Establishment of a children's Drugs and Therapeutics Committee to ensure evidence-based and cost-effective medical treatment for children.

The prevalence of undocumented medical treatments among children is a significant issue, as well as many EU countries lack access to newly developed children-friendly medicines. Consequently, there is a pressing need for supplementary resources that can facilitate informed decision-making regarding children's medication. We therefore aim to describe the process of establishing a children's Drug and Therapeutics Committee (cDTC), as well as the preparing and implementation of recommendations for children in the capital region of Denmark. Following the guidelines outlined by the World Health Organization, we established a cDTC, and recommendations for paediatric medication practice were constructed from assessments of medication use patterns among children in the capital region between 2019 and 2021. The recommendations were meticulously crafted based on evaluation of the current marketing authorization landscape and existing best available evidence. In 2019, the capital region established the first cDTC supported by expert councils and an editorial board. A total of 2429 purchase item numbers covering 1 222 846 defined daily doses and 592 088 purchased packages covering 10 200 000 defined daily doses were identified in the secondary and primary sectors, respectively. Three comprehensive lists covering recommendations for newborns and children were published between 2021 and 2020 totaling 331 recommended pharmaceutical products. The recommendations primarily intended for use in the secondary healthcare sector were implemented through the revision of 38 paediatric- and six neonatal product ranges throughout capital region. In conclusion, recommendation lists for children governed by a cDTC provide a rational auxiliary tool that can be immediately implemented in the clinic.

Experience with sotrovimab treatment of SARS-CoV-2-infected patients in Denmark.

AIMS: To evaluate the experience with use of sotrovimab following severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in high-risk groups. METHODS: In a nationwide, population-based cohort study, we identified all individuals treated with sotrovimab (N = 2933) and stratified them by 4 high-risk groups: (A) malignant haematological disease, (B) solid organ transplantation, (C) anti-CD20 therapy ≤1 year and (D) other risks. Cox regression analysis was used to calculate hazard ratios for hospitalization, death and associated prognostic factors. RESULTS: Of 2933 sotrovimab-treated individuals, 83% belonged to high-risk groups (37.6% haematological malignancy, 27.4% solid organ transplantation and 17.5% treatment with anti-CD20 ≤1 year). Only 17.8% had other risks (11.8% were pregnant, 10.7% primary immunodeficiency, 21.2% other malignancy, 4.3% received anti-CD20 >1 year and 52.0% other/unknown causes). Within 90 days of infusion, 30.2% were hospitalized and 5.3% died. The main prognostic factors were the predefined high-risk groups, mainly malignant haematological disease and age ≥65 years. Number of COVID-19 vaccines (≥3) was associated with a decreased risk of hospitalization. The Delta but not the Omicron BA.2 variant was associated with a higher risk of death compared to the BA.1 variant. CONCLUSION: More than 90% of the patients treated with sotrovimab belonged to the very high-risk groups as described in the Danish guidelines. Sotrovimab-treated individuals remained at a high risk of hospitalization and death which was strongly associated with the underlying immunocompromised state and age. Having received >3 COVID-19 vaccines was association with decreased risk of death and hospitalization.

Use of Therapeutic Drug Monitoring in Amiodarone Treatment: A Systematic Review of Recent Literature.

BACKGROUND: Amiodarone is a class III antiarrhythmic drug used to prevent supraventricular and ventricular tachyarrhythmias. It has substantial toxicity; however, the use of therapeutic drug monitoring (TDM) seems unclear in the absence of a therapeutic range or an association between amiodarone blood concentration and effect. In this review, the authors examined the reported amiodarone blood concentration measurements in the last 10 years and subsequently noted the frequency by which TDM was used to optimize therapy. METHODS: In March 2022, the Embase and MEDLINE databases were searched for articles published in English in the previous 10 years using the keywords "amiodarone," "therapeutic drug monitoring," or "serum/plasma/blood". RESULTS: This study included 19 of the 478 articles identified. TDM has not been studied in conjunction with regular amiodarone maintenance therapy. One study used TDM during the initial treatment phase but the amiodarone dose was not changed. In 3 other case reports, TDM was used to guide amiodarone treatment through drug-drug interactions, and plasma levels of the active metabolite mono-N-desethyl-amiodarone (MDEA) verified 2 amiodarone toxicities. CONCLUSIONS: Because the antiarrhythmic effect of amiodarone is not correlated with blood concentrations and is easily detectable by electrocardiogram, the routine use of TDM in maintenance therapy is controversial, as evidenced by a scarcity of published literature in the recent decade. Furthermore, amiodarone toxicity is evident with normal/low amiodarone or MDEA levels; hence, TDM of amiodarone provides no therapeutic benefit to patients.

