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Background: Community pharmacists are in the position to contribute to fall prevention, but this is not yet common practice. Objective: The aim of this study was to evaluate the implementation of a community pharmacy-based fall prevention service. Methods: A fall prevention service, consisting of a fall risk screening and assessment including a medication review, was implemented in pharmacies during three months. A preparative online training was provided to the pharmacy team to enhance adoption of the service. Included patients were aged ≥70 years, using ≥5 drugs of which ≥1 fall risk-increasing drug. The implementation process was quantitively assessed by registering medication adaptations, recommendations, and referrals. Changes in patient scores on the Short Fall Efficacy Scale-International (FES-I) and a fall prevention knowledge test were documented at one month follow-up. Implementation was qualitatively evaluated by conducting semi-structured interviews with pharmacists before and after the project, based on the consolidated framework of implementation research. Results: The service was implemented in nine pharmacies and 91 consultations were performed. Medication was adapted of 32 patients. Patients' short FES-I scores were significantly higher at follow-up (p = 0.047) and patients’ knowledge test scores did not differ (p = 0.86). Pharmacists experienced the following barriers: lack of time, absence of staff, and limited multidisciplinary collaboration. Facilitators were training, motivated staff, patient engagement, and project scheduling. Conclusion: The service resulted in a substantial number of medication adaptations and lifestyle recommendations, but many barriers were identified that hamper the sustained implementation of the service.

Historical antecedents of pharmaceutical sciences are sound on product orientation based on (analytical) chemistry, drug delivery and basic pharmacology. Over the last decades we have seen a transition towards a stronger disease orientation. This raises questions on whether, how and to what extent unmet medical need (UMN) is important in priority setting, funding and impact in pharmaceutical sciences. An online survey in 2020 collected perspectives of internationally recognised pharmaceutical scientists (N = 92), mainly from academia and industry, on drivers and influencing factors in pharmaceutical sciences. The study offers a unique global perspective, demonstrating a solid command of the global needs in pharmaceutical sciences. The survey revealed that UMN is currently seen as one of the three most important drivers, also in addition to emerging trends in science and opportunities driven by collaboration. There are expectations that UMN's impact becomes more influential. This was consistent for both industry and academic respondents. The majority of respondents also indicated that anticipated lessons learned from COVID-19 will strengthen the impact of UMN on science and leadership. This is important as prioritisation of research towards UMN can address the clinical needs where needed the most.

Objectives Onasemnogene Abeparvovec-xioi (AVXS-101) is a gene therapy intended for curative treatment of spinal muscular atrophy (SMA) with an expected price of around €2 000 000. The goal of this study is to perform a cost-effectiveness analysis of treatment of SMA I patients with AVXS-101 in The Netherlands including relapse scenarios. Methods An individual-based state-transition model was used to model treatment effect and survival of SMA I patients treated with AVXS-101, nusinersen and best supportive care (BSC). The model included five health states: three health states according to SMA types, one for permanent ventilation and one for death. Deterministic and probabilistic sensitivity analyses were performed. Effects of relapsing to lower health states in the years following treatment was explored. Results The base-case incremental cost-effectiveness ratio (ICER) for AVXS-101 versus BSC is €138 875/QALY, and €53 447/QALY for AVXS-101 versus nusinersen. If patients relapse within 10 years after treatment with AVXS-101, the ICER can increase up to 6-fold, with effects diminishing thereafter. Only relapses occurring later than 50 years after treatment have a negligible effect on the ICER. To comply with Dutch willingness-to-pay reference values, the price of AVXS-101 must decrease to €680 000. Conclusions Based on this model, treatment with AVXS-101 is unlikely to be cost-effective under Dutch willingness-to-pay reference values. Uncertainty regarding the long-term curative properties of AVXS-101 can result in multiplication of the ICER. Decision-makers are advised to appropriately balance these uncertainties against the price they are willing to pay now.

Purpose To describe the extent to which patients with mental health problems after admission to an Intensive Care Unit (ICU) initiate and use psychotropic medication. Methods All adult patients who stayed in the ICU of the University Medical Center Utrecht for 48 h or more between 2013 and 2017, alive after 1 year and not admitted to the ICU with brain injury, were eligible. Questionnaires were used to identify mental health problems, depression, anxiety and posttraumatic stress disorder (PTSD) and psychotropic medication use. Results Of the 1328 former ICU patients, 24.3% (n = 323) had developed any of the mental health problems. Of this group, 29.7% (n = 96) used psychotropic medication one year after discharge versus the 10.6% (n = 107) of patients without these problems (OR 3.17, 95% CI 2.29–4.38). They were further 4.33 (95% CI 2.62–7.16) times more likely to initiate psychotropic medication (18.7% vs 4.8%) after ICU admission. Similar patterns were observed for individual groups of psychotropics: antidepressants, antipsychotics and benzodiazepines. Discussion Former ICU patients with mental health problems were almost four times more likely to use psychotropic medication than former ICU patients without these problems. Future research should investigate whether mental health problems are properly diagnosed and treated in former ICU patients.

