dosages applied, 5. Data collected, 6. Discussion of the findings, 7. Deductions made, and 8. Documentation are in accord with the objectives of the study and meet the requirements of evidence-based medicine. This tool, although easy to apply, requires a high level of clinical pharmacology expertise, especially in the fields of drug disposition, pharmacokinetics, and drug action.

[Anticancer drug research in Hungary, 1950-2000]. / Daganat-kemoterápiás kutatások Magyarországon az 1950−2000 közötti években.

The present review about the history of anticancer drug research in Hungary intends to call attention to the importance of studies on their mode of action. Several lines of evidence suggest that clinically usable oncopharmacological properties could be revealed by this way. Among the numerous compounds certain alkylating sugar alcohols and 2'-deoxyuridine derivatives were submitted to detailed investigations concerning their mode of action. Myelobromol with selective action on the myeloid elements of bone marrow has been justified for its application in chronic myeloid leukemia therapy and also in bone marrow ablation before transplantation. Mitolactol is able to cross bloodbrain barrier, consequently could control certain brain tumors. 5-etil-2'-deoxyuridine by reducing dihydropyrimidine dehydrogenase activity is able to increase 5-fluorouracil concentration in the blood, resulting in improved antitumor effect. In contrast, 5-hexil-2'-deoxyuridine, as an inhibitor of glycoconjugate pathway by reducing heparan sulfate production, has the ability to prevent metastasis. Noteworthy, the remarkable effects of vinca alkaloids, antiestrogens, and GNRH analogues were also presented in this review.

Achieving the World Health Organization's vision for clinical pharmacology.

Clinical pharmacology is a medical specialty whose practitioners teach, undertake research, frame policy, give information and advice about the actions and proper uses of medicines in humans and implement that knowledge in clinical practice. It involves a combination of several activities: drug discovery and development, training safe prescribers, providing objective and evidence-based therapeutic information to ethics, regulatory and pricing bodies, supporting patient care in an increasingly subspecialized arena where co-morbidities, polypharmacy, altered pharmacokinetics and drug interactions are common and developing and contributing to medicines policies for Governments. Clinical pharmacologists must advocate drug quality and they must also advocate for sustainability of the Discipline. However for this they need appropriate clinical service and training support. This Commentary discusses strategies to ensure the Discipline is supported by teaching, training and policy organizations, to communicate the full benefits of clinical pharmacology services, put a monetary value on clinical pharmacology services and to grow the clinical pharmacology workforce to support a growing clinical, academic and regulatory need.

Advanced Practice Pharmacists: a retrospective evaluation of the efficacy and cost of ClinicaL Pharmacist PractitionErs managing ambulatory Medicare patients in North Carolina (APPLE-NC).

BACKGROUND: Clinical Pharmacist Practitioners are advanced practicing pharmacists in North Carolina that provide disease-specific management. The purpose of this retrospective cohort study was to compare the efficacy and charges from referrals to a Clinical Pharmacist Practitioner by the primary care provider, to those managed by a primary care provider alone. METHODS: Patients were separated into cohorts depending if they had at least two appointments with a Clinical Pharmacist Practitioner from November 2008 to November 2011. A primary care provider saw all patients at least twice during the study period. Cohorts were then matched by age, gender, and disease states. Medicare billed data was evaluated from outpatient visits related to hypertension, diabetes mellitus, and peripheral neuropathy, as well as emergency department visits and inpatient admissions. Cost of medications was estimated using 2009 AWP data corresponding to medication histories within the electronic medical record. Efficacy was defined as ability to reach disease state goal determined using national guidelines and reduction in pain score. Efficacy was analyzed by difference-in-differences test and all other numerical data tested by paired t-tests. RESULTS: The Clinical Pharmacist Practitioners cohort experienced more outpatient visits (1338 vs. 858, p < 0.001), fewer emergency department visits (115 vs. 190, p < 0.05), and similar inpatient admissions (88 vs. 117, p > 0.05) than the primary care providers cohort, respectively. The Clinical Pharmacist Practitioners cohort showed changes in charges of +22.6 % for outpatient visits, -45.5 % emergency department visits, and -13.2 % inpatient admissions relative to the primary care provider cohort. There was no difference in average daily medication cost (Clinical Pharmacist Practitioners $38.52 vs. primary care providers $38.23, p = 0.97) or achievement of disease state goals. CONCLUSION: APPLE-NC demonstrated that through referrals, Clinical Pharmacist Practitioners provide services comparable in charges and efficacy to primary care providers. Consequently, the current increased need for primary care practitioners can be met in part by increasing the utilization of advanced practice pharmacists for chronic disease management. TRIAL REGISTRATION: This does not apply for this retrospective cohort study.

Medicines management: an interview study of nurses at a secure psychiatric hospital.