Improved Survival Among Hospitalized Patients With Coronavirus Disease 2019 (COVID-19) Treated With Remdesivir and Dexamethasone. A Nationwide Population-Based Cohort Study.

BACKGROUND: There are limited data on outcomes of moderate to severe coronavirus disease 2019 (COVID-19) among patients treated with remdesivir and dexamethasone in a real-world setting. We sought to compare the effectiveness of standard of care (SOC) alone versus SOC plus remdesivir and dexamethasone. METHODS: Two population-based nationwide cohorts of individuals hospitalized with COVID-19 during February through December 2020 were studied. Death within 30 days and need of mechanical ventilation (MV) were compared by inverse probability of treatment weighted (ITPW) logistic regression analysis and shown as odds ratio (OR) with 95% confidence interval (CI). RESULTS: The 30-days mortality rate of 1694 individuals treated with remdesivir and dexamethasone in addition to SOC was 12.6% compared to 19.7% for 1053 individuals receiving SOC alone. This corresponded to a weighted OR of 30-day mortality of 0.47 (95% CI: .38-.57) for patients treated with remdesivir and dexamethasone compared to patients receiving SOC alone. Similarly, progression to MV was reduced (OR 0.36; 95% CI: .29-.46). CONCLUSIONS: Treatment of moderate to severe COVID-19 during June through December that included remdesivir and dexamethasone was associated with reduced 30-day mortality and need of MV compared to treatment in February through May.

The Danish model for the quick and safe implementation of infliximab and etanercept biosimilars.

PURPOSE: A rapidly increasing use of biological drugs has led to substantial costs. Shift to biosimilars enables considerable reduction of these costs without jeopardizing the treatment of patients, but most countries have extensive possibilities of untapped cost-savings. The aim of this study was to describe the Danish quick and near-complete implementation of the two first TNF inhibitor biosimilars (infliximab and etanercept). METHODS: We shed light on the considerations and experiences made during the implementation, and present key figures from the implementation. RESULTS: The infliximab biosimilar constituted 90.6% of the total amount of infliximab four months following patent expiration of the biooriginator. Similar results were seen for etanercept biosimilar. Substantial cost reductions were experienced in the way that e.g. the infliximab-shift reduced cost by two thirds. CONCLUSION: We believe that a thorough preparation and an organizational setting supporting the implementation is crucial for the successful implementation. This same implementation model will be used for future biosimilars.

Content and validation of the Electronic Patient Medication module (EPM)-the administrative in-hospital drug use database in the Capital Region of Denmark.

Aims: Registries on in-hospital drug use are sparse, especially those that can be linked to nationwide registries. In this study, we present and validate the Electronic Patient Medication module (EPM)-the electronic administrative database on in-hospital drug use covering the Capital Region of Denmark. Methods: The research database (EPM-research) is an adaptation of the database underlying the electronic administrative database for in-hospital drug use (EPM-clinic). The validation study was comprised of two sub-studies. Sub-study 1: Accordance of registration between EPM-clinic and EPM-research was investigated by analyzing randomly chosen retrospective patient records. Sub-study 2: Workflows and real-life registration practices were investigated through visits to three different (two medical and one emergency) departments. An observer followed a nurse while dispensing and administering drugs. This information was compared with EPM-research. The primary endpoint for both sub-studies was accordance of generic name between registrations. Secondary endpoints were exact brand name, dose, and time of each administration. Accordance (proportions) with 95% confidence intervals (CI) using the Clopper-Pearson method were calculated. The study was approved by the Danish Data Protection Agency (BFH-2016-058-04906) and the Danish Patient Safety Authority (3-3013-1884/1/). Results: In sub-study 1 227 retrospective drug administrations were reviewed. Accordance of generic name was 100.0% (CI 98.4%-100.0%). In sub-study 2 176 drug administrations were observed of which 173 were recorded with identical generic name, resulting in 98.3% (CI 95.1%-99.6%) accordance of data. Conclusions: Our validation of the EPM-research showed very high accordance. With detailed information on in-hospital drug use, the EPM-research may be a useful tool in pharmacoepidemiological research.

