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Aims: Aripiprazole is one of the most commonly prescribed antipsychotic drugs to children and adolescents worldwide, but it is associated with serious side‐effects, including weight gain. This study assessed the population pharmacokinetics of aripiprazole and its active metabolite and investigated the relationship between pharmacokinetic parameters and body mass index (BMI) in children and adolescents with autism spectrum disorder (ASD) and behavioural problems. Secondary outcomes were metabolic, endocrine, extrapyramidal and cardiac side‐effects and drug effectiveness. Methods: Twenty‐four children and adolescents (15 males, 9 females) aged 6–18 years were included in a 24‐week prospective observational trial. Drug plasma concentrations, side‐effects and drug effectiveness were measured at several time points during follow‐up. Relevant pharmacokinetic covariates, including CYP2D6, CYP3A4, CYP3A5 and P‐glycoprotein (ABCB1) genotypes, were determined. Nonlinear mixed‐effects modelling (NONMEM®) was used for a population pharmacokinetic analysis with 92 aripiprazole and 91 dehydro‐aripiprazole concentrations. Subsequently, model‐based trough concentrations, maximum concentrations and 24‐h area under the curves (AUCs) were analysed to predict outcomes using generalized and linear mixed‐effects models. Results: For both aripiprazole and dehydro‐aripiprazole, one‐compartment models best described the measured concentrations, with albumin and BMI as significant covariates. Of all the pharmacokinetic parameters, higher sum (aripiprazole plus dehydro‐aripiprazole) trough concentrations best predicted higher BMI z‐scores (P <.001) and higher Hb1Ac levels (P =.03) during follow‐up. No significant association was found between sum concentrations and effectiveness. Conclusions: Our results indicate a threshold with regard to safety, which suggests that therapeutic drug monitoring of aripiprazole could potentially increase safety in children and adolescents with ASD and behavioural problems. [ABSTRACT FROM AUTHOR]

Pharmacogenomics (PGx) relates to the study of genetic factors determining variability in drug response. Implementing PGx testing in paediatric patients can enhance drug safety, helping to improve drug efficacy or reduce the risk of toxicity. Despite its clinical relevance, the implementation of PGx testing in paediatric practice to date has been variable and limited. As with most paediatric pharmacological studies, there are well‐recognised barriers to obtaining high‐quality PGx evidence, particularly when patient numbers may be small, and off‐label or unlicensed prescribing remains widespread. Furthermore, trials enrolling small numbers of children can rarely, in isolation, provide sufficient PGx evidence to change clinical practice, so extrapolation from larger PGx studies in adult patients, where scientifically sound, is essential. This review paper discusses the relevance of PGx to paediatrics and considers implementation strategies from a child health perspective. Examples are provided from Canada, the Netherlands and the UK, with consideration of the different healthcare systems and their distinct approaches to implementation, followed by future recommendations based on these cumulative experiences. Improving the evidence base demonstrating the clinical utility and cost‐effectiveness of paediatric PGx testing will be critical to drive implementation forwards. International, interdisciplinary collaborations will enhance paediatric data collation, interpretation and evidence curation, while also supporting dedicated paediatric PGx educational initiatives. PGx consortia and paediatric clinical research networks will continue to play a central role in the streamlined development of effective PGx implementation strategies to help optimise paediatric pharmacotherapy. [ABSTRACT FROM AUTHOR]

Aims: P‐glycoprotein (P‐gp) and CYP3A4‐interacting drugs influence plasma levels of non‐vitamin K antagonist oral anticoagulants (NOACs). However, the clinical relevance is questioned. Therefore, the impact of pharmacokinetically‐interacting drugs on the effectiveness and safety of NOACs in patients with atrial fibrillation (AF) was investigated. Methods: A meta‐analysis was performed based on randomized controlled trials and observational studies retrieved from Pubmed and Embase that investigated the impact of concomitantly used P‐gp/CYP3A4‐interacting drugs on the risk–benefit profile of NOACs in AF patients. Results: Fifteen studies were included, investigating 21 711 and 306 421 NOAC‐treated AF patients with and without P‐gp/CYP3A4 inhibitor use respectively, while only 1 study included P‐gp/CYP3A4 inducers. In NOAC‐treated AF patients, concomitant use of P‐gp/CYP3A4 inhibitors was associated with significantly higher major bleeding (relative risk [RR] 1.10, 95% confidence interval [CI; 1.01–1.19]) and all‐cause mortality risks (RR 1.14, 95%CI [1.05–1.23]) compared to not using P‐gp/CYP3A4 inhibitors, while the risks of stroke/systemic embolism (RR 0.88, 95%CI [0.77–1.01]), intracranial bleeding (RR 0.89, 95%CI [0.68–1.15]) and gastrointestinal bleeding (RR 1.09, 95%CI [0.91–1.30]) were not significantly different. Concomitant use of amiodarone with NOACs was associated with lower thromboembolic (RR 0.75, 95%CI [0.61–0.92]), similar major bleeding (RR 0.92, 95%CI [0.80–1.07]) but higher mortality risks (RR 1.21, 95%CI [1.05–1.39]). Coadministration of verapamil or diltiazem was associated with higher major bleeding risks (RR 1.64, 95%CI [1.31–2.06]), but comparable thromboembolic (RR 1.10, 95%CI [0.75–1.61]) and mortality risks (RR 1.01, 95%CI [0.77–1.33]). Conclusion: Given the higher bleeding and mortality risks in NOAC‐treated AF patients concomitantly using P‐gp/CYP3A4 inhibitors, close monitoring is warranted. [ABSTRACT FROM AUTHOR]

Mitotane is the only adrenolytic drug approved by the Food and Drug Administration for treating adrenocortical carcinoma (ACC). This drug has cytotoxic effects on tumour tissues; it induces cell death and antisecretory effects on adrenal cells by inhibiting the synthesis of adrenocortical steroids, which are involved in the pathogenesis of ACC. However, high doses of mitotane are usually necessary to reach the therapeutic plasma concentration, which may result in several adverse effects. This suggests that important pharmacological processes, such as first pass metabolism, tissue accumulation and extensive time for drug elimination, are associated with mitotane administration. Few studies have reported the pharmacological aspects and therapeutic effects of mitotane. Therefore, the aim of this review was to summarize the chemistry, pharmacokinetics and pharmacodynamics, and therapeutic and toxic effects of mitotane. This review also discusses new perspectives of mitotane formulation that are currently under investigation. Understanding the pharmacological profile of mitotane can improve the monitoring and efficacy of this drug in ACC treatment and can provide useful information for the development of new drugs with specific action against ACC with fewer adverse effects. [ABSTRACT FROM AUTHOR]

Aims: Ningetinib is a tyrosine kinase inhibitor for the treatment of non‐small cell lung cancer (NSCLC). The present study aims to investigate the drug interaction of ningetinib and gefitinib and the mechanism of high plasma exposure of N‐demethylated ningetinib (M1) in NSCLC patients. Methods: Patients with NSCLC were recruited. Metabolism and transport assays were performed using in vitro models. Deuterated M1 was used to study the effects of ningetinib and gefitinib on M1 efflux in Institute of Cancer Research (ICR) mice. Results: Upon co‐administration of ningetinib with gefitinib, the plasma exposure of M1 was reduced by 80%, whereas that of ningetinib was not affected. In vitro experiments indicated that CYP1A1 was primarily responsible for M1 formation. Gefitinib was demonstrated to be a strong inhibitor of CYP1A1 with Ki value of 0.095 μM. M1 was identified as a substrate of efflux transporters P‐gp and BCRP, while ningetinib and gefitinib were demonstrated to be their inhibitors, which was consistent with the results in mice. However, the inhibitory effect of gefitinib on efflux in vivo was negligible in the presence of ningetinib. Conclusion: The high plasma exposure of M1 in patients was attributed to the inhibition of M1 efflux by ningetinib and its low tissue affinity. When co‐administered, gefitinib inhibited the formation of M1, but due to the low metabolic yield of M1 in vivo, the pharmacokinetics of ningetinib was not influenced. Inhibition of CYP1A1 may increase the concentration of ningetinib in target tissues, and the long‐term safety and efficacy of ningetinib combined with gefitinib should be evaluated. [ABSTRACT FROM AUTHOR]

Aims: Chemotherapy‐induced neutropenia has been associated with an increase in overall survival in non‐small cell lung cancer patients. Therefore, neutrophil counts could be an interesting biomarker for drug efficacy as well as linked directly to toxicity. For drugs where neutropenia is dose limiting, neutrophil counts might be used for monitoring drug effect and for dosing optimisation. Methods: The relationship between drug effect on the first cycle neutrophil counts and patient survival was explored in a Phase III clinical trial where patients with non‐small cell lung cancer were treated with docetaxel. Once the association has been established, dosing optimisation was performed for patients with severe toxicities (neutropenia) without compromising drug efficacy (overall survival). Results: After taking into account baseline prognostic factors, such as Eastern Cooperative Oncology Group performance status, smoking status, liver metastasis, tumour burden, neutrophil counts and albumin levels, a model‐predicted drug effect on the first cycle neutrophil counts was strongly associated with patient survival (P =.005). Utilising this relationship in a dose optimisation algorithm, 194 out of 366 patients would have benefited from a dose reduction after the first cycle of docetaxel. The simulated 1‐year survival probabilities associated with the original dose and the individualised dose were not different. Conclusion: The strong relationship between drug effect on the first cycle neutrophil counts and patient survival suggests that this variable could be used to individualise dosing, possibly without needing pharmacokinetic samples. The algorithm highlights that doses could be reduced in case of severe haematological toxicities without compromising drug efficacy. [ABSTRACT FROM AUTHOR]