AIMS: To explore mental health nurses' knowledge, attitudes and clinical judgement concerning medicines management in an inpatient setting with a view to enhancing training. BACKGROUND: Medicines management is a key role of mental health nurses, but little research has been conducted into their training needs. DESIGN: An exploratory mixed-methods design was used involving individual interviews with participants to investigate their responses to hypothetical medicine administration scenarios. METHODS: Interviews were held with a convenience sample of 50 Registered Nurses working in a specialist mental health hospital between November 2012-February 2013. Participants were presented with clinical vignettes describing eight scenarios they might encounter as part of their medicines management role and asked about how they would respond. Responses were assessed by two independent raters against ten quality standards underpinning the vignettes. RESULTS: The median number of responses that were judged to demonstrate adequate awareness of associated quality standards was 4 (range 1-7), indicating that many participants did not appear to be aware of, or compliant with, current UK medicines management guidance and local policy. Many would not report a 'near miss' or medicines administration error. There was a lack of awareness of guidance on verbal prescribing, consent to treatment rules and the administration of off-label/unlicensed drugs. Past year attendance on a medicines management course, time since registration and self-reported knowledge of national standards for medicines administration did not discriminate between total score on the 10 quality standards. CONCLUSION: The medicines management training needs of participants appeared not to be fully met by the existing learning sources. The use of vignettes to assess nurses' training needs requires evaluation in other settings.

Characterization of a standardized glucagon challenge test as a pharmacodynamic tool in pharmacological research.

The aim of this study was to characterize a glucagon challenge test as a tool in diabetes research by assessing the inter- and intra-individual variability, and investigating the activity of the autonomic nervous system (ANS) during the challenge, as this might have an indirect impact on glucose homeostasis. The study was performed in 24 healthy volunteers separated in 2 groups. The first group of 12 volunteers underwent a 5-h glucagon challenge during a pancreatic clamp procedure with infusion of [6,6-2H2]-glucose infusion in combination with heart rate variability measurements. In the second group, 12 other healthy volunteers underwent two 6-h glucagon challenges separated by 6 weeks, and fat biopsies were taken for analysis of glucagon receptor expression. Serum glucose rose rapidly after glucagon infusion, and reached a plateau at 90 min. The time profiles suggested rapid development of tolerance for glucagon-induced hyperglycemia. During the glucagon challenge intra- and inter-individual variabilities for hepatic glucose production, the rate of disappearance of glucose, and plasma glucose were approximately 10-15% for all variables. Hyperglucagonemia did not affect heart rate variability. Human adipose tissue had a low, but variable, expression of glucagon receptor mRNA. This standardized glucagon challenge test has a good reproducibility with only limited variability over 6 weeks. It is a robust tool to explore in detail the contribution of glucagon in normal and altered glucose homeostasis and can also be used to evaluate the effects of drugs antagonizing glucagon action in humans without confounding changes in ANS tone.

Guidelines for the recording and evaluation of pharmaco-sleep studies in man: the International Pharmaco-EEG Society (IPEG).

The International Pharmaco-EEG Society (IPEG) presents guidelines summarising the requirements for the recording and computerised evaluation of pharmaco-sleep data in man. Over the past years, technical and data-processing methods have advanced steadily, thus enhancing data quality and expanding the palette of sleep assessment tools that can be used to investigate the activity of drugs on the central nervous system (CNS), determine the time course of effects and pharmacodynamic properties of novel therapeutics, hence enabling the study of the pharmacokinetic/pharmacodynamic relationship, and evaluate the CNS penetration or toxicity of compounds. However, despite the presence of robust guidelines on the scoring of polysomnography -recordings, a review of the literature reveals inconsistent -aspects in the operating procedures from one study to another. While this fact does not invalidate results, the lack of standardisation constitutes a regrettable shortcoming, especially in the context of drug development programmes. The present guidelines are intended to assist investigators, who are using pharmaco-sleep measures in clinical research, in an effort to provide clear and concise recommendations and thereby to standardise methodology and facilitate comparability of data across laboratories.

Adverse drug reactions.

Our ability to understand fully the characteristics of clinically important adverse drug reactions is hindered by a lack of emphasis on biological mechanisms, patient susceptibility factors and long-term outcomes. Assessment of drug safety needs to move beyond industry and regulatory perspectives, towards a greater focus on evidence-based preventive and management strategies that will allow patients and physicians to deal with adverse drug reactions at the bedside. This would ideally involve close collaboration between clinical pharmacologists and pharmacoepidemiologists skilled at interrogating the increasingly sophisticated electronic healthcare databases. In light of the myriad safety scares that are constantly emerging, patients and physicians would be best served by a centrally funded independent network of rapid-response drug safety researchers who can use techniques of teleoanalysis to describe fully the magnitude of risk, the potential biological mechanisms and patients' susceptibility factors.

Integrating pharmacology and clinical pharmacology in universities.