Quality assessment of structure and language elements of written responses given by seven Scandinavian drug information centres.

PURPOSE: The aim of this study was to identify structure and language elements affecting the quality of responses from Scandinavian drug information centres (DICs). METHODS: Six different fictitious drug-related queries were sent to each of seven Scandinavian DICs. The centres were blinded for which queries were part of the study. The responses were assessed qualitatively by six clinical pharmacologists (internal experts) and six general practitioners (GPs, external experts). In addition, linguistic aspects of the responses were evaluated by a plain language expert. RESULTS: The quality of responses was generally judged as satisfactory to good. Presenting specific advice and conclusions were considered to improve the quality of the responses. However, small nuances in language formulations could affect the individual judgments of the experts, e.g. on whether or not advice was given. Some experts preferred the use of primary sources to the use of secondary and tertiary sources. Both internal and external experts criticised the use of abbreviations, professional terminology and study findings that was left unexplained. The plain language expert emphasised the importance of defining and explaining pharmacological terms to ensure that enquirers understand the response as intended. In addition, more use of active voice and less compressed text structure would be desirable. CONCLUSIONS: This evaluation of responses to DIC queries may give some indications on how to improve written responses on drug-related queries with respect to language and text structure. Giving specific advice and precise conclusions and avoiding too compressed language and non-standard abbreviations may aid to reach this goal.

The impact of legislation on drug substances used off-label in paediatric wards--a nationwide study.

PURPOSE: This nationwide study is aimed at describing to what extent the European Paediatric Regulation has met therapeutic needs in children. METHODS: Data for each drug substance in defined daily doses (DDD) were extracted from the national Danish data base. We evaluated if drug substances were used off-label and whether they had a paediatric investigation plan (PIP). This study did not include drug prescriptions for individual paediatric patients; thus, it was not possible to make use of all off-label categories previously used. Additionally, paediatric standard assortments (SA) were compared to the European survey on paediatric medicinal products. RESULTS: Thirteen percent of the 100 most used drug substances were determined as being used off-label, four of which had a PIP and one had a full waiver. Only one of the three drug substances used off-label most often, accounting for 85 % of such use, had a PIP. Neonates were included in one-third of PIPs and adolescents in 15. Nineteen out of 21 PIPs had a waiver and 14 PIPs were deferred. In line with the European survey, carbapenems, corticosteroids and proton pump inhibitors were frequent found in SAs. CONCLUSION: PIPs only cover a small proportion of the drugs found to be used off-label in this study. Despite waivers granted, drug substances were used nonetheless. Unmet regulatory needs are still considerable in some therapeutic areas in neonates as well as in children.

Factors associated with time consumption when answering drug-related queries to Scandinavian drug information centres: a multi-centre study.

PURPOSE: There is little research-based documentation on the services provided by drug information centres (DICs). The aim of this multi-centre study was to explore for the first time the factors associated with time consumption when answering drug-related queries at eight different but comparable DICs. METHODS: During an 8-week period, staff members at eight Scandinavian DICs recorded the number of minutes during which they responded to queries. Mixed model linear regression analyses were used to explore the factors associated with time consumption when answering queries. RESULTS: The mean time consumption per query was 178 min (range 4-2540 min). The mean time consumed per query increased by 28 (95 % confidence interval (CI) 23 to 33, p < 0.001) min higher for queries for which there was a lack of documentation and 139 (95 % CI 74 to 203, p < 0.001) min higher when conflicting information was present in the literature. Staff members with less than 1 year of experience consumed a mean of 91 more minutes (95 % CI 32 to 150, p = 0.003) per query than staff members with more than 2 years of experience. CONCLUSIONS: This study demonstrates the large variation in time consumed answering queries posed to Scandinavian DICs. The results highlight the need for highly competent staff members and easy access to drug information sources. Further studies are required to explore the association between time consumption and response quality.