Aims: The purpose of this study is to examine the safety and efficacy of eltrombopag as first‐line treatment for thrombocytopenia among paediatric patients after haematopoietic stem cell transplantation (HSCT). Methods: Forty‐three childhood patients with thrombocytopenia after HSCT who received eltrombopag were retrospectively analysed. Result: Eltrombopag was began at the median of 27 days after HSCT and lasted for 24 days. Thirty‐five children responded to eltrombopag therapy, and the cumulative platelet recovery rate was 88.9%. The cumulative incidence of platelet recovery was lower (83.9 vs 100%; P =.035) in patients with decreased numbers of megakaryocytes before starting eltrombopag than in those with normal. Factors associated with a significantly elevated response to eltrobopag from univariate analysis were donor type. Results from the multiple regression analysis found that weight (hazard ratio [HR] = 0.7, 95% confidence interval [CI] 0.5–0.9, P =.022), platelet engraftment time (HR = 1.0, 95%CI 1.0–1.0, P =.012) and bone marrow megakaryocytes (HR = 8.0, 95%CI 1.5–43.3, P =.016) before starting eltrombopag were the independent risk factors. Based on Youden's index algorithm in the receiver‐operating characteristic curve, the optimal cut‐off value of the maintenance dose of eltrombopag in predicting nonresponders was 4 mg/kg. The area under the receiver‐operating characteristic curve was 0.923 with sensitivity of 97.8%, specificity of 87.9%, positive predictive value of 72.3%, and negative predictive value of 92%. None of the paediatric patients stopped using eltrombopag due to side effect or intolerability. Conclusion: Eltrombopag is effective and safe in paediatric patients with thrombocytopenia after HSCT. The number of megakaryocytes in bone marrow before eltrombopag treatment may serve as a predictor of the response to eltrombopag. We recommend that the maintenance dose of eltrombopag should not exceed 4 mg/kg/d. [ABSTRACT FROM AUTHOR]

Aims: To assess whether randomized clinical trials (RCTs) proposed to evaluate the treatment of patients with COVID‐19 with hydroxychloroquine (HQ) or chloroquine early in the pandemic included plans to measure outcomes that would translate into meaningful efficacy/effectiveness and safety outcomes. Methods: The World Health Organization International Clinical Trials Registry Platform database was searched for registers of RCTs evaluating HQ or chloroquine, alone or in combination, compared with other treatments for patients diagnosed with COVID‐19. The final search was performed on 8 April 2020. Results: Among 51 registered RCTs (median sample size 262; interquartile range: 100, 520), 34 (67%) reported a clinical outcome, 12 (24%) a surrogate outcome, and 5 (10%) a combination of clinical and surrogate outcomes as primary endpoints. Six (15%) trials included the World Health Organization scale for clinical improvement as a primary clinical outcome. Clinical improvement and mortality accounted for 45% of the unique domains among 18 clinical outcome domains of efficacy. Twenty‐four (47%) RCTs did not describe plans to assess safety outcomes; when assessed, safety outcomes were determined in generic terms of total, severe or serious adverse events. Conclusion: The RCTs investigating HQ or chloroquine during the early stages of the COVID‐19 pandemic included heterogeneous and insufficient approaches to measure efficacy/effectiveness and safety relevant to patients and clinical practice. These findings provide insights to inform clinical and regulatory decisions that can be drawn about the efficacy/effectiveness and safety of these agents in patients with COVID‐19. Trialists need to adapt quickly to the research progress on COVID‐19, ensuring that core outcome measures are assessed in ongoing RCTs. [ABSTRACT FROM AUTHOR]

Aims: Mesalamine is the first‐line therapy for treating mild‐to‐moderate ulcerative colitis. Multiple mesalamine formulations are available, with similar safety and efficacy profiles. Mesalamine is commonly administered as divided dosing, although once‐daily dosing may provide benefits for patients. We evaluated the pharmacokinetics of three dosing regimens of two oral delayed‐release mesalamine formulations in healthy adult volunteers. Methods: A randomised, open‐label, parallel‐group study of mesalamine pharmacokinetics following Lialda 2 × 1.2 g once daily (QD) (dose A), Asacol 6 × 400 mg QD (dose B), or Asacol 2 × 400 mg three times daily (TID) (dose C) over 7 days. Assessments included 5‐aminosalicylic acid (5‐ASA) and N‐acetyl 5‐aminosalicylic acid (N‐Ac‐5‐ASA, primary metabolite) pharmacokinetics (Ae(%), AUC0‐24 and Cmax), safety and tolerability. Results: All enrolled volunteers (n = 37) completed the study. Steady state was achieved for all treatments by day 4. Ratios (95% CI) of means for steady‐state AUC0‐24 (dose A vs B 90.3% [39.8, 204.8], dose A vs C 123.5% [55.3, 275.7], dose B vs C 136.8% [61.3, 305.5]) and Cmax (dose A vs B 106.0% [46.4, 242.2], dose A vs C 133.0% [59.1, 299.0], dose B vs C 125.5% [55.8, 282.1]) were similar for all 5‐ASA treatments. Mean urinary excretion of 5‐ASA plus N‐Ac‐5‐ASA was comparable between treatments (dose A 21.3%, dose B 20.2%, dose C 17.9%). All treatment regimens were well tolerated; no safety issues were observed. Conclusions: Plasma and urine pharmacokinetics for Asacol TID, Asacol QD, and Lialda QD are similar, suggesting similar daily systemic exposures can be obtained with either TID or QD dosing. NCT00751699. [ABSTRACT FROM AUTHOR]

Background: Pre‐emptive pharmacogenomic (PGx) testing is potentially an efficient approach to improve drug safety and efficacy but the target population to test is unclear. Objectives: We aim to describe the prescription pattern of PGx drugs among adult medical outpatients. Methods: We estimated the 5‐year cumulative incidence (CI) for receiving three groups of PGx drugs using competing risks analysis: (i) all PGx drugs, (ii) PGx drugs with guidelines and (iii) PGx drugs with serious clinical effects. Comparisons of CIs were also done by patient characteristics using Gray's test. Results: The 5‐year CIs of receiving any new PGx drug, PGx drug with guidelines and serious clinical effects were 42.6%, 37.3% and 13.7%, respectively. The 5‐year CI of receiving any new PGx drug was higher for patients >40 years old (43.6% vs ≤40 years old 36.0%, P < 2.2 × 10−22), Malays and Indians (50.3% and 49.8% vs Chinese 31.1%, P < 2.2 × 10−22), those who attended one of the following four specialties at the index visit compared to other specialties (infectious diseases [46.2% vs 42.6%, P = 2.9 × 10−4], psychiatry [48.3% vs 42.3%, P = 7.4 × 10−13], renal [49.8% vs 40.9%, P < 2.2 × 10−22], and rheumatology and immunology [54.8% vs 41.7%, P < 2.2 × 10−22]) and those prescribed ≥5 drugs at index visit (51.7% vs 0‐4 drugs 41.7%, P < 2.2 × 10−22). Conclusions: Medical outpatients have a substantial probability of benefiting from pre‐emptive PGx testing and this is higher in certain subgroups of patients. [ABSTRACT FROM AUTHOR]

Aims: In the absence of a commonly agreed dosing protocol based on pharmacokinetic (PK) considerations, the dose and treatment duration for hydroxychloroquine (HCQ) in COVID‐19 disease currently vary across national guidelines and clinical study protocols. We have used a model‐based approach to explore the relative impact of alternative dosing regimens proposed in different dosing protocols for hydroxychloroquine in COVID‐19. Methods: We compared different PK exposures using Monte Carlo simulations based on a previously published population pharmacokinetic model in patients with rheumatoid arthritis, externally validated using both independent data in lupus erythematous patients and recent data in French COVID‐19 patients. Clinical efficacy and safety information from COVID‐19 patients treated with HCQ were used to contextualize and assess the actual clinical value of the model predictions. Results: Literature and observed clinical data confirm the variability in clinical responses in COVID‐19 when treated with the same fixed doses. Confounding factors were identified that should be taken into account for dose recommendation. For 80% of patients, doses higher than 800 mg day on day 1 followed by 600 mg daily on following days might not be needed for being cured. Limited adverse drug reactions have been reported so far for this dosing regimen, most often confounded by co‐medications, comorbidities or underlying COVID‐19 disease effects. Conclusion: Our results were clear, indicating the unmet need for characterization of target PK exposures to inform HCQ dosing optimization in COVID‐19. Dosing optimization for HCQ in COVID‐19 is still an unmet need. Efforts in this sense are a prerequisite for best benefit/risk balance. [ABSTRACT FROM AUTHOR]

Personalization of oral small molecule anticancer drug doses based on individual patient blood drug levels, also known as therapeutic drug monitoring (TDM), has the potential to significantly improve the effectiveness of treatment by maximizing drug efficacy and minimize toxicity. However, this option has not yet been widely embraced by the oncology community. Some reasons for this include increased logistical complexity of dose individualization, the lack of clinical laboratories that measure small molecule drug concentrations in support of patient care, and the lack of reimbursement of costs. However, the main obstacle may be the lack of studies clearly demonstrating that monitoring of oral small molecule anticancer drug levels actually improves clinical outcomes. Without unequivocal evidence in support of TDM‐guided dose individualization, especially demonstration of improved survival with TDM in randomized controlled trials, wide acceptance of this approach by oncologists and reimbursement by insurance companies is unlikely, and patients may continue to suffer as a result of receiving incorrect drug doses. This article reviews the current status of TDM of oral small molecule drugs in oncology and intends to provide strategic insights into the design of studies for evaluating the utility of TDM in this clinical context. [ABSTRACT FROM AUTHOR]