Rationale An estimated 15% of saphenous vein grafts (SVGs) occlude in the first year after coronary artery bypass grafting (CABG) despite aspirin therapy. Graft occlusion can result in symptoms, myocardial infarction, and death. SVG occlusion is primarily caused by atherothrombosis, in which platelet activation plays a pivotal role. Evidence regarding the effect of stronger platelet inhibition on SVG patency after CABG is limited. The main objective of the POPular CABG trial is to determine whether dual antiplatelet therapy with aspirin plus ticagrelor improves SVG patency when compared to aspirin alone. Study The POPular CABG is a randomized, double-blind, placebo-controlled, multicenter trial investigating the effect of adding ticagrelor to standard aspirin therapy on the rate of SVG occlusion. A total of 500 patients undergoing CABG with ≥ 1 SVG are randomized to ticagrelor or placebo. The primary end point is SVG occlusion rate, assessed with coronary computed tomography angiography at 1 year. Secondary end points are stenoses and occlusions in both SVGs and arterial grafts and SVG failure at 1 year, defined as a composite of SVG occlusion on coronary computed tomography angiography or coronary angiography, SVG revascularization, myocardial infarction in the territory supplied by an SVG, or sudden death. Safety end points are bleeding events at 30 days and 1 year. Conclusion The POPular CABG trial investigates whether adding ticagrelor to standard aspirin after CABG reduces the rate of SVG occlusion at 1 year.

BACKGROUND: Localized prostate cancer (PCa) treatments provide high survival rates, with patients often surviving a decade or longer after treatment. Therefore, treatment options are progressively based on quality of life. The objective of this research was to investigate magnitude of response shift (RS) in health-related quality of life (HRQOL) responses in men with clinically localized PCa using a generic questionnaire and a disease-specific questionnaire in an observational longitudinal patient registry study. PATIENTS AND METHODS: A cohort study was conducted using the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) database. Patients were annually surveyed using the Medical Outcomes Study Questionnaire Short Form 36 (SF-36) and the UCLA Prostate Cancer Index (PCI) HRQOL measures. A total of 3161 active patients were eligible for a one-off supplemental study asking retrospective HRQOL scores (then-test). We calculated RS, observed change, and RS adjusted change. Statistical difference was determined by t test. RESULTS: Patients consistently reported higher recalled pretreatment HRQOL compared to baseline scores for SF-36 and PCI, confirming the existence of a RS (P < .05). On average, PCI demonstrated larger RS by a factor of 2 than SF-36. More specific, RS was greater especially in SF-36 physical domains compared to mental health items. PCI measured PCa-specific physical adverse effects only. Patients whose cancer had recurred reported slightly lower SF-36 RS than those whose cancer had not recurred. CONCLUSION: RS occurrence was measured in both the disease-specific questionnaire and the generic HRQOL questionnaire, demonstrating continued low health and symptom scores after RS adjustment. Therefore, health professionals should adjust for this phenomenon when assessing patient's HRQOL treatment responses, and clinicians should address their continued sexual and urinary functional loss.

Objectives This study describes the initiation of the Dutch Lung Cancer Audit for Lung Oncology (DLCA-L) and reports the first results of three years of clinical auditing. Methods The initiation, dataset, and data quality of the DLCA-L are described. For the analyses, all patients registered from 2017 to 2019 were included. Descriptive statistics were used to assess the first outcomes of the DLCA-L, including results from quality indicators, patient- and tumor characteristics, and the real-world use of immunotherapy. Results The DLCA-L was initiated after the surgery and radiotherapy audit for lung cancer. In total, 33.788 NSCLC patients and 4.293 SCLC patients were registered in the DLCA-L from 2017 to 2019. Seventy-three (97 %) Dutch hospitals participated in the DLCA-L in 2019. The registry became nation-wide in 2020. The data quality improved over the years, with complete cases in 90 % of the NSCLC patients. In total, 15 quality indicators were established based on DLCA-L data to improve processes and clinical outcomes. An example of these quality indicators was brain imaging at diagnosis of stage III NSCLC patients, which increased from 80 % in 2017 to 90 % in 2019 and hospital variation was reduced. The DLCA-L provided data on immunotherapy use in stage IV NSCLC (n = 4.415) patients. These patients had a median age of 67 years and 11 % of the patients had an ECOG PS ≥ 2. The number of patients treated with immunotherapy in different hospitals varied between 2 patients to 163 patients per hospital. Conclusion The DLCA-L has become a valuable and complete data source with national coverage in 2020. A high number of registered patients and limited missing data resulted in better insights into hospital processes and outcomes of lung cancer care. Quality indicators were, with success, used to establish improvements and minimize hospital variation. The DLCA-L also provides hospitals real-world information on the use of (systemic) therapies.

Introduction There is broad consensus that community pharmacists should focus on the provision of pharmaceutical care. Studies, however, have shown that community pharmacists still spend a considerable amount of time on traditional activities such as dispensing instead of cognitive pharmaceutical services (CPS). It is not clear whether community pharmacists prefer their current time-utilization or if they are willing to spend more time on CPS. Aim The aim of this study was to identify how community pharmacists ideally would prioritize CPS compared to other daily activities. Methods A cross-sectional study design with Q-methodology was used to identify different viewpoints regarding task prioritization. Community pharmacists were asked to rank a total of 48 daily activities. Data was collected online using FlashQ©. Q-sorts were analyzed by principal component factor analysis and varimax rotation using PQmethod 2.35. Results In total, 166 community pharmacists participated in this study. Three distinguishing groups were found based on task prioritization explaining 59% of the total variance among respondents. All groups ranked the provision of CPS as important, in differing degrees. Group 1 ranked CPS as most important and was also the group that contained most participants. Group 2 and 3 ranked quality assurance as most important with CPS as second. Logistics and pharmacy management were ranked low by all groups. Discussion and conclusion Community pharmacists rank the provision of CPS as important. So factors, probably other than task prioritization, are keeping the pharmacist from focusing on CPS in daily practice. In other studies, time constraints are mostly mentioned as major barrier. Activities such as logistics and pharmacy management are given less priority and should be delegated to supporting staff members as much as possible, to enable pharmacists to focus their available time on activities they deem important.