Treatment effect modifiers in hospitalised patients with COVID-19 receiving remdesivir and dexamethasone.

BACKGROUND: The combined effectiveness of remdesivir and dexamethasone in subgroups of hospitalised patients with COVID-19 is poorly investigated. METHODS: In this nationwide retrospective cohort study, we included 3826 patients with COVID-19 hospitalised between February 2020 and April 2021. The primary outcomes were use of invasive mechanical ventilation and 30-day mortality, comparing a cohort treated with remdesivir and dexamethasone with a previous cohort treated without remdesivir and dexamethasone. We used inverse probability of treatment weighting logistic regression to assess associations with progression to invasive mechanical ventilation and 30-day mortality between the two cohorts. The analyses were conducted overall and by subgroups based on patient characteristics. RESULTS: Odds ratio for progression to invasive mechanical ventilation and 30-day mortality in individuals treated with remdesivir and dexamethasone compared to treatment with standard of care alone was 0.46 (95% confidence interval, 0.37-0.57) and 0.47 (95% confidence interval, 0.39-0.56), respectively. The reduced risk of mortality was observed in elderly patients, overweight patients and in patients requiring supplemental oxygen at admission, regardless of sex, comorbidities and symptom duration. CONCLUSIONS: Patients treated with remdesivir and dexamethasone had significantly improved outcomes compared to patients treated with standard of care alone. These effects were observed in most patient subgroups.

Is a targeted intensive intervention effective for improvements in hypertension control? A randomized controlled trial.

BACKGROUND: High blood pressure (BP) is one of the most important risk factors for stroke, and antihypertensive therapy significantly reduces the risk of cardiovascular morbidity and mortality. However, achieving a regulated BP in hypertensive patients is still a challenge. OBJECTIVE: To evaluate the impact of an intervention targeting GPs' management of hypertension. METHODS: A cluster randomized trial comprising 124 practices and 2646 patients with hypertension. In the Capital Region of Denmark, the participating GPs were randomized to an intensive or to a moderately intensive intervention group or to a control group and in Region Zealand and Region of Southern Denmark, practices were randomized into a moderately intensive intervention and to a control group. The main outcome measures were change in proportion of patients with high BP and change in systolic BP (SBP) and diastolic BP (DBP) from the first to the second registration. RESULTS: The proportion of patients with high BP in 2007 was reduced in 2009 by ~9% points. The mean SBP was reduced significantly from 2007 to 2009 by 3.61 mmHg [95% confidence interval (CI): -4.26 to -2.96], and the DBP was reduced significantly by 1.99 mmHg (95% CI: -2.37 to -1.61). There was no additional impact in either of the intervention groups. CONCLUSION: There was no impact of the moderate intervention and no additional impact of the intensive intervention on BP.

A systematic review of blood eosinophils and continued treatment with inhaled corticosteroids in patients with COPD.