The widely used platinum agent carboplatin represents a good example of an anticancer drug where clear relationships between pharmacological exposure and clinical response and toxicity have previously been shown. Within the setting of childhood cancer, there are defined groups of patients who present a particular challenge when dosing with carboplatin, including neonates and infants, those who are anephric, and poor prognosis patients receiving high‐dose chemotherapy. For these groups, nonstandard chemotherapy dosing regimens are currently utilised, often with different approaches between clinical study protocols and between treatment centres. For the treatment of these patient populations in the UK, there is now significant experience in carrying out therapeutic drug monitoring, aiming to consistently achieve target drug exposures, maximise drug efficacy and minimise treatment‐related side effects. An ongoing clinical trial is currently providing information on drug exposure for a wide range of anticancer agents in these hard to treat patient populations. In addition to supporting dosing decisions for individual patients, the collection and analysis of these data may allow the development of future dosing regimens. For example, current reduced dosing approaches for neonates and infants based on age or body weight, may well be better replaced by regimens based on a sound pharmacological rationale. The successful use of adaptive carboplatin dosing in childhood cancer should encourage the development of therapeutic drug monitoring approaches more widely in an oncology setting. [ABSTRACT FROM AUTHOR]

The field of pharmacogenomics has made great strides in oncology over the last 20 years and indeed a significant number of pre‐emptive genetic tests are now routinely undertaken prior to anticancer drug administration. Many of these gene–drug interactions are the fruits of candidate gene and genome‐wide association studies, which have largely focused on common genetic variants (allele frequency>1%). Examples where there is clinical utility include genotyping or phenotyping for G6PD to prevent rasburicase‐induced RBC haemolysis, and TPMT to prevent thiopurine‐induced bone marrow suppression. Other associations such as CYP2D6 status in determining the efficacy of tamoxifen are more controversial because of contradictory evidence from different sources, which has led to variability in the implementation of testing. As genomic technology becomes ever cheaper and more accessible, we must look to the additional data our genome can provide to explain interindividual variability in anticancer drug response. Clearly genes do not act on their own and it is therefore important to investigate genetic factors in conjunction with clinical factors, interacting concomitant drug therapies and other factors such as the microbiome, which can all affect drug disposition. Taking account of all of these factors, in conjunction with the somatic genome, is more likely to provide better predictive accuracy in determining anticancer drug response, both efficacy and safety. This review summarises the existing knowledge related to the pharmacogenomics of anticancer drugs and discusses areas of opportunity for further advances in personalisation of therapy in order to improve both drug safety and efficacy. [ABSTRACT FROM AUTHOR]

Aim: The goal of this study is to present the utility of quantitative modelling for extrapolation of drug safety and efficacy to underrepresented populations in controlled clinical trials. To illustrate this, the stepwise development of an integrated disease/pharmacokinetics/pharmacodynamics model of antipyretic efficacy of ibuprofen in children with cystic fibrosis (CF) is presented along with therapy optimization suggestions. Method: Published clinical trials, in vitro data, and drug physiochemical properties were used to develop an ibuprofen‐mediated antipyresis model for febrile children also having CF. Workflow included first developing a mechanistic absorption model using in vitro‐in vivo extrapolation followed by physiologically‐based pharmacokinetic (PBPK) modelling. The verified PBPK model was then scaled to paediatric patients with CF. Once verified, the PBPK model was linked to an indirect response model of antipyresis for simulation of the overall antipyretic efficacy of ibuprofen in CF children. Results: Model simulations showed therapeutic inequivalence between healthy children and paediatric patients with CF; Cmax and AUC decreased by 39% (32–46%) and 44% (36–52%), respectively, in patients. Further, and in agreement with literature reports, predicted pharmacodynamics time courses suggest a slower onset and faster offset of action in patients compared to healthy children, 30 and 60 minutes, respectively. Exploratory simulations suggest an increase in dosing frequency for CF children as a better therapeutic strategy. Conclusion: Model‐informed approaches to leveraging knowledge obtained throughout the life cycle of drug development may play a key role in extrapolating drug efficacy and safety to underrepresented populations. [ABSTRACT FROM AUTHOR]

Aims: There is a trend for more flexibility in timing of evidence generation in relation to marketing authorization, including the option to complete phase III trials after authorization or not at all. This paper investigated the relation between phase II and III clinical trial efficacy in oncology. Methods: All oncology drugs approved by the European Medicines Agency (2007–2016) were included. Phase II and phase III trials were matched based on indication and treatment and patient characteristics. Reported objective response rates (ORR), median progression‐free survival (PFS) and median overall survival (OS) were analysed through weighted mixed‐effects regression with previous treatment, treatment regimen, blinding, randomization, marketing authorization type and cancer type as covariates. Results: A total of 81 phase II‐III matches were identified including 252 trials. Mean (standard deviation) weighted difference (phase III minus II) was −4.2% (17.4) for ORR, 2.1 (6.7) months for PFS and −0.3 (5.1) months for OS, indicating very small average differences between phases. Differences varied substantially between individual indications: from −46.6% to 47.3% for ORR, from −5.3 to 35.9 months for PFS and from −13.3 to 10.8 months for OS. All covariates except blinding were associated with differences in effect sizes for at least 1 outcome. Conclusions: The lack of marked average differences between phases may encourage decision‐makers to regard the quality of design and total body of evidence instead of differentiating between phases of clinical development. The large variability emphasizes that replication of study findings remains essential to confirm efficacy of oncology drugs and discern variables associated with demonstrated effects. [ABSTRACT FROM AUTHOR]

Aims: With a prevalence of 16%, diabetes mellitus (DM) is one of the most frequent non‐communicable comorbidities of tuberculosis (TB). DM is a major risk factor for adverse TB outcomes and may require personalized TB drug dosing regimens. However, information on the inclusion of DM in TB drug trials is lacking. We aimed to assess the percentage of recent TB drug efficacy trials that included DM patients. Methods: A systematic review was performed and reported according to PRISMA guidelines. PubMed, Science Direct, and ClinicalTrials.gov databases were systematically searched for TB drug trials published between 1 January 2012 and 12 September 2017. Primary outcome was the percentage of TB drug trials performed around the world that included DM patients. Results: Out of the included 41 TB drug trials, 12 (29.3%) reported DM comorbidity among the study participants. Nine trials (21.9%) excluded all patients with DM comorbidity, ten (24.4%) excluded only insulin‐dependent or uncontrolled DM, and 10 (24.4%) did not mention whether DM was included or excluded. Of the 12 trials that included DM comorbidity, the majority did not report the diagnostic criteria for DM and none reported outcomes in the DM subpopulation. Inclusion of DM was higher in drug‐resistant‐TB trials (67%, P = .003, vs drug‐susceptible) and trials performed in Asia (60%, P = .006, vs Africa). Conclusions: Fewer than 1/3 recent TB drug trials reported the inclusion of DM. To better reflect real‐world DM prevalence and differential TB drug effectiveness, inclusion of DM patients requires increased attention for future TB drug trials. [ABSTRACT FROM AUTHOR]

Aims: This study aimed to identify population/regional differences in drug efficacy and the influencing factors among East Asians to be considered when planning multiregional clinical trials (MRCTs) to facilitate rapid drug approval in Asians. Methods: A retrospective analysis of efficacy (intergroup difference in endpoint between control and study drug treatment) among East Asian populations for 3 drug categories, antidiabetic, respiratory and psychotropic agents, was conducted in collaboration with pharmaceutical companies using their MRCT data. Common endpoints by drug category were selected; background factors that commonly affected the endpoints among regions were analysed first; then the population/regional differences were evaluated by the interaction term region‐by‐treatment using an analysis of covariance model after adjusting for background factors. Results: Among 17 endpoints for eight pharmaceutical products from 3 drug categories, no substantial population/regional differences were detected in the 3 drug categories examined (P > .05), except for haemoglobin A1c change between Japan and Korea for an antidiabetic drug, insulin glulisine (P = .0068). However, no such regional differences were evident in patients with clinically important higher haemoglobin A1c baseline values (majority subgroup). Variability in disease severity at baseline and concomitant drugs were determined to be potential influencing factors for regional differences. Conclusions: This study suggests that the regional variability in efficacy of these 3 drug categories is not large among East Asians, and reveals the importance of considering background factors when planning MRCTs. Further studies are needed to evaluate regional variability in the efficacy of other drug categories and clarify the factors leading to regional differences in East Asians. [ABSTRACT FROM AUTHOR]