Aims To assess baseline and change after 26-weeks in health-related quality of life (HRQoL) among adults with type 2 diabetes mellitus (T2DM) initiating one of the new glucose lowering drugs (GLD) in daily practice. Methods Inception cohort of patients who initiated one of dipeptidyl peptidase 4 inhibitors (DPP-4), glucagon-like peptide-1 analogues (GLP-1) or sodium-glucose cotransporter inhibitors (SGLT2) drugs. A baseline questionnaire collected socio-demographic and self-reported clinical data. HRQoL was assessed by the Euroqol-5D. Participants were divided into: (1) incident new users (INU) (who used for the first time one of the monitored GLD and had no current or prior experience with DPP-4/GLP-1/SGLT2) and (2) prevalent new users (PNU) (who had previously used at least one GLD of the monitored drug classes, but not the inception drug). Multivariate regression explored factors associated with a meaningful change in HRQoL. Results 1303 patients. Over 26 weeks, a mean positive change in the EQ-5D scores, were observed. No differences between INU and PNU were found. Participants with worse health conditions (e.g. presence and number of chronic diseases, obese) at baseline were more likely to experience larger improvements in HRQoL. Conclusions Over 26-weeks, T2DM patients starting with, or switching to new GLD maintained or modestly increased their HRQoL.

Background Multidose drug dispensing (MDD) is used to help patients take their medicines appropriately. Little is known about drug regimen changes within these MDD systems and how they are effectuated by the community pharmacist. Manual immediate adjustments of the MDD system could introduce dispensing errors. MDD guidelines therefore recommend to effectuate drug regimen changes at the start of a new MDD system. Objective The aim of this study was to investigate the frequency, type, procedure followed, immediate necessity, and time taken to make MDD adjustments. Methods This was a cross-sectional study in eight community pharmacies in the Netherlands. All adjustments to MDD systems were systematically documented for 3 weeks by the community pharmacist. Results Overall, 261 MDD adjustments involving 364 drug changes were documented for 250 patients: 127 (35%) drug changes involved the addition of a new drug, 124 (34%) a change in dosage, and 95 (26%) drug discontinuation. Of the MDD adjustments, 135 (52%) were effectuated immediately: 81 (31%) by adjusting the MDD system manually, 49 (19%) by temporarily dispensing the drug separately from the MDD system, and 5 (2%) by ordering a new MDD system. Pharmacists considered that 36 (27%) of the immediate MDD adjustments could have been deferred until the next MDD system was produced. Immediate adjustment took significantly longer than deferred adjustment (p Conclusions This study shows that in patients using MDD systems, over half of the drug regimen changes are adjusted immediately. The necessity of these immediate changes should be critically evaluated.

Quizartinib, a second-generation FLT3 inhibitor, is in clinical development for the treatment of acute myeloid leukemia. We studied its pharmacokinetic interactions with the multidrug efflux transporters ABCB1 and ABCG2 and the multidrug metabolizing enzyme CYP3A, using in vitro transport assays and knockout and transgenic mouse models. Quizartinib was transported by human ABCB1 in vitro, and by mouse (m)Abcb1 and mAbcg2 in vivo. Upon oral administration, the brain accumulation of quizartinib was 6-fold decreased by mAbcb1 and 2-fold by mAbcg2 (together: 12-fold). Unexpectedly, the absence of mAbcb1 resulted in a ∼2-fold lower plasma exposure in Abcb1a/1b−/− and Abcb1a/1b;Abcg2−/− mice, suggesting that loss of mAbcb1 causes compensatory alterations in alternative quizartinib elimination or uptake systems. mAbcb1 and mAbcg2 themselves did not appear to restrict quizartinib oral availability. Oral and intravenous pharmacokinetics of quizartinib were not substantially altered between wild-type, Cyp3a knockout and CYP3A4-humanized mice. All three strains showed relatively high (33–51%) oral bioavailability. If this also applies in humans, this would suggest a limited risk of CYP3A-related inter-individual variation in exposure for this drug. Our results provide a possible rationale for using pharmacological ABCB1/ABCG2 inhibitors together with quizartinib when treating malignant lesions situated in part or in whole behind the blood-brain barrier.

INTRODUCTION: In- and exclusion criteria of randomized clinical trials (RCTs) aim to include a homogeneous study-population. This study compared characteristics of lung cancer patients from phase III RCTs evaluating tyrosine kinase inhibitors (TKIs) or immune checkpoint inhibitors (ICIs) with characteristics of lung cancer patients in a real world setting in the United Kingdom.METHODS: A retrospective study was conducted using the Clinical Practice Research Datalink GOLD. Patients (N = 9239) with a first ever lung cancer registration between 2014 and 2018 were identified. Eligibility for inclusion was assessed for twelve RCTs (evaluating TKIs or ICIs). Reasons for potential exclusion and the number of unmet criteria were assessed for each RCT independently. OS was assessed using Kaplan-Meier and Cox proportional hazards analyses.RESULTS: The proportion of potentially eligible patients was 74.3% and 51.9% for TKI and ICI RCTs, respectively. History of another malignancy, renal insufficiency or concomitant drug-use were main reasons for exclusion. OS was considerably longer for potentially eligible patients. Hazards ratios varied from 1.17 (95% confidence interval, 1.11-1.24) to 1.35 (1.20-1.42) across the RCTs.CONCLUSION: This study showed that a considerable proportion of lung cancer patients in a real-world setting would have been ineligible for participation in phase III RCTs and that potentially ineligible patients experienced a shorter OS.