Inhaled corticosteroid (ICS) in patients with chronic obstructive pulmonary disease (COPD) has been debated for 20 years. In our systematic literature review and meta-analysis, we addressed the following: Should patients with COPD and a blood eosinophil count (EOS) of, respectively, a) < 150 cells/µl, b) 150-300 cells/µl, and c) > 300 cells/µl continue treatment with ICS? Protocol registered in PROSPERO (CRD42020178110) and funded by the Danish Health Authority. We searched Medline, Embase, CINAHL and Cochrane Central on 22nd July 2020 for randomized controlled trials (RCT) of ICS treatment in patients with COPD (≥40 years, no current asthma), which analyzed outcomes by EOS count and where >50% of patients used ICS prior. We used the GRADE method. Meta-analyzes for the outcomes were divided into EOS subgroups and analyzed for differences. We identified 11 RCTs with a total of 29,654 patients. A significant difference (p < 0.00001) between the three subgroups' reduction of risk of moderate to severe exacerbation was found. Rate ratios for EOS counts: <150 cells/µL was 0.88 (95%CI: 0.83, 0.94); 150-300 cells/µL was 0.80 (95%CI: 0.69, 0.94); >300 cells/µL was 0.57 (95%CI: 0.49, 0.66). Overall, the certainty of the effect estimates was low to very low due to risk of bias, unexplained heterogeneity, few RCTs, and wide confidence intervals. A clear correlation was demonstrated between effect of continued ICS treatment (number of exacerbations, lung function, and quality of life) and increasing EOS count. Our meta-analyses suggested that treatment with ICS seemed beneficial for everyone except patients with EOS count below 150 cells/µl.

Discontinuation of diabetes medication in the 10 years before death in Denmark: a register-based study.

BACKGROUND: Discontinuation of diabetes medication in the last years of life has been suggested to improve quality of life while deemed safe to implement. However, the extent, patterns, and secular changes in discontinuation of glucose-lowering medication in older people with type 2 diabetes have been scarcely described. We therefore aimed to describe the trends in the use of glucose-lowering medication during the last 10 years of life of older people and explore how key clinical and socioeconomic covariates are associated with these patterns. METHODS: In this register-based cohort study, all individuals with type 2 diabetes who died aged 80 years or older between Jan 1, 2006, and Dec 31, 2018, were identified through the Danish Diabetes Register and linked to the Danish National Prescription Registry. We followed the population backwards in time from death to date of last medication intake. To estimate the cumulative proportion of people on glucose-lowering medication, a Poisson regression model for the rate of medication as a function of time before death (0 to 10 years before death) and calendar year of death (2006-18) was fitted. Both single-substance and combination glucose-lowering medications were included and categorised as insulins, sulfonylureas, metformin, DPP-4 inhibitors, GLP-1 analogues, SGLT2 inhibitors, acarbose, and thiazolidinediones. Insulin was further subdivided into four groups: fast-acting, intermediate-acting, long-acting, and mixed insulin. To identify which covariates were associated with discontinuation, estimates were adjusted for sex, age at death, diabetes duration at time of death, the total number of diabetes complications at time of death (from no complications to four or more), level of education, immigrant status, and income quartile. FINDINGS: 52 523 individuals (28 746 [54·7%] females and 23 777 [45·3%] males) were identified, with a mean age at type 2 diabetes diagnosis of 77 years (SD 8), median age at death of 86 years (IQR 83-90), and median diabetes duration at death of 9 years (IQR 5-14). We found a considerable discontinuation of glucose-lowering medication during the last 10 years of life, with the proportion of people on glucose-lowering medication starting at between 89% (95% CI 87-91) in 2006 and 87% (86-88) in 2018 at 10 years before death and decreasing to between 52% (50-54) in 2006 and 38% (37-39) in 2018 at the time of death. Specifically, we found that the proportion of people on sulfonylureas, at any time before death, decreased substantially from 2006 to 2018, whereas the proportion on metformin and DPP-4 inhibitors increased with calendar year of death. Changes were less pronounced for the remaining medications. The overall discontinuation patterns changed with increasing calendar year of death, such that discontinuation rates increased and occurred earlier (further away from time of death) with increasing calendar year. Discontinuations were generally more pronounced during the last year of life. Proportions of people on medication and patterns of discontinuation, as well as the association with covariates, varied with medication class. Covariates most frequently associated with changes in discontinuation rates were sex, age at death, type 2 diabetes duration at death, and number of complications. For example, females were less likely to receive metformin than males at all years before death (rate ratio 0·91 (95% CI 0·89-0·94, p<0·0001), and there was a negative association between the proportion of individuals on metformin and increasing age at death (rate ratio per year increase 0·96 [0·96-0·96], p<0·0001) and type 2 diabetes duration (0·95 per year increase [0·94-0·95], p<0·0001). INTERPRETATION: Our results suggest that increased focus on and implementation of discontinuation of glucose-lowering medication in recent years might have had an effect on discontinuation patterns, particularly during the last year of life. FUNDING: None.