Aims: The aim of the present meta‐analysis was to evaluate the efficacy and safety of sapropterin dihydrochloride in phenylketonuria (PKU) patients. Methods: The following databases were searched for randomized controlled trials (RCT) regarding PKU patients treated with sapropterin dihydrochloride: PubMed, Embase, Cochrane Library and clinicaltrials. Two authors independently selected studies, assessed the risk of bias and extracted data. The meta‐analysis was performed in RevMan 5.3 provided by the Cochrane Collaboration. Results: Four studies met the inclusion criteria. In PKU patients with low blood phenylalanine (Phe) concentration, no significant difference was indicated for the decrease of Phe level (weighted mean difference (WMD) = −7.75 μmol L−1; 95% confidence intervals (CI): −82.63 to 67.13, P = 0.84, I2 = 0%), however, the dietary Phe tolerance was significantly improved in the sapropterin group (WMD = 19.89 mg kg−1 d−1; 95% CI: 10.26 to 29.52, P < 0.0001, I2 = 0%). In PKU patients with high blood Phe level, sapropterin showed a significant lowering in blood Phe concentration (WMD = −225.31 μmol L−1; 95% CI: −312.28 to −138.34, P < 0.00001, I2 = 0%). There was no significant difference for adverse events. Conclusions: Sapropterin could bring benefit for PKU patients with high or low Phe level, due to Phe reduction in a short time or dietary Phe tolerance improvement respectively. Sapropterin has an acceptable safety profile. [ABSTRACT FROM AUTHOR]

Temporal patterns of acetaminophen use exceeding the recommended daily maximum dosage of 4 g over a 5‐year period (4/1/2011–3/31/2016) were evaluated in an online 1‐week diary study of 14 434 adult acetaminophen users who also reported acetaminophen use in the previous month. Specific medications taken were identified by list‐based prompting; respondents were not required to know their medications contained acetaminophen. Details of use were recorded daily; total daily dosage was determined programmatically. Prevalence of >4 g use over time was modelled and tested for linear changes. The overall prevalence of >4 g use (6.3% of users and 3.7% of usage days) did not change over the 5 years: odds ratio (OR) persons, 1.02 (95% CI, 0.98–1.09); OR days, 0.98 (0.92–1.05). Deviations from label directions were largely unchanged, though concomitant use increased slightly. Thus, over a recent 5‐year period, there was no evidence of change in how often acetaminophen use exceeded the labelled maximum daily dose. [ABSTRACT FROM AUTHOR]

Aims: The relationship between blinatumomab exposure and efficacy endpoints (occurrence of complete remission [CR] and duration of overall survival [OS]) or adverse events (occurrence of cytokine release syndrome [CRS] and neurological events) were investigated in adult patients with relapsed/refractory acute lymphoblastic leukaemia (r/r ALL) receiving blinatumomab or standard of care (SOC) chemotherapy to evaluate appropriateness of the blinatumomab dosing regimen. Methods: Exposure, efficacy and safety data from adult patients (n = 646) with r/r ALL receiving stepwise (9 then 28 μg/day, 4‐week cycle) continuous intravenous infusion (n = 537) of blinatumomab or SOC (n = 109) chemotherapy were pooled from phase 2 and 3 studies. The occurrence of CR, neurological and CRS events, and duration of OS were analysed using Cox proportional hazards models or logistic regression, as appropriate. Confounding factors were tested multivariately as needed. Results: Blinatumomab steady‐state concentration following 28 μg/day dosing was associated with the probability of achieving CR (odds ratio and 95% confidence interval: 1.073 [1.033–1.114]), and a longer duration of OS compared to SOC (hazard ratio and 95% confidence interval: 0.954 [0.936–0.973], P < .05) in multivariate analyses. The exposure–safety analyses indicated that blinatumomab steady‐state concentration following the 9 or 28 μg/day dose was not associated with increased probability of CRS or neurological events, after accounting for blinatumomab treatment effect (P > .05). Conclusions: Blinatumomab step‐dosing regimen of 9/28 μg/day provided treatment benefit in achieving CR and increasing the duration of OS over SOC and was appropriate in management of CRS and neurological events in patients with r/r ALL. [ABSTRACT FROM AUTHOR]

Aims: To evaluate the availability of pharmacokinetic, safety and efficacy analyses specifically targeted at elderly, prior to the authorization of drugs. Methods: A cross‐sectional, structured review of publicly available initial approval documents of Food and Drug Administration‐approved drugs was performed. The 10 most frequently on‐label prescribed drug classes, drugs with known pharmacokinetic differences in the elderly or drugs that are relatively contraindicated in elderly (e.g. anticholinergics or benzodiazepines) were included in the analyses. Results: In total, 1129 unique active pharmaceutical ingredients were found eligible for the analyses, of these, 506 were found in the Food and Drug Administration database (45%). The initial approval documents were available for 182 drugs. For the majority of the drugs, the initial approval documents in the database showed information on pharmacokinetics in elderly (n = 113; 62%). Furthermore, over time, the availability of information with regard to elderly increased statistically significantly from 0% in the period 1970–1979 to 76% for the period 2010–2018. Information on safety and efficacy was less frequently present, i.e. 42% and 45%, respectively and, moreover, the availability of information did not improve over time. Conclusion: The under‐representation of elderly in clinical trials thereby challenging the external validity of benefit/risk assessments of launched drugs was confirmed. Priority should be given to a study population that is representative for the target population. [ABSTRACT FROM AUTHOR]

Aims: Paracetamol is the analgesic most used by older people. The physiological changes occurring with ageing influence the pharmacokinetics (PK) of paracetamol and its variability. We performed a population PK‐analysis to describe the PK of intravenous (IV) paracetamol in fit older people. Simulations were performed to illustrate target attainment and variability of paracetamol exposure following current dosing regimens (1000 mg every 6 h, every 8 h) using steady‐state concentration (Css‐mean) of 10 mg l–1 as target for effective analgesia. Methods: A population PK‐analysis, using NONMEM 7.2, was performed based on 601 concentrations of paracetamol from 30 fit older people (median age 77.3 years, range [61.8–88.5], body weight 79 kg [60–107]). All had received an IV paracetamol dose of 1000 mg (over 15 min) after elective knee surgery. Results: A two‐compartment PK‐model best described the data. Volume of distribution of paracetamol increased exponentially with body weight. Clearance was not influenced by any covariate. Simulations of the standardized dosing regimens resulted in a Css of 9.2 mg l–1 and 7.2 mg l–1, for every 6 h and every 8 h respectively. Variability in paracetamol PK resulted in Css above 5.4 and 4.1 mg l–1, respectively, in 90% of the population and above 15.5 and 11.7, respectively, in 10% at these dosing regimens. Conclusions: The target concentration was achieved in the average patient with 1000 mg every 6 h, while every 8 h resulted in underdosing for the majority of the population. Furthermore, due to a large (unexplained) interindividual variability in paracetamol PK a relevant proportion of the fit older people remained either under‐ or over exposed. [ABSTRACT FROM AUTHOR]

Aims: Rising antimicrobial resistance (AMR) is a global health crisis. India has among the highest resistance rates and antibiotic consumption internationally. Extensive use of fixed‐dose combination (FDC) antibiotics and of unapproved formulations are claimed contributory factors but there has been no systematic examination of formulations or volumes sold. The aim of the present study was to investigate the regulatory approval status and sales volumes of systemic antibiotics marketed in India. Methods: This was an ecological study using regulatory records in India, the UK and the US to determine the approval status in each country of systemic antibiotic FDCs and single‐drug formulations (SDFs) sold in India. Pharmatrac® sales data were used to determine the formulations and volumes sold (2007–2012), branded‐product numbers and manufacturers. Results: Of 118 systemic antibiotic FDC formulations sold in India, 43 (36%) were approved but 75 (64%) had no record of regulatory approval; four (3%) formulations were approved in the UK and/or US. Almost half of formulations (58/118; 49%) comprised dual antimicrobials, most unapproved in India (43/58; 74%), and many were pharmacologically problematic. In contrast, 80/86 (93%) SDFs were approved in India and over two‐thirds in the UK and/or US. Total antibiotic sales increased by 26%, from 2056 million units (2007–08) to 2583 million units (2011–12). FDC sales rose by 38% vs. 20% for SDFs. By 2011–12, FDCs comprised one‐third of sales (872 million units). Over one‐third of FDCs sold (300.26 million units; 34.5%) were of unapproved formulations. Multinational companies manufactured unapproved formulations and accounted for 19% of all FDC and SDF sales annually. Conclusions: Sales in India of antibiotic FDCs, including unapproved formulations, are rising. In the context of increasing AMR rates nationally and globally, unapproved antibiotic FDCs undermine India's national AMR strategy and should be banned from sale. [ABSTRACT FROM AUTHOR]

Aims: A recent double‐blind placebo‐controlled crossover 70‐day trial demonstrated that a fixed combination of dextromethorphan and quinidine (DM/Q) improves speech and swallowing function in most patients with amyotrophic lateral sclerosis. In this study, a subset of participants, many of whom did not substantially improve while on DM/Q, were re‐evaluated using computer‐based speech analyses and expert clinician ratings of the overall severity of speech impairment. Methods: Speech samples were recorded from the subset of 10 patients at four visits made at approximately 30‐day intervals. The recordings were analysed by automated computer‐based analysis of speech pausing patterns. Severity of speech impairment was rated by three experienced speech‐language pathologists using direct magnitude estimation. Scores on patient‐reported and clinician‐administered scales of bulbar motor involvement were obtained at each visit. Results: The effects of DM/Q were detected on several of the objective speech measures, including total pause duration (s) (Cohen's d = 0.73, 95% confidence interval (CI) –1.70, 0.24), pause time (%) (d = 0.77, 95% CI –1.75, 0.21), and mean speech event duration (s) (d = 0.52, 95% CI –0.44, 1.47), but not on clinician ratings of speech or the speech components of the self‐report or clinician‐administered scales. Conclusions: These findings suggest that even patients with modest improvement while on DM/Q may experience quantifiable improvements in speech when assessed using sensitive and objective measures. This study provides additional evidence of the positive impact of DM/Q on one or more of the neural systems that control bulbar motor function and production of speech. [ABSTRACT FROM AUTHOR]