Continuing development of safe and effective new medicines is critically important for global health, social prosperity and the economy. The drug discovery-development pipeline depends critically on close partnerships between scientists and clinicians and on educational programmes that ensure that the pharmacological workforce, in its broadest sense, is fit for purpose. Here I consider factors that have influenced the development of basic and clinical pharmacology in UK universities over the past 40 years and discuss ways in which basic pharmacologists, clinical pharmacologists and scientists from different disciplines can work together effectively, while retaining their professional identities and fostering developments in their disciplines. Specifically, I propose the establishment of Institutes of Drug Discovery and Development, whose activities could include development and implementation of a translational pharmacology research strategy, drawing on the collective expertise of the membership and the university as whole; provision of a forum for regular seminars and symposia to promote the discipline, encourage collaboration and develop a cohesive community; provision of a research advisory service, covering, for example, data management, applications for ethics permission, clinical trials design, statistics and regulatory affairs; liaison with potential funders and leadership of major funding bids, including funding for doctoral training; provision of advice on intellectual property protection and the commercialization of research; liaison with corporate partners to facilitate collaboration, knowledge transfer and effective translation; and leadership of undergraduate and postgraduate education in basic and clinical pharmacology and related sciences for medical and science students, including continuing professional development and transferable skills.

Clinical usefulness of electronic drug-drug interaction checking in the care of cardiovascular surgery inpatients.

OBJECTIVES: Drug-related problems (DRPs) are events or circumstances involving drug therapy that actually or potentially interfere with desired health outcomes. This study tested the applicability of clinical decision support software in identifying and managing DRPs among cardiovascular surgery inpatients. METHODS: Two clinical pharmacologists attended ward rounds on a low-dependency cardiovascular surgery ward every 2 weeks over a 7-month period. Three hundred and three patients were assessed. On average, patients received 17 scheduled and 'as required' medicines. DRPs were identified 'manually' via assessment of electronic prescription charts and patient records and 'electronically' using clinical decision support software (Pharmavista). The numbers of alerts for optimizing medication safety generated by the two methods were compared. RESULTS: Manual checking identified 346 DRPs leading to 346 alerts in 201 patients (overall 1.1 alerts/patient). Relevant interactions accounted for 44% of DRPs detected by clinical pharmacologists. Clinical decision support software, which could only report interactions, however, generated 1,370 alerts (average 4.5 alerts/patient). Only 147 (11%) drug-drug interaction alerts were identical to those identified by manual checking; the remaining 89% were considered not clinically relevant. CONCLUSIONS: Compared to identification of DRPs by clinical pharmacologists, the clinical decision support software performed poorly due to over-alerting and inability to assess for problems not caused by drug-drug interactions.

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.

How to improve the clinical development paradigm and its division into phases I, II and III.

Based on the observation that over the last 30 years the cost of development has risen regularly as the number of new chemical entities reaching the market has fallen, how can "savings" be made in terms of clinical development, the objective being more rapid access to a drug for medical needs that are not covered? Several instruments exist to enable innovative products to be made available more quickly: temporary use authorisations, which are not concerned by this work (ATUs), conditional marketing authorisations (MAs) and MAs under exceptional circumstances. These aspects have been taken up in the European medicines agency (EMA)'s "Road Map", which states "A key issue for Regulators will be if a more "staggered" approval should be envisaged, characterised by a better defined/more restricted population of good responders, followed by a broadening of the population post-authorisation when more "real life" data are available. In addition, maximising the value of information generated in the post-authorisation phase should be developed through the use of cohorts and other prospectively collected use data, especially in the case of conditional marketing authorisations." The rules of procedure of the Transparency Commission for their part provide for the notion of preliminary examination: in order to prepare as best as possible the examination of dossiers of products assumed to be innovative and to limit delays, the office can undertake a preliminary study as soon as the dossier has been filed at the Committee for medicinal products for human use (CHMP). It may, at this time, request the firm to provide further information and may call on external experts. The implementation of this preliminary study does not exonerate the firm of the obligation of filing a complete dossier. The post inscription studies requested by the Transparency Commission (ISPEP - public health benefit and post-marketing studies) are usually requested in the case of hesitations regarding the level of improvement of the medical benefit (ASMR) [level II/III or IV/V]. Such requests mainly concern uncertainties regarding the transposability, the patient profile or correct usage in real life. Among the studies whose results were provided, in 15 cases the results were in line with expectations, in 6 cases they resulted in downward re-evaluations and the final 3 cases were inconclusive. The final recommendations of the round table were: Defining the medical need that is not covered by working in consultation (Industry and Health Authorities); Providing a Complementary Investigations Plan (PIC) after the MA at a very early stage to reinforce the early MA, and/or HTA (health technology assessment) preparation and monitoring (possible constraining actions); Enhanced use of modelling techniques and their transposability; "Intussusception" of phases to optimise the development of a complete dossier; Early "scientific opinions" (EMA, French Health Products Safety Agency [Afssaps], French Health Authority [HAS]); Raising the awareness of the authorities, industry, doctors and patients with regard to controlled observational studies; Developing the use of public data bases.