The anticancer drug temozolomide is the only drug with proven activity against high-grade gliomas and has therefore become a part of the standard treatment of these tumors. P-glycoprotein (P-gp; ABCB1) and breast cancer resistance protein (BCRP; ABCG2) are transport proteins, which are present at the blood-brain barrier and limit the brain uptake of substrate drugs. We have studied the effect of P-gp and BCRP on the pharmacokinetics and pharmacodynamics of temozolomide, making use of a comprehensive set of in vitro transport experiments and in vivo pharmacokinetic and antitumor efficacy experiments using wild-type, Abcg2−/−, Abcb1a/b−/−, and Abcb1a/b;Abcg2−/− mice. We here show that the combined deletion of Abcb1a/b and Abcg2 increases the brain penetration of temozolomide by 1.5-fold compared to wild-type controls (P < .001) without changing the systemic drug exposure. Moreover, the same increase was achieved when temozolomide was given to wild-type mice in combination with the dual P-gp/BCRP inhibitor elacridar (GF120918). The antitumor efficacy of temozolomide against three different intracranial tumor models was significantly enhanced when Abcb1a/b and Abcg2 were genetically deficient or pharmacologically inhibited in recipient mice. These findings call for further clinical testing of temozolomide in combination with elacridar for the treatment of gliomas, as this offers the perspective of further improving the antitumor efficacy of this already active agent.

Background: Amplitude spectrum area (AMSA) of ventricular fibrillation (VF) has been associated with survival from out-of-hospital cardiac arrest (OHCA). Ischemic heart disease has been shown to change AMSA. We studied whether the association between AMSA and survival changes with acute ST-elevation myocardial infarction (STEMI) as cause of the OHCA and/or previous MI. Methods: Multivariate logistic regression with log-transformed AMSA of first artifact-free VF segment was used to assess the association between AMSA and survival, according to presence of STEMI or previous MI, adjusting for resuscitation characteristics, medication use and comorbidities. Results: Of 716 VF-patients included from an OHCA-registry in the Netherlands, 328 (46%) had STEMI as cause of OHCA. Previous MI was present in 186 (26%) patients. Survival was 66%; neither previous MI (P = 0.11) nor STEMI (P = 0.78) altered survival. AMSA was a predictor of survival (ORadj: 1.52, 95%-CI: 1.28-1.82). STEMI was associated with lower AMSA (8.4 mV-Hz [3.7-16.5] vs. 12.3 mV-Hz [5.6-23.0]; P

Introduction Two solid dispersions of docetaxel (denoted ModraDoc001 capsule and ModraDoc006 tablet (both 10 mg)) were co-administered with 100 mg ritonavir (/r) and investigated in a bi-daily once weekly (BIDW) schedule. Safety, maximum tolerated dose (MTD), pharmacokinetics (PK) and preliminary activity were explored. Methods Adult patients with metastatic solid tumours were included in two dose-escalation arms. PK sampling was performed during the first week and the second or third week. Safety was evaluated using US National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0. Antitumour activity was assessed every 6 weeks according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.0. Results ModraDoc001 capsule/r and ModraDoc006 tablet/r were administered to 17 and 28 patients, respectively. The most common adverse events were nausea, vomiting, diarrhoea and fatigue, mostly of grade 1–2 severity. Grade 3/4 neutropenia/neutropenic fever was observed in 2 patients (4%). The MTD was determined as 20/20 mg ModraDoc001/r and 30/20 mg ModraDoc006/r (morning/afternoon dose) once weekly. The mean area under the plasma concentration–time curve (AUC 0–48 ) ± standard deviation at the MTD for ModraDoc001/r and ModraDoc006/r were 686 ± 388 ng/ml*h and 1126 ± 382 ng/ml*h, respectively. Five partial responses were reported as best response to treatment. Conclusion Oral administration of BIDW ModraDoc001/r or ModraDoc006/r is feasible. The once weekly 30/20 mg ModraDoc006 tablet/r dose-level was selected for future clinical development. Antitumour activity is promising.

BLU-554 is a potent, highly selective oral FGFR4 inhibitor. A bioanalytical assay for quantification of BLU-554 in mouse plasma and six tissue homogenates (brain, kidney, liver, lung, small intestine, and spleen) was developed and validated using liquid chromatography with tandem mass spectrometric detection and with erlotinib as internal standard. After protein precipitation with acetonitrile in a 96-well format and separation on an XBridge® Peptide BEH C18 column by gradient elution using 0.2% (v/v) ammonium hydroxide (in water) and methanol, analytes were ionized by positive electrospray and monitored in the selected reaction monitoring mode by triple quadrupole mass spectrometry. The assay was validated in a 1–1000 ng/ml concentration range using calibration in mouse plasma. Precisions (intra–day and inter–day) were in the range 2.8–10.1% and accuracies were in between 88.5 and 96.6% for all levels in all matrices. The assay was successfully applied for a pilot pharmacokinetic and tissue distribution study in wild-type mice.