Aims: Although high blood pressure (BP) is common in acute stroke and associated with poor outcome, the Efficacy of Nitric Oxide in Stroke (ENOS) trial showed no beneficial effect of antihypertensive treatment in this situation. Antihypertensive agents have accentuated effects in dehydrated patients. We assessed the impact of dehydration on haemodynamics, the effects of antihypertensive treatment, and prognosis in the ENOS trial. Methods: ENOS randomized 4011 patients with acute stroke and raised systolic BP to a glyceryl trinitrate (GTN) patch or no GTN patch, and to continue or to stop existing antihypertensive treatment within 48 h of onset. The primary outcome was functional outcome (modified Rankin Scale, mRS) at day 90. Blood markers of dehydration at baseline were collected at two sites (n = 310) and their relationship with haemodynamics and outcome was assessed. Results: There were no significant associations between dehydration markers and fall in blood pressure from baseline to day 1, and no significant interaction with allocated treatment. Overall, increasing urea was associated with an unfavourable shift in mRS [odds ratio 3.43, 95% confidence interval (CI) 1.42, 8.32; P = 0.006] and increased risk of death at day 90 (hazard ratio 4.55, 95% CI 1.51, 13.66; P = 0.007). Conclusions: Blood pressure‐lowering treatment was safe in dehydrated patients, with no precipitous changes in BP, thus supporting its use in acute stroke prior to blood markers of dehydration becoming available. Increased baseline urea was associated with poor prognosis after stroke. [ABSTRACT FROM AUTHOR]

Aims: While a plethora of systematic reviews have provided evidence of efficacy, effectiveness and safety of direct‐acting oral anticoagulants (DOACs) in the management of nonvalvular atrial fibrillation, there has been little emphasis on clinicians' perspectives. This systematic review aimed to critically appraise, synthesize and present the available evidence of clinicians' views and experiences. Methods: Studies published in English from January 2006 to July 2017 reporting the views and/or experiences of doctors, nurses or pharmacists on any individual DOAC or as a pharmacological group were included. Studies were assessed for quality by two researchers, data extracted and findings synthesized using a narrative approach. Results: Following exclusion of duplicates, 777 titles, 394 abstracts and 196 studies were screened. Ten studies were included in the review, nine of which were quantitative (cross‐sectional surveys) and one qualitative (semistructured interviews), with marked heterogeneity in outcomes reported. Studies were conducted exclusively in Europe and the USA. In those studies reporting clinician preference, DOACs were first choice over warfarin in naïve patients, based on perceptions of evidence of effectiveness equivalent or superior to warfarin and superior safety. Other advantageous factors were in those with an unstable International Normalized Ratio and likely to miss appointments. There were, however, concerns relating to management of over‐anticoagulation and experiences of observed bleeding rates. Conclusion: There is a limited evidence base of clinicians' perspectives of DOACs, necessitating further research, particularly given the trajectory of increased use worldwide. [ABSTRACT FROM AUTHOR]

Aims: Filgotinib (GS‐6034, formerly GLPG0634) is an oral, selective Janus kinase 1 (JAK1) inhibitor that showed early response and sustained efficacy in patients with rheumatoid arthritis and with Crohn's disease. The aim of the present study was to investigate the impact of age and renal impairment (RI) on the pharmacokinetics (PK) of filgotinib and its main metabolite. Methods: The effect of age was assessed in two groups of 10 elderly healthy subjects (65–74 and ≥75 years of age) and a control group of 10 younger healthy subjects (40–50 years of age). The impact of RI was investigated in three groups of subjects with mild (n = 6), moderate (n = 6) and severe (n = 3) RI [estimated glomerular filtration rate (eGFR) 60–89, 30–59 and 15–29 ml min–1 1.73 m–2, respectively] and a control group (n = 9) with normal renal function (eGFR ≥90 ml min–1 1.73 m–2). The PK of filgotinib and its metabolite were evaluated following filgotinib 100 mg once‐daily doses for 10 days. Results: At steady state, the exposure [area under the concentration–time curve over the dosing interval (AUC0–24 h)] of filgotinib and its metabolite was moderately higher (1.45‐ and 1.33‐fold, respectively) in the elderly subjects (≥75 years) compared with younger subjects. Renal clearance for filgotinib and its metabolite decreased with the degree of RI, leading to a maximum increase in AUC0–24 h of 1.54‐fold for filgotinib and 2.74‐fold for the metabolite in subjects with severe RI. Filgotinib was generally safe and well tolerated. Conclusions: Age and mild to moderate impairment of renal function had limited impact on the PK of filgotinib. In subjects with severe RI, the exposure to the metabolite of filgotinib was elevated, consistent with its renal elimination pathway. [ABSTRACT FROM AUTHOR]

Aims: The aim of this study was to evaluate the drug–drug interaction between pimodivir, a novel, non‐nucleoside polymerase basic protein 2 (PB2) subunit inhibitor of the influenza A virus polymerase complex, and oseltamivir, to assess the feasibility of this combination therapy. Furthermore, single‐ and multiple‐dose pharmacokinetics and safety of pimodivir in healthy volunteers were assessed. Methods: In Part 1 of this open‐label Phase 1 study, healthy volunteers (n = 18) were randomized to one of six cross‐over treatment sequences, each comprising administration of oseltamivir 75 mg or pimodivir 600 mg or combination thereof twice daily on Days 1–4, followed by a single morning dose on Day 5. Between each treatment session, there was a minimum 5‐day washout period. In Part 2, healthy volunteers (n = 16) randomly received pimodivir 600 mg or placebo (3:1) twice daily on Days 1–9, followed by a single morning dose on Day 10. Pharmacokinetics of pimodivir, oseltamivir and oseltamivir carboxylate, and safety were assessed. Results: In Part 1, co‐administration of pimodivir with oseltamivir increased the Cmax of pimodivir by 31% (90% CI: 0.92–1.85) with no change in Cmin or AUC12h. Pimodivir had no effect on oseltamivir or oseltamivir carboxylate pharmacokinetics. In Part 2, after single‐ and multiple‐dose administration of pimodivir, there was a 1.2‐ and 1.8‐fold increase in Cmax and AUC12h, respectively, between Day 1 and Day 10. The most frequently reported treatment‐emergent adverse event was diarrhoea (n = 7 each in Part 1 and 2). Conclusion: Combination treatment with pimodivir and oseltamivir in healthy volunteers showed no clinically relevant drug–drug interactions. No safety concerns were identified with pimodivir 600 mg twice daily alone or in combination with oseltamivir 75 mg twice daily. [ABSTRACT FROM AUTHOR]

Aims: We aimed to develop a standardized chart review method to identify drug‐related hospital admissions (DRA) in older people caused by non‐preventable adverse drug reactions and preventable medication errors including overuse, underuse and misuse of medications: the DRA adjudication guide. Methods: The DRA adjudication guide was developed based on design and test iterations with international and multidisciplinary input in four subsequent steps: literature review; evaluation of content validity using a Delphi consensus technique; a pilot test; and a reliability study. Results: The DRA adjudication guide provides definitions, examples and step‐by‐step instructions to measure DRA. A three‐step standardized chart review method was elaborated including: (i) data abstraction; (ii) explicit screening with a newly developed trigger tool for DRA in older people; and (iii) consensus adjudication for causality by a pharmacist and a physician using the World Health Organization‐Uppsala Monitoring Centre and Hallas criteria. A 15‐member international Delphi panel reached consensus agreement on 26 triggers for DRA in older people. The DRA adjudication guide showed good feasibility of use and achieved moderate inter‐rater reliability for the evaluation of 16 cases by four European adjudication pairs (71% agreement, κ = 0.41). Disagreements arose mainly for cases with potential underuse. Conclusions: The DRA adjudication guide is the first standardized chart review method to identify DRA in older persons. Content validity, feasibility of use and inter‐rater reliability were found to be satisfactory. The method can be used as an outcome measure for interventions targeted at improving quality and safety of medication use in older people. [ABSTRACT FROM AUTHOR]

Aims: To predict the probability of a seizure‐free (SF) state in patients with epilepsy (PWEs) after treatment with levetiracetam and to identify the clinical and electroencephalographic (EEG) factors that affect outcomes. Methods: Retrospective analysis of PWEs treated with levetiracetam for 3 years identified 22 patients who were SF and 24 who were not. Before starting levetiracetam, 11 clinical factors and four EEG features (sample entropy of α, β, θ, δ) were identified. Overall, 80% of each the two groups were chosen to establish a support vector machine (SVM) model with 5‐fold cross‐validation, hold‐out validation and jack‐knife validation. The other 20% were used to predict the efficacy of levetiracetam. The mean impact value (MIV) algorithm was used to rank the relativity between factors and outcomes. Results: Compared with SF patients, not SF patients displayed a specific decrease in EEG sample entropy in α band from the F4 channel, β band from Fp2 and F8 channels, θ band from C3 channel (P < 0.05). The SVM model based on the clinical and EEG features yielded 72.2% accuracy of 5‐fold cross‐validation, 75.0% accuracy of jack‐knife validation, 67.7% accuracy of hold‐out validation in the training set and had a high prediction accuracy of 90% in test set (sensitivity was 100%, area under the receiver operating characteristic curve was 0.96). The feature of β band from Fp2 weighs heavily in the prediction model according to the mean impact value algorithm. Conclusions: The efficacy of levetiracetam on newly diagnosed PWEs could be predicted using an SVM model, which could guide antiepileptic drug selection. [ABSTRACT FROM AUTHOR]