Midazolam Pharmacokinetics in Obese and Non-obese Children and Adolescents.

BACKGROUND: Midazolam is a first-line drug for the treatment of status epilepticus, both by buccal and intravenous administration. In children and adolescents with obesity, midazolam pharmacokinetics may be altered, and the current dosing guidelines may therefore be insufficient. OBJECTIVE: The objective of this study was to investigate the pharmacokinetics of midazolam, after intravenous administration, in obese and non-obese adolescents aged 11-18 years. METHODS: All trial participants received a 1-µg midazolam microdose as an intravenous bolus. 13 blood samples were collected per participant at pre-specified timepoints. Plasma concentration-time data were fitted to pharmacokinetic models using non-linear mixed-effects modeling. Covariates such as weight, age, and body mass index standard deviation score were tested to explain the inter-individual variability associated with the pharmacokinetic parameters. RESULTS: Sixty-seven adolescents were included in the analysis. The pharmacokinetics of midazolam was best described with a two-compartment model. The rate of distribution was faster, and the peripheral volume of distribution was larger in adolescents with a high body mass index standard deviation score compared with adolescents with a lower standard deviation score. Simulations revealed that long-term infusions based on total body weight could lead to high plasma concentrations in adolescents with obesity. Furthermore, simulated plasma concentrations after a fixed buccal dose indicated that adolescents with obesity may be at risk of sub-therapeutic midazolam plasma concentrations. CONCLUSIONS: The body mass index standard deviation score was shown to have a significant influence on the peripheral volume of distribution and the inter-compartmental clearance of midazolam. The current dosing guidelines for status epilepticus, where the midazolam dose is adjusted to total body weight or age, may lead to supra- and sub-therapeutic plasma concentrations, respectively, in adolescents with obesity. TRIAL REGISTRATION: EudraCT: 2014-004554-34.

Important Aspects of Pharmacist-led Medication Reviews in an Acute Medical Ward.

In some hospitals, clinical pharmacists review the medication to find drug-related problems (DRPs) in acutely admitted patients. We aimed to identify the nature of identified DRPs and investigate factors of potential importance for the clinical implementation of pharmacist suggestions. In 100 randomly selected medication review (MR) notes, we retrospectively evaluated the clinical implementation and classified (1) timing and communication of the review; (2) DRPs and related suggestions for the physician; and (3) DRPs' potential clinical relevance to patients as 'beneficial', 'somewhat beneficial', 'no relevance' or 'other relevance'. Of 327 DRPs (0-13 DRPs per patient), 42% were implemented. The clinical implementation was higher if the MR note was made prior to (instead of after) the physician's admission, and even higher if the suggestions were communicated verbally (instead of only in writing) to the physicians (44% versus 79%, p < 0.05). The clinical relevance of the DRPs was either 'beneficial' (16%), 'somewhat beneficial' (43%), 'no relevance' (22%) or 'other relevance' (19%). The 'beneficial' DRPs had a higher clinical implementation (53%) than 'no relevance' (34%) (p < 0.05). The most frequently implemented suggestions were based on DRPs concerning 'indication for drug treatment not noticed', 'inappropriate drug form' and 'drug dose too low', with implementation rates of 83%, 67% and 63%, respectively. In our sample, the pharmacist's MR suggestions were only implemented by physicians in 42% of the cases, but review prior to physician contact and verbal communication of the suggestions, higher clinical relevance and specific types of DRPs were associated with a higher implementation rate.

Use of References in Responses from Scandinavian Drug Information Centres.