DNA hypermethylation is an epigenetic event that is commonly found in malignant cells and is used as a therapeutic target for β-decitabine (β-DEC) containing hypomethylating agents (eg Dacogen® and guadecitabine). β-DEC requires cellular uptake and intracellular metabolic activation to β-DEC triphosphate before it can get incorporated into the DNA. Once incorporated in the DNA, β-DEC can exert its hypomethylating effect by trapping DNA methyltransferases (DNMTs), resulting in reduced 5-methyl-2'-deoxycytidine (5mdC) DNA content. β-DEC DNA incorporation and its effect on DNA methylation, however, have not yet been investigated in patients treated with β-DEC containing therapies. For this reason, we developed and validated a sensitive and selective LC-MS/MS method to determine total intracellular β-DEC nucleotide (β-DEC-XP) concentrations, as well as to quantify β-DEC and 5mdC DNA incorporation relative to 2'-deoxycytidine (2dC) DNA content. The assay was successfully validated according to FDA and EMA guidelines in a linear range from 0.5 to 100 ng/mL (β-DEC), 50 to 10,000 ng/mL (2dC), and 5 to 1,000 ng/mL (5mdC) in peripheral blood mononuclear cell (PBMC) lysate. An additional calibrator at a concentration of 0.1 ng/mL was added for β-DEC to serve as a limit of detection (LOD). Clinical applicability of the method was demonstrated in patients treated with guadecitabine. Our data support the use of the validated LC-MS/MS method to further explore the intracellular pharmacokinetics in patients treated with β-DEC containing hypomethylating agents.

Purpose Real‐world evidence (RWE) includes data from retrospective or prospective observational studies and observational registries and provides insights beyond those addressed by randomized controlled trials. RWE studies aim to improve health care decision making. Methods The International Society for Pharmacoeconomics and Outcomes Research (ISPOR) and the International Society for Pharmacoepidemiology (ISPE) created a task force to make recommendations regarding good procedural practices that would enhance decision makers' confidence in evidence derived from RWD studies. Peer review by ISPOR/ISPE members and task force participants provided a consensus‐building iterative process for the topics and framing of recommendations. Results The ISPOR/ISPE Task Force recommendations cover seven topics such as study registration, replicability, and stakeholder involvement in RWE studies. These recommendations, in concert with earlier recommendations about study methodology, provide a trustworthy foundation for the expanded use of RWE in health care decision making. Conclusion The focus of these recommendations is good procedural practices for studies that test a specific hypothesis in a specific population. We recognize that some of the recommendations in this report may not be widely adopted without appropriate incentives from decision makers, journal editors, and other key stakeholders.

Item does not contain fulltext OBJECTIVE: The aim of this study was to investigate whether acute kidney injury (AKI) after coronary artery bypass grafting can be attributed to intraoperative hypotension during cardiopulmonary bypass (IOH-CPB). DESIGN: Retrospective analysis. SETTING: Tertiary-care hospital. PARTICIPANTS: Patients undergoing on-pump coronary artery bypass grafting from June 2011 to January 2014. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: IOH-CPB was defined as blood pressure below several absolute and relative mean arterial pressure (MAP) thresholds and as the area under the curve for absolute MAP thresholds. AKI was defined as an absolute increase in serum creatinine of>/=26 micromol/L within 48 hours or an increase to 150% or more within 7 days of surgery. Poisson regression with robust standard errors both before and after adjustment for confounders was used. Of the 1,891 patients included, 386 (20%) developed AKI. In univariable analysis, all IOH-CPB thresholds defined as a MAP of 50 mmHg or less and as a decrease in MAP of 60% from baseline were associated with a 1.07-to-1.11 times increased risk of AKI per 10 minutes of IOH-CPB (p

Erlotinib is a first-generation epithelial growth factor receptor inhibitor used in the treatment of non-small cellular lung cancers. Our previously published method on a Thermo TSQ Quantum Ultra triple quadrupole mass spectrometer for the quantitation of erlotinib, OSI-420, and OSI-413 and some other kinase inhibitors was transferred to a more sensitive Sciex QTRAP5500 system. Both methods showed comparable performance in the previous range (5–5000 and 1–1000 ng/mL for erlotinib and OSI-420) with comparable accuracies and precisions (98.9–106.2 vs 98.7.0–104.0, and 3.7–13.4 vs 4.6–13.2), and a high level of agreement between the methods (R2 = 0.9984 and 0.9951) for the quality control samples. The new system however was also capable of quantifying lower concentrations of both erlotinib and OSI-420 (0.5 and 0.1 ng/mL) with sufficient accuracy and precision. Along with the increased sensitivity we included the semi-quantitative determination of additional erlotinib metabolites M2, M3, M5, M6, M7, M8, M9, M10, M11, M12, M16 (hydroxy-erlotinib), M17, M18, M19, M20, M21 in a 0.1–1000 ng/mL range to the method. With a simple crash, dilute, and shoot sample preparation with acetonitrile and a 4.5 min analytical run time the method outperformed most other published methods in speed and simplicity and was suitable for TDM. Further, enhancement of the understanding of the pharmacokinetics of erlotinib and its metabolites was demonstrated.