During the past decade we have been witnessing a rise in medical cannabis use, yet the evidence for the safety and efficacy of the various cannabinoid compounds is scarce. The State of Israel has always been at the forefront of clinical and translational research in support of Evidence Based Medicine. With respect to cannabis Israel has created a medical and regulatory environment that enables clinical studies with cannabis which may lead to improved Evidence Based use of these compounds. This opinion paper discusses selected studies into the safety and effects of cannabis derived products. [ABSTRACT FROM AUTHOR]

Aims: Serelaxin is a recombinant human relaxin‐2 peptide being developed for the treatment of acute heart failure (AHF). The present analyses aimed to evaluate serelaxin pharmacokinetics following intravenous administration and to identify covariates that may explain pharmacokinetic variability in healthy subjects and patients. Methods: Serum concentration–time data for 613 subjects from nine phase I and II studies were analysed using a nonlinear mixed‐effects model to estimate population pharmacokinetics and identify significant covariates. A quantile regression analysis was also conducted to assess the relationship between clearance and covariates by including sparse data from a phase III study. Results: A three‐compartment disposition model was established to describe serelaxin pharmacokinetics. Three out of 23 covariates, including baseline body mass index (BMI) and estimated glomerular filtration rate (eGFR) and study A1201, were identified as significant covariates for clearance but with a moderate impact on steady‐state concentration, reducing the intersubject variability from 44% in the base model to 41% in the final model with covariates. The steady‐state volume of distribution (Vss) was higher in patients with AHF (544 ml kg–1) or chronic heart failure (434 ml kg–1), compared with typical nonheart failure subjects (347 ml kg–1). Quantile regression analysis showed that a 20% increase in BMI or a 20% decrease in eGFR decreased serelaxin clearance by 9.2% or 5.2%, respectively. Conclusions: Patients with HF showed higher Vss but similar clearance (and therefore steady‐state exposure) vs. non nonheart failure subjects. BMI and eGFR were identified as the main covariates explaining intersubject variability in clearance; however, the impact of these covariates on steady‐state concentration was moderate and therefore unlikely to be clinically relevant. [ABSTRACT FROM AUTHOR]

Aims: Domperidone is used to treat gastrointestinal symptoms in patients with Parkinson's disease (PD) and is linked to an increased risk of mortality. We sought to examine the risk of all‐cause mortality associated with domperidone exposure in PD. Methods: We conducted a cohort study using data from the Clinical Practice Research Datalink database (1987–2011). The first recorded PD diagnosis defined index date. Time‐dependent Cox proportional hazards models estimated hazard ratios (HRs) of all‐cause mortality associated with domperidone use. PD patients were stratified by domperidone use (current/recent/past), with never used as the referent. Current domperidone users were stratified by daily dose, domperidone duration and other anti‐Parkinson's medications. A secondary analysis compared PD patients to matched (1:1) non‐PD patients. Results: A total of 5114 PD patients were identified. Current use of domperidone among PD patients was associated with a two‐fold increase in all‐cause mortality (HRadj = 2.00, 95% confidence interval [CI]: 1.64–2.45), as compared to patients never exposed to domperidone. All‐cause mortality risk was highest in those starting domperidone in the previous month [HRadj = 2.97, 95% CI: 2.06–4.27]. When compared to matched non‐PD patients, PD was associated with a 43% increased risk of all‐cause mortality, yet this increased to a 2.4‐fold increased risk among PD patients currently using domperidone. Conclusion: Current use of domperidone was associated with a two‐fold increased mortality risk in PD patients, as compared to PD patients that never used domperidone. The risk is highest in the first month of use and does not appear to be attributable to PD alone. [ABSTRACT FROM AUTHOR]

Aims: Accurately estimating kidney function is essential for the safe administration of renally cleared drugs such as ganciclovir. Current practice recommends adjusting renally eliminated drugs according to the Cockcroft–Gault equation. There are no data on the utility of the Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD‐EPI) equations in ganciclovir dosing. To evaluate which renal function equation best predicts ganciclovir clearance. Methods: The performance of the Cockcroft–Gault equation, isotope dilution mass spectrometry (IDMS)‐traceable 4‐variable MDRD study (MDRD4‐IDMS) equation and CKD‐EPI equation in determining ganciclovir clearance were assessed retrospectively in patients treated with ganciclovir from 2004–2015. The MDRD4‐IDMS and CKD‐EPI equations adjusted to individual body surface area (MDRD4‐IDMS·BSA and CKD‐EPI·BSA, respectively) were also evaluated. Patients with intravenous ganciclovir peak and trough concentrations in their medical records were included in the study. Ganciclovir clearance was calculated from serum concentrations using a one‐compartment model. The five equations were compared based on their predictive ability, the coefficient of determination, through a linear regression analysis. The results were validated in a group of patients. Results: One hundred patients were included in the final analysis. Seventy‐four patients were analysed in the learning group and 26 in the validation group. The coefficient of determination was 0.281 for Cockcroft–Gault, 0.301 for CKD‐EPI·BSA, 0.308 for MDRD4‐IDMS·BSA, 0.324 for MDRD4‐IDMS and 0.360 for CKD‐EPI. Subgroup analysis also showed that CKD‐EPI is a better predictor of ganciclovir clearance. Analysis of the validation group confirmed these results. Conclusions: The CKD‐EPI equation correlates better with ganciclovir clearance than the Cockcroft‐Gault and MDRD4‐IDMS equations, even the clinical difference between the equations is scarce. [ABSTRACT FROM AUTHOR]

Aims: The aim of this study was to investigate the putative link between dipeptidyl peptidase‐4 inhibitor (DPP‐4i) use and the risk of fracture in patients with type 2 diabetes. Methods: This propensity‐score‐matched population‐based cohort study was performed between 2009 and 2013 on patients with type 2 diabetes who were stable metformin users. A total of 3996 patients with type 2 diabetes used DPP‐4i as a second‐line antidiabetic drug. The same number of matched non‐DPP‐4i users were followed up until fracture occurrence, health insurance policy termination, or the end of 2013. The incidence rates of overall and cause‐specific fractures were estimated based on the Poisson assumption. A multiple Cox proportional hazard model was used to estimate the covariate‐adjusted hazard ratio (HR) and 95% confidence interval (CI) to determine the association between DPP‐4i use and overall and cause‐specific fractures stratified by age and sex. Results: Over a maximum follow‐up period of 5 years, 340 DPP‐4i users and 419 non‐DPP‐4i users were newly diagnosed with fractures, yielding incidence rates of 28.03 and 32.04 per 1000 people per year, respectively. The Cox proportional hazard model revealed that DPP‐4i use significantly reduced the risk of all‐cause fractures and upper extremity fractures, with adjusted HRs of 0.86 (95% CI: 0.74–0.99) and 0.75 (95% CI: 0.59–0.95), respectively. The aforementioned associations of DDP‐4i use with fracture were sustained across sex and age stratifications. Conclusions: The results of this study supported the premise that DPP‐4i usage is associated with a reduced risk of all‐cause fractures and upper extremity fractures in patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Aims: Previous trials on the effectiveness of genotype‐guided warfarin dosing vs. conventional dosing have been inconclusive. We conducted a systematic review and meta‐analysis of randomized trials comparing genotype‐guided to conventional dosing strategies. Methods: PubMed and the Cochrane Library were searched up to 23 October 2017. Results: A total of 76 and 94 entries were retrieved were retrieved from PubMed and the Cochrane Library, respectively. A total of 2626 subjects in the genotype‐guided dosing (mean age 63.3 ± 5.8 years; 46% male) and 2604 subjects in the conventional dosing (mean age 64.7 ± 6.1 years; 46% male) groups (mean follow‐up duration 64 days) from 18 trials were included. Compared with conventional dosing, genotype‐guided dosing significantly shortened the time to first therapeutic international normalized ratio (INR) (mean difference 2.6 days, standard error 0.3 days; P < 0.0001; I2 0%) and time to first stable INR (mean difference 5.9 days, standard error 2.0 days; P < 0.01; I2 94%). Genotype‐guided dosing also increased the time in therapeutic range (mean difference 3.1%, standard error 1.2%; P < 0.01; I2 80%) and reduced the risks of both excessive anticoagulation, defined as INR ≥4 [risk ratio (RR) 0.87; 95% confidence interval (CI) 0.78, 0.98; P < 0.05; I2: 0%), and bleeding (RR 0.82; 95% CI 0.69, 0.98; P < 0.05; I2 31%). No difference in thromboembolism (RR 0.84; 95% CI 0.56, 1.26; P = 0.40; I2 0%) or mortality (RR 1.16; 95% CI 0.46, 2.91; P = 0.76; I2 0%) was observed between the two groups. Conclusions: Genotype‐guided warfarin dosing offers better safety with less bleeding compared with conventional dosing strategies. No significant benefit on thromboembolism or mortality was evident. [ABSTRACT FROM AUTHOR]

Aims: The aims of this systematic review were to: (1) critically appraise, synthesize and present the available evidence on the views and experiences of stakeholders on pharmacist prescribing and; (2) present the perceived facilitators and barriers for its global implementation. Methods: Medline, CINAHL, International Pharmaceutical Abstracts, PsychArticles and Google Scholar databases were searched. Study selection, quality assessment and data extraction were conducted independently by two reviewers. A narrative approach to data synthesis was undertaken due to heterogeneity, the nature of study types and outcome measures. Results: Sixty‐five studies were identified, mostly from the UK (n = 34), followed by Australia (n = 13), Canada (n = 6) and USA (n = 5). Twenty‐seven studies reported pharmacists' perspectives, with fewer studies focusing on patients' (n = 12), doctors' (n = 6), the general public's (n = 4), nurses' (n = 1), policymakers' (n = 1) and multiple stakeholders' (n = 14) perspectives. Most reported positive experiences and views, regardless of stage of implementation. The main benefits described were: ease of patient access to healthcare services, improved patient outcomes, better use of pharmacists' skills and knowledge, improved pharmacist job satisfaction, and reduced physician workload. Any lack of support for pharmacist prescribing was largely in relation to: accountability for prescribing, limited pharmacist diagnosis skills, lack of access to patient clinical records, and issues concerning organizational and financial support. Conclusion: There is an accumulation of global evidence of the positive views and experiences of diverse stakeholder groups and their perceptions of facilitators and barriers to pharmacist prescribing. There are, however, organizational issues to be tackled which may otherwise impede the implementation and sustainability of pharmacist prescribing. [ABSTRACT FROM AUTHOR]

An editorial is presented on the developments in the treatment of chronic myeloid leukaemia (CML) with the introduction of BCR-ABL1 tyrosine kinase inhibitors (TKIs). It expresses the view that CML is a highly controllable disease with the availability of TKIs, and treatment-free remission is a new therapeutic goal for the eligible patients.