Background: The aim of this study was to compare use of references in responses from Scandinavian drug information centres (DICs). Methods: Six different fictitious drug-related queries were sent to each of seven Scandinavian DICs. The six queries concerned adverse effects, pharmacokinetics, pregnancy, complementary medicine, polypharmacy, and breast feeding. References in the responses were categorised into five types of drug information sources: primary (original studies), secondary (reviews), tertiary (drug monographs, handbooks, etc.), DIC database, or personal communication. Results: Two hundred and forty-four references were used in the 42 responses. The mean number of references varied from 3.0 to 10.6 for the six queries. The largest difference between centres with regard to number of references used (range 1⁻17) was found for the query on complementary medicine. In total, 124 references (50.8%) were tertiary, and only 10 of the 42 responses (23.8%) did not have any tertiary references included. Complementary medicine, breast feeding, and pregnancy were query types associated with relatively frequent use of primary references. Use of DIC database was not uncommon, but personal communications were seldom used. Conclusions: Scandinavian DICs differ substantially in number and type of references to identical drug-related queries. Tertiary sources are mainly preferred irrespective of type of query.

The CYTONOX trial.

INTRODUCTION: In Denmark, it is estimated that 3-5% of children are obese. Obesity is associated with pathophysiological alterations that may lead to alterations in the pharmacokinetics of drugs. In adults, obesity was found to influence important drug-metabolising enzyme pathways. The impact of obesity-related alterations on drug metabolism and its consequences for drug dosing remains largely unknown in both children and adults. An altered drug metabolism may contribute significantly to therapeutic failure or toxicity. The aim of this trial is to investigate the in vivo activity of CYP3A4, CYP2E1 and CYP1A2 substrates in obese versus non-obese children. METHODS: The CYTONOX trial is an open-label explorative pharmacokinetic trial. We intend to include 50 obese and 50 non-obese children. The primary end points are: in vivo clearance of CYP3A4, CYP2E1 and CYP1A2 substrates, which will be defined by using well-tested probes; midazolam, chlorzoxazone and caffeine. Each of the probes will be administered as a single dose. Subsequently, blood and urine samples will be collected at pre-specified times. CONCLUSION: The aim of the CYTONOX trial is to investigate the in vivo activity of CYP3A4, CYP2E1 and CYP1A2 in obese and non-obese children. The results are expected to be used in the future as a basis for drug dosing recommendations in obese children. FUNDING: The study was funded by the Danish Regions' "Medicinpuljen". The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. TRIAL REGISTRATION: EudraCT: 2014-004554-34.

Clinical Pharmacology in Denmark in 2016 - 40 Years with the Danish Society of Clinical Pharmacology and 20 Years as a Medical Speciality.

The Danish Society of Clinical Pharmacology was founded in 1976, and mainly thanks to the persistent efforts of the society, clinical pharmacology became an independent medical speciality in Denmark in 1996. Since then, clinical pharmacology has gone from strength to strength. In the Danish healthcare system, clinical pharmacology has established itself as an indispensible part of the efforts to promote the rational, safe and economic use of drugs. Clinical pharmacologists are active in drug committees both in hospitals and in the primary sector. All clinical pharmacology centres offer a local medicines information service. Some centres have established an adverse drug effect manager function. Only one centre offers a therapeutic drug monitoring service. Clinical pharmacologists are responsible for the toxicological advice at the Danish Poison Information Centre at Bispebjerg University Hospital in the Capital Region. The Department of Clinical Pharmacology at Aarhus University Hospital works closely together with forensic toxicologists and pathologists, covering issues regarding illicit substances, forensic pharmacology, post-mortem toxicology, expert testimony and research. Therapeutic geriatric and psychiatric teach-inns for specialist and junior doctors are among the newest initiatives organized by clinical pharmacologists. Clinical pharmacologists work also in the Danish Medicines Agency and in the Danish pharmaceutical industry, and the latter has in particular a great growth potential for creating new jobs and career opportunities for clinical pharmacologists. As of July 2016, the Danish Society of Clinical Pharmacology has 175 members, and 70 of these are specialists in clinical pharmacology corresponding to approximately 2.5 specialists per 1000 doctors (Denmark has in total 28,000 doctors) or approximately 12 specialists per one million inhabitants.