The fluoropyrimidine anticancer drugs, especially 5-fluorouracil (5-FU) and capecitabine, are frequently prescribed for several types of cancer, including breast, colorectal, head and neck and gastric cancer. In the current drug labels of 5-FU and capecitabine in the European Union and the United States, no adaptive dosing strategies are incorporated for polymorphic metabolism of 5-FU. Although treatment with fluoropyrimidines is generally well tolerated, a major clinical limitation is that a proportion of the treated population experiences severe, sometimes life-threatening, fluoropyrimidine-related toxicity. This toxicity is strongly affected by interindividual variability in activity of dihydropyrimidine dehydrogenase (DPD), the main metabolic enzyme for inactivation of fluoropyrimidines, with an estimated 3%-8% of the population being partially DPD deficient. A reduced functional or abrogated DPD enzyme is often caused by genetic polymorphisms in DPYD, the gene encoding for DPD, and heterozygous carriers of such DPYD polymorphisms have a partial DPD deficiency. When these partially DPD deficient patients are treated with a full dose of fluoropyrimidines, they are generally exposed to toxic levels of 5-FU and its metabolites, and the risk of developing severe treatment-related toxicity is therefore significantly increased.Currently, functional and clinical validity is well established for four DPYD variants (DPYD*2A, c.2846A>T, c.1679T>G and c.1236G>A), as those variants have retrospectively and in a large population study prospectively been shown to be associated with increased risk of fluoropyrimidine-associated toxicity. Patient safety of fluoropyrimidine treatment can be significantly improved by pre-emptive screening for DPYD genotype variants and dose reductions in heterozygous DPYD variant allele carriers, thereby normalizing 5-FU exposure. Based on the critical appraisal of currently available data, adjusting the labels of capecitabine and 5-FU by including recommendations on pre-emptive screening for DPYD variants and DPYD genotype-guided dose adjustments should be the new standard of care.

A highly sensitive method was developed to quantitate the antileishmanial agent paromomycin in human plasma, with a lower limit of quantification of 5 ng/mL. Separation was achieved using an isocratic ion-pair ultra-high performance liquid chromatographic (UPLC) method with a minimal concentration of heptafluorobutyric acid, which was coupled through an electrospray ionization interface to a triple quadrupole - linear ion trap mass spectrometer for detection. The method was validated over a linear calibration range of 5 to 1000 ng/mL (r2≥0.997) with inter-assay accuracies and precisions within the internationally accepted criteria. Volumes of 50 μL of human K2EDTA plasma were processed by using a simple protein precipitation method with 40 μL 20 % trichloroacetic acid. A good performance was shown in terms of recovery (100 %), matrix effect (C.V. ≤ 12.0 %) and carry-over (≤17.5 % of the lower limit of quantitation). Paromomycin spiked to human plasma samples was stable for at least 24 h at room temperature, 6 h at 35 °C, and 104 days at −20 °C. Paromomycin adsorbs to glass containers at low concentrations, and therefore acidic conditions were used throughout the assay, in combination with polypropylene tubes and autosampler vials. The assay was successfully applied in a pharmacokinetic study in visceral leishmaniasis patients from Eastern Africa.

Tivozanib is a potent and selective inhibitor of VEGFR1-3, recently approved by the EMA for first-line treatment of renal cell carcinoma. We used wild-type, knockout, and transgenic mouse strains to study the effects of the drug transporters ABCB1, ABCG2, and OATP1A/1B, and of the CYP3A enzymes on the oral availability and tissue distribution of tivozanib. Tivozanib was transported by human ABCB1 and mouse Abcg2 in polarized MDCK-II cells. Upon oral administration, tivozanib showed rapid absorption and the plasma concentration-time curves showed secondary peaks in all mouse strains, suggesting enterohepatic recirculation. The brain-to-plasma ratios were significantly increased in Abcb1a/1b-/- (2.2-fold) and Abcb1a/1b;Abcg2-/- (2.6-fold) mice compared to wild-type mice, indicating a modest protective role of these transporters in the blood-brain barrier. Slco1a/1b-/- mice showed a 1.2-fold lower liver-to-plasma ratio than wild-type mice, suggesting a minor role of mOatp1a/1b in tivozanib liver distribution. Oral plasma pharmacokinetics of tivozanib was not significantly altered in these mouse strains, nor in Cyp3a knockout and CYP3A4-humanized mice. The modest effect of ABC transporters on tivozanib brain accumulation, if also true in humans, might mean that this drug is not strongly limited in its therapeutic efficacy against malignant lesions situated partly or completely behind the blood-brain barrier.

Miltefosine is an oral agent against the neglected tropical disease leishmaniasis, which is mostly endemic in resource-poor areas. Dried blood spot (DBS) sampling is an attractive alternative to plasma sampling for pharmacokinetic studies in these remote areas, but introduces additional variability in analyte quantification due to possible blood spot inhomogeneity and variability in blood spot volume and haematocrit values. Volumetric absorptive microsampling (VAMS) potentially overcomes a few of these issues as the VAMS device absorbs a fixed volume that is processed as a whole. We developed and validated an LC-MS/MS method for the quantification of miltefosine with this novel sampling technique with good performance in terms of linearity, selectivity, accuracy (bias within ±10.8%), precision (CV%≤11.9%), recovery, carry-over and matrix effect. VAMS samples were stable for at least one month at room temperature and 37°C. The impact of haematocrit on assay accuracy was reduced compared to conventional DBS sampling, but indicated a declining recovery with increased haematocrit due to haematocrit dependency in recovery from the sampling device. A clinical validation will be required to investigate whether VAMS is an appropriate and cost-effective alternative sampling method to conventional DBS sampling.

A simple and rapid bioanalytical method was developed for the simultaneous quantification of irinotecan and SN-38 in mouse plasma and tissue homogenates using High-Performance Liquid Chromatography with Fluorescence detection (HPLC-FL). Camptothecin was used as internal standard and protein precipitation with acetonitrile-methanol (1:1, v/v) followed by acidification with 0.5 M hydrochloric acid was used for sample pre-treatment. The analytes and the internal standard were detected using an excitation and emission wavelength of 368 and 515 nm, respectively. The linearity, selectivity, accuracy and precision, carry-over, limit of detection and lower limit of quantification of the method are described. The method was linear from 7.5 to 1500 ng/mL for irinotecan and from 5 to 1000 ng/mL for SN-38. For all matrices, the accuracy bias and precision variation were within ±15% and ≤15%, respectively. This method was successfully applied to study the pharmacokinetics of irinotecan and SN-38 using in vivo mouse models.