Aims: To characterize the pharmacokinetics, pharmacodynamics and safety of esaxerenone, a mineralocorticoid receptor antagonist, in healthy adult Japanese men. Methods: Double‐blind, placebo‐controlled, sequential, dose‐escalation studies were conducted in subjects randomized to receive oral once‐daily esaxerenone (ranges: 5–200 mg [single‐dose]; 10–100 mg over 10 days [multiple‐dose]) or placebo under fasting conditions. Plasma concentrations were analysed by liquid chromatograph–tandem mass spectrometry. Pharmacokinetic parameters were determined by noncompartment analysis. Plasma/urine levels of pharmacodynamic biomarkers for mineralocorticoid receptor activity were evaluated. Results: In total, 48/48 and 39/40 subjects completed the single‐ and multiple‐dose studies, respectively. Exposures were generally dose‐proportional. The tmax, t1/2 and CL/F remained unchanged, independent of dose; the respective ranges were 1.5–4.0 h, 22.3–25.1 h, and 4.0–5.2 l h–1 (multiple‐dose study). Vz/F ranged from 136.5 to 283.7 l in the multiple‐dose study, and exposure reached steady state by day 4. The mean observed accumulation ratio, by dose, ranged from 1.36–1.98. The urinary Na+/K+ ratio increased after single‐dose administration; however, its relationship to the doses tested remains unclear. Plasma renin activity, active renin concentration and aldosterone concentration increased dose‐dependently. Although blood potassium levels increased dose‐dependently in the multiple‐dose study (reaching a maximum mean ± standard deviation of 4.63 ± 0.354 mmol l–1 in the 100‐mg group), no safety/tolerability‐related problems were detected in either study. Conclusions: Exposure levels in healthy adults receiving esaxerenone were generally dose‐proportional. Dose‐dependent changes in plasma pharmacodynamic biomarkers for the mineralocorticoid receptor were identified during multiple‐dose treatment and support the pharmacological activity of esaxerenone. No important safety concerns were identified. [ABSTRACT FROM AUTHOR]

Aims: The existence of a sex‐by‐formulation interaction in bioequivalence studies implies that the bioequivalence results (i.e., the test/reference ratio of the pharmacokinetic parameters) obtained in one sex are not similar to those obtained in the other sex. Therefore, results obtained in studies including only males would not be representative of the results that would have been obtained in females and vice versa. Recently, a sex‐by‐formulation interaction has been reported in a study for efavirenz tablets. The purpose of this paper is to investigate whether a sex‐by‐formulation interaction is actually observed in the bioequivalence studies conducted with efavirenz tablets. Methods: The existence of sex‐by‐formulation interaction was investigated in the two studies conducted in our centre, where the same test and reference products were investigated in a pilot study with 12 subjects and a pivotal study with 36 subjects. Results: In the pilot study, the point estimates for the test/reference ratio of geometrics means of Cmax in females and males were more than 20% different (95.42% vs.79.38%, i.e., 120.21%), but in a subsequent pivotal study the difference was less than 2% (111.14% vs. 109.98%, i.e., 101.66%). Conclusions: A sex‐by‐formulation interaction is suggested in the study with a small sample size, but it disappears when the study is repeated with a larger sample size. In conclusion, the analysis of subgroups should be conducted with caution when the size of the subgroups is not powered to show bioequivalence. There seems to be no reason to require bioequivalence studies for efavirenz in both sexes. [ABSTRACT FROM AUTHOR]

Aims: Nephrotic syndrome (NS) is the most common clinical manifestation of glomerular disease in children. Currently, tacrolimus (TAC) is widely used in children with NS. However, pharmacokinetic data in children with nephrotic syndrome is limited. This study was intended to evaluate the population pharmacokinetics (PPK) of TAC in paediatric NS and to optimize dosing regimen. Methods: Blood samples from NS children treated with TAC were collected and the blood concentrations of TAC were detected using HPLC‐MS/MS. A PPK model was developed using NONMEM software. Pharmacogenetic analysis was carried out in the CYP3A5 gene. Results: The data from 28 children were used for PPK analysis. A one‐compartment model and first‐order elimination were accorded with the TAC data in paediatric NS. A covariate analysis showed that body weight and CYP3A5 genotype significantly affected TAC pharmacokinetics. Monte Carlo simulation indicated that NS children with CYP3A5*3/*3 receiving 0.10 mg kg−1 dose−1 twice daily and NS children with CYP3A5*1 receiving 0.25 mg kg−1 dose−1 twice daily TAC could achieve the target concentrations of 5–10 ng ml−1. Conclusion: The PPK of TAC was estimated in children with NS and a CYP3A5 genotype‐based dosing regimen was set up based on simulations. [ABSTRACT FROM AUTHOR]

Aims: Lipid formulations of amphotericin B, rather than conventional amphotericin (c‐amB), are increasingly used despite limited data comparing these preparations in children. Data on the incidence of adverse effects with amphotericin B at standard doses are scarce. This study aimed to compare the adverse effects associated with standard doses of c‐amB and liposomal amphotericin (l‐amB) in children. Methods: Children admitted to the Royal Children's Hospital Melbourne and treated with c‐amB or l‐amB between January 2010 and September 2013 were included. Clinical and laboratory data were retrospectively extracted from medical records to compare amphotericin‐related infusion reactions, nephrotoxicity (glomerulotoxicity and tubulopathy) and hepatotoxicity. Results: Seventy‐six children received c‐amB and 39 received l‐amB. Standard drug administration (recommended dose and infusion time) occurred in 74% (56/76) of patients on c‐amB and 85% (33/39) on l‐amB. In these 89 children, infusion‐related reactions were similar for both c‐amB and l‐amB (23% (13/56) vs. 9% (3/33); P = 0.15); none occurred in children aged <90 days. There was no difference in amphotericin‐associated glomerulotoxicity (c‐amB 14% (8/56) vs. l‐amB 21% (7/33); P = 0.40) or in the median maximum potassium requirements (c‐amB 3.1 vs. l‐amB 2.3 mmol kg−1 d−1; P = 0.29). Hepatotoxicity occurred more frequently with l‐amB than c‐amB (83% (24/29) vs. 56% (20/36); P = 0.032). Conclusions: When appropriately administered, l‐amB was associated with more hepatotoxicity than c‐amB, with no difference in infusion‐related reactions or nephrotoxicity. Differences in adverse effects between the preparations is not as marked in children as reported in adults. [ABSTRACT FROM AUTHOR]

Aims: To identify pharmacogenetic and demographic variables that influence the systemic exposure to metformin in an admixed Brazilian cohort. Methods: The extreme discordant phenotype was used to select 106 data sets from nine metformin bioequivalence trials, comprising 256 healthy adults. Eleven single‐nucleotide polymorphisms in SLC22A1, SLC22A2, SLC47A1 SLC47A2 and in transcription factor SP1 were genotyped and a validated panel of ancestry informative markers was used to estimate the individual proportions of biogeographical ancestry. Two‐step (univariate followed by multivariate) regression modelling was developed to identify covariates associated with systemic exposure to metformin, accessed by the area under the plasma concentration–time curve, between 0 and 48 h (AUC0–48h), after single oral doses of metformin (500 or 1000 mg). Results: The individual proportions of African, Amerindian and European ancestry varied widely, as anticipated from the structure of the Brazilian population The dose‐adjusted, log‐transformed AUC0–48h's (ng h ml−1 mg−1) differed largely in the two groups at the opposite ends of the distribution histogram, namely 0.82, 0.79–0.85 and 1.08, 1.06–1.11 (mean, 95% confidence interval; P = 6.10−26, t test). Multivariate modelling revealed that metformin AUC0–48h increased with age, food and carriage of rs12208357 in SLC22A1 but was inversely associated with body surface area and individual proportions of African ancestry. Conclusions: A pharmacogenetic marker in OCT1 (SLC22A1 rs12208357), combined with demographic covariates (age, body surface area and individual proportion of African ancestry) and a food effect explained 29.7% of the variability in metformin AUC0–48h. [ABSTRACT FROM AUTHOR]

Following a severe case of rhabdomyolysis in our University Hospital after a co‐administration of atorvastatin and fusidic acid, we describe this interaction as this combination is not clearly contraindicated in some countries, particularly for long‐term treatment by fusidic acid. All cases of rhabdomyolysis during a co‐administration of a statin and fusidic acid were identified in the literature and in the World and Health Organization database, VigiBase®. In the literature, 29 cases of rhabdomyolysis were identified; mean age was 66 years, median duration of co‐administration before rhabdomyolysis occurrence was 21 days, 28% of cases were fatal. In the VigiBase®, 182 cases were retrieved; mean age was 68 years, median duration of co‐administration before rhabdomyolysis was 31 days and 24% of cases were fatal. Owing to the high fatality associated with this co‐administration and the long duration of treatment before rhabdomyolysis occurrence, fusidic acid should be used if there is no appropriate alternative, as long as statin therapy is interrupted for the duration of fusidic acid therapy, and perhaps a week longer. Rarely will interruption of this sort have adverse consequences for the patient. [ABSTRACT FROM AUTHOR]

Aims: Population pharmacokinetics is an essential tool that helps guide individualized dosing regimens. The aims of this systematic review are to provide knowledge concerning population pharmacokinetics of valproic acid (VPA) and to identify factors influencing VPA pharmacokinetic variability. Methods: PubMed and Embase databases were systematically searched from inception to June, 2017. Relevant articles from reference lists were also included. All population pharmacokinetic studies of VPA conducted in humans and that employed a nonlinear mixed effect modelling approach were included in this review. Results: Twenty‐six studies were included in this review. Most studies characterized VPA pharmacokinetics as a one‐compartment model. Three studies reported a two‐compartment model. Body weight, dose and age were significant predictors for VPA volume of distribution (Vd). The estimated Vd for one‐compartment models ranged from 8.4 to 23.3 l. For two‐compartment models, peripheral volumes of distribution ranged from 4.08 to 42.1 l. Frequently reported significant predictors for VPA clearance (CLVPA) included body weight, VPA dose, concomitant medications, gender and age. The estimated CLVPA ranged from 0.206 to 1.154 l h−1 and the inter‐individual variability ranged from 13.40 to 35.90%. Two studies reported population pharmacokinetics/pharmacodynamics of VPA in patients with epilepsy. Seventeen studies evaluated the performance of their final models. Conclusions: Significant predictors influencing VPA pharmacokinetics as well as model methodologies are highlighted in this review. For clinical application, CLVPA could be predicted using body weight, VPA dose, concomitant medications, gender or age. For future research, there is a knowledge gap regarding population pharmacokinetics/pharmacodynamics of VPA in a population other than epileptic patients. [ABSTRACT FROM AUTHOR]

Aims: Sacubitril/valsartan is indicated for the treatment of heart failure and reduced ejection fraction (HFrEF). Furosemide, a loop diuretic commonly used for the treatment of HFrEF, may be coadministered with sacubitril/valsartan in clinical practice. The effect of sacubitril/valsartan on the pharmacokinetics and pharmacodynamics of furosemide was evaluated in this open label, two‐period, single‐sequence study in healthy subjects. Methods: All subjects (n = 28) received 40 mg oral single‐dose furosemide during period 1, followed by a washout of 2 days. In period 2, sacubitril/valsartan 200 mg (97/103 mg) was administered twice daily for 5 days and a single dose of 40 mg furosemide was coadministered on day 6. Serial plasma and urine samples were collected to determine the pharmacokinetics of furosemide and sacubitril/valsartan and the pharmacodynamics of furosemide. The point estimates and the associated 90% confidence intervals for pharmacokinetic parameters were evaluated. Results: Coadministration of furosemide with sacubitril/valsartan decreased the maximum observed plasma concentration (Cmax) [estimated geometric mean ratio (90% confidence interval): 0.50 (0.44, 0.56)], area under the plasma concentration–time curve (AUC) from time 0 to infinity [0.72 (0.67, 0.77)] and 24‐h urinary excretion of furosemide [0.74 (0.69, 0.79)]. When coadministered with sacubitril/valsartan, 0–4‐h, 4–8‐h and 0–24‐h diuresis in response to furosemide was reduced by ~7%, 21% and 0.2%, respectively, while natriuresis was reduced by ~ 28.5%, 7% and 15%, respectively. Post hoc analysis of the pivotal phase III Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM‐HF) indicated that the median furosemide dose was similar at baseline and at the end of the study in the sacubitril/valsartan group. Conclusions: Sacubitril/valsartan reduced plasma Cmax and AUC and 24‐h urinary excretion of furosemide, while not significantly affecting its pharmacodynamic effects in healthy subjects. [ABSTRACT FROM AUTHOR]

Aim: Regorafenib is a multikinase inhibitor under investigation for use in neovascular age‐related macular degeneration. In this phase I study, regorafenib eye drops were administered to healthy volunteers to provide information on safety, tolerability and systemic exposure. Methods: This was a single‐centre, randomized, double‐masked, parallel‐group, dose‐escalation, placebo‐controlled study. Subjects received regorafenib eye drops (30 mg ml−1, 25 μl) as a 0.75 mg single dose (Cohort 1), 0.75 mg twice daily (bid) or thrice daily (tid) over 14 days (Cohorts 2 and 3, respectively), 1.5 mg tid unilaterally for 3 days, then bilaterally for up to 14 days (Cohort 4), or placebo. Plasma samples were taken to estimate systemic exposure. Safety and functional assessments were performed throughout the study. Results: Thirty‐six subjects received regorafenib and 12 received placebo. Regorafenib was safe and well tolerated over the dose range. No pathological changes occurred in the anterior, vitreous or posterior eye compartments. Mild eyelid redness, oedema and conjunctival hyperaemia were observed across all regorafenib cohorts; these were comparable with the effects seen with placebo. Predominant symptoms were blurred vision in the active and placebo groups. Systemic safety evaluations showed no clinically relevant findings. Absolute systemic exposure after multiple administrations of regorafenib eye drops at a dose of 0.75 mg was 600–700‐fold lower than after multiple oral administration of 160 mg day−1, the dose approved in cancer indications. Conclusion: These results indicate a favourable safety and tolerability profile of regorafenib eye drops up to 30 mg ml−1 tid for use in clinical studies. [ABSTRACT FROM AUTHOR]

AIMS Topical growth factors accelerate wound healing in patients with diabetic foot ulcers (DFU). Due to the absence of head-to-head comparisons, we carried out Bayesian network meta-analysis to compare the efficacy and safety of growth factors. METHODS Using an appropriate search strategy, randomized controlled trials on topical growth factors compared with standard of care in patients with DFU, were included. Proportion of patients with complete healing was the primary outcome. Odds ratio (95% confidence interval) was used as the effect estimate and random effects model was used for both direct and indirect comparisons. Markov Chain Monte Carlo simulation was used to obtain pooled estimates. Rankogram was generated based on surface under the cumulative ranking curve (SUCRA). RESULTS A total of 26 studies with 2088 participants and 1018 events were included. The pooled estimates for recombinant epidermal growth factor (rhEGF), autologous platelet rich plasma (PRP), recombinant human platelet-derived growth factor (rhPDGF) were 5.72 [3.34, 10.37], 2.65 [1.60, 4.54] and 1.97 [1.54, 2.55] respectively. SUCRA for rhEGF was 0.95. Sensitivity analyses did not reveal significant changes from the pooled estimates and rankogram. No differences were observed in the overall risk of adverse events between the growth factors. However, the growth factors were observed to lower the risk of lower limb amputation compared to standard of care. CONCLUSION To conclude, rhEGF, rhPDGF and autologous PRP significantly improved the healing rate when used as adjuvants to standard of care, of which rhEGF may perform better than other growth factors. The strength of most of the outcomes assessed was low and the findings may not be applicable for DFU with infection or osteomyelitis. The findings of this study needs to be considered with caution as the results might change with findings from head-to-head studies. [ABSTRACT FROM AUTHOR]

AIMS Information on utilization of oral anticoagulants (OACs) in nursing homes is scarce. This study aimed to (i) describe OAC use in German nursing home residents, (ii) examine factors influencing whether treatment is initiated with vitamin K antagonists (VKAs) or non-VKA oral anticoagulants (NOACs) and (iii) assess which conditions predict switching to NOAC instead of continuing VKA. METHODS Using claims data (2010–2014), we studied a cohort of new nursing home residents aged ≥65 years receiving OAC. Further, OAC use in patients with atrial fibrillation (AF) was examined over the years. RESULTS Overall, 16 804 patients (median age: 85 years, 75% female, 44% with renal disease) were included. The majority received phenprocoumon as first OAC (58.0%), followed by rivaroxaban (28.1%). Over the study period, NOAC use increased substantially. Initiating NOAC instead of VKA was predicted by a previous stroke (adjusted odds ratio: 1.76; 95% confidence interval: 1.49–2.08). In contrast, renal disease predicted VKA initiation (0.66; 0.59–0.75) as did the presence of a prosthetic heart valve. Switching from VKA to NOAC was predicted by a stroke (2.55; 2.00–3.24), bleeding events and a recent hospitalization. During 2010–2014, the proportion of AF patients with a CHADS2 score ≥2 receiving OAC increased from 27% to 46%. CONCLUSIONS NOACs are increasingly used in German nursing homes, both for initial anticoagulation but also in VKA pre-treated patients. Switching from VKA to NOAC was substantially influenced by aspects such as intended higher effectiveness and safety but probably also practicability due to less blood monitoring. [ABSTRACT FROM AUTHOR]