BRAF(V600E) mutant melanomas treated with inhibitors of the BRAF and MEK kinases almost invariably develop resistance that is frequently caused by reactivation of the mitogen activated protein kinase (MAPK) pathway. To identify novel treatment options for such patients, we searched for acquired vulnerabilities of MAPK inhibitor-resistant melanomas. We find that resistance to BRAF+MEK inhibitors is associated with increased levels of reactive oxygen species (ROS). Subsequent treatment with the histone deacetylase inhibitor vorinostat suppresses SLC7A11, leading to a lethal increase in the already-elevated levels of ROS in drug-resistant cells. This causes selective apoptotic death of only the drug-resistant tumor cells. Consistently, treatment of BRAF inhibitor-resistant melanoma with vorinostat in mice results in dramatic tumor regression. In a study in patients with advanced BRAF+MEK inhibitor-resistant melanoma, we find that vorinostat can selectively ablate drug-resistant tumor cells, providing clinical proof of concept for the novel therapy identified here.

Objectives: Reimbursement decisions are conventionally based on evidence from randomised controlled trials (RCTs) which often have high internal validity but low external validity. Real-world data (RWD) may provide complimentary evidence for relative effectiveness assessments (REAs) and cost-effectiveness assessments (CEAs). This study examines whether RWD is incorporated in Health Technology Assessment (HTA) of melanoma drugs by European HTA agencies, differences in RWD use between agencies and across time. Methods: HTA reports published between 01.01.2011 and 31.12.2016 were retrieved from websites of agencies representing 5 jurisdictions: England (NICE), Scotland (SMC), France (HAS), Germany (IQWiG) and the Netherlands (ZIN). A standardized data-extraction form was used to extract information on RWD inclusion for both REAs and CEAs. A panel of senior HTA assessors representing the 5 agencies was consulted to check the robustness of data extracted and interpretation. Results: Fifty-two reports were retrieved. All 52 reports contained REAs; CEAs were present in 25. RWD was included in 28 of 52 REAs (54%); mainly to estimate melanoma prevalence. RWD was included in 22 of 25 (88%) of CEAs; mainly to extrapolate long-term effectiveness and/or identify drug-related costs drugs. Differences emerged between agencies regarding RWD use in REAs; ZIN and IQWiG cited RWD for evidence on prevalence whereas NICE, SMC and HAS additionally cited RWD use for drug effectiveness. No visible trend for RWD use in REAs and CEAs over time was observed. Conclusions: In general, RWD inclusion was higher in CEAs than REAs. It was mostly used to estimate melanoma prevalence in REAs or to predict long-term effectiveness in CEAs. Differences emerged between agencies' use of RWD. However, no visible trends for RWD use over time were observed. Future research should explore the use of RWD in HTA of drugs in other disease indications and in conditional reimbursement schemes.

Background and purpose: In order to deliver patient-centred pharmaceutical care, pharmacy students need to develop the appropriate competences and skills. During their regular study program, they have limited long-term patient contact. We therefore implemented a student-patient buddy project to give students opportunity to practice and learn from the patient contact. Educational activity and setting: A student-patient buddy project was implemented in a 10-week first-year master experiential learning course, including a community pharmacy internship. The pharmacist paired the student with a community-dwelling patient. Student learning activities included: (1) three meetings at the university to prepare and discuss buddy contact moments, (2) three buddy contact moments, (3) discussion with the internship providing pharmacist, and (4) a written reflection report. Findings: In total, 66 students participated from April to June 2021. Most students found patient contact fun and a useful learning experience. Students mentioned that patients were very open and there was opportunity to build a relationship. The first conversation was experienced as exciting and sometimes difficult. Understanding the person was perceived as important. Internship pharmacists were positive about the project and saw learning benefits for students, as well as added value for the pharmacy, mainly because patients seemed to appreciate the contact. A student-patient buddy project is a good way to expand the limited long-term “real” patient care experiences of pharmacy students. This enables them to practice communication and building relationships with patients.

Background: Ventricular fibrillation (VF) waveform analyses are considered a reliable proxy for OHCA characteristics in out-of-hospital cardiac arrest (OHCA), but patient characteristics such as cardiovascular medication use might also be associated with changes in VF waveform measures. Objectives: To assess associations between cardiovascular medication use and amplitude spectrum area (AMSA) of VF, while correcting for the presence of cardiovascular disease (CVD), CVD risk factors, and OHCA characteristics. Methods: We included 990 VF patients from an OHCA registry in the Netherlands, with available information on medical history and cardiovascular medication use. Associations between cardiovascular medication use and AMSA were tested in a multivariate linear regression model, adjusting for CVD, CVD risk factors, and OHCA characteristics. Model performance was shown using R-square and R-change. We also calculated whether medication use was associated with faster dissolution of AMSA to lower values with increasing time delay. Results: In the multivariate analysis, when corrected for CVD, CVD risk factors and OHCA characteristics, only potassium-sparing agents were associated with a lower AMSA when compared to patients using other cardiovascular medications (OR 0.46 [95% CI 0.100.81]; P < 0.012). The decrease in AMSA with increasing EMS-call-to-ECG delay was the same for patients with and without cardiovascular medication use (all P > 0.05). Only a small part of the variance in AMSA could be explained by medication use (R-square 0.003 0.026). Adding OHCA characteristics to the model resulted in the largest R square change (0.090.15). Conclusions: It is unlikely that there is a strong and clinically relevant independent pharmacologic effect of cardiovascular medication use on AMSA. In OHCA, AMSA might be used as patient management tool without considering cardiovascular medication use.: It is unlikely that there is a strong and clinically relevant independent pharmacologic effect of cardiovascular medication use on AMSA. In OHCA, AMSA might be used as patient management tool without considering cardiovascular medication use.

Introduction: Chronic obstructive pulmonary disease (COPD) is characterised by persistent airflow obstruction and respiratory symptoms. While short course systemic GCs are prescribed in patients with acute COPD exacerbations, little is known of the risk of fractures with intermittent exposure to high-dose GC and the effect of proxies of disease severity.Methods: A case-control study was conducted using the Danish National Hospital Discharge Registry (NHDR) between January 1996 to December 2011. Conditional logistics regression models were used to derive adjusted odds ratios (OR) risk of fractures in subjects with COPD stratified by intermittent high-dose, and proxies of disease severity.Result: A total of 635,536 cases and the same number of controls were identified (mean age 67.5 +/- 13.8, 65% female). COPD patients with intermittent use of high average daily dose oral glucocorticoids did not have an increased risk of any, osteoporotic, hip or clinically symptomatic vertebral fracture compared to non-COPD patients (adj. OR 0.65; 95% CI: 0.50-0.86, 0.70; 95% CI: 0.70-0.99, 1.17; 95% CI: 0.59-2.32, 1.98; 95% CI: 0.59-6.65 respectively). We identified an elevated risk of osteoporotic fracture among patients who visited the emergency unit (adj. OR 1.47; 95% CI 1.20-1.79) or were hospitalised in the past year for COPD (adj. OR 1.76; 95% CI 1.66-1.85). Current GC use among COPD patients was associated with an increased risk of osteoporotic, hip and clinically symptomatic vertebral fractures compared to patients without COPD.Conclusion: Intermittent high-dose GCs was not associated with an increased risk of any, osteoporotic, hip or clinically symptomatic vertebral fractures in patients with COPD. Current GC use was however associated with an increased risk of hip and clinically symptomatic vertebral fractures. Therefore, emphasis on prophylactic treatment of fractures may not be essential in patients with COPD receiving intermittent dose of GCs, whereas this should be considered for high-dose long-term users with advanced COPD disease stage, postmenopausal women and men over 40 years. (C) 2018 Elsevier Inc. All rights reserved.

AIMS: C-reactive protein (CRP) is an important biomarker in systemic inflammation in COPD; reports have suggested inhaled corticosteroids (ICS) attenuate CRP levels. We evaluated the risk of moderate-to-severe exacerbations, severe exacerbations and all-cause mortality among patients with COPD currently exposed to Inhaled corticosteroids (ICS) stratified by CRP levels compared to never ICS users with low CRP levels.METHODS: We included subjects age 40 or more who had a diagnosis of COPD from January 1, 2005 to January 31, 2014 from the UK Clinical Practice Research Datalink (CPRD). ICS exposure was determined time-dependently, as current, recent, past or never users. We evaluated the risk of moderate-to-severe exacerbations, severe exacerbations and all-cause mortality among ICS users stratified by CRP levels.RESULTS: 17,722 subjects diagnosed with COPD met the inclusion criteria. Among current or never ICS with elevated CRP levels we found, no significantly reduced risk of moderate-to-severe or severe exacerbations. For patients currently exposed ICS with CRP levels ≥8 mg/L there was no reduced risk of moderate-to-severe exacerbations (adjusted hazard ratio [adj. HR] 0.99; 95% confidence interval [CI] 0.76-1.31) or severe exacerbations (adj.HR 1.52; 95% CI 0.71-3.27). However, we found an increased risk of all-cause mortality among COPD patients with CRP levels ≥8 mg/L irrespective of ICS exposure.CONCLUSION: We did not find a reduced risk of moderate and/or severe COPD exacerbations among COPD patients with varying CRP levels currently exposed to ICS. However, low-grade systemic inflammation was associated with all-cause mortality among COPD patients.

Background Prospective DPYD genotyping prevents severe fluoropyrimidine (FP)-induced toxicity by decreasing dosages in DPYD variant allele carriers. FP dosages in chemoradiation therapy (CRT) are lower than those in other FP-containing regimens. Pharmacogenetic guidelines do not distinguish between regimens, leaving physicians in doubt to apply dose reductions. Our aim was to investigate severe toxicity in DPYD variant allele carriers receiving CRT. Methods Medical records of 828 patients who received FP-based CRT were reviewed from three centres. Severe (grade ≥III) toxicity in DPYD variant allele carriers receiving upfront FP dose reductions according to pharmacogenetic dosing guidelines and DPYD variant allele carriers not receiving FP dose reductions was compared with DPYD wild-type patients receiving standard dose of FPs in CRT. Results DPYD variant allele carriers treated with standard dosages (N = 34) showed an increased risk of severe gastrointestinal (adjusted OR = 2.58, confidence interval [CI] = 1.02–6.53, P = 0.045) or severe haematological (adjusted OR = 4.19, CI = 1.32–13.25, P = 0.015) toxicity compared with wild-type patients (N = 771). DPYD variant allele carriers who received dose reductions (N = 22) showed a comparable frequency of severe gastrointestinal toxicity compared with wild-type patients, but more (not statistically significant) severe haematological toxicity. Hospitalisations for all DPYD variant allele carriers were comparable, independent of dose adjustments; however, the mean duration of hospitalisation was significantly shorter in the dose reduction group (P = 0.010). Conclusions Standard FP dosages in CRT resulted in an increased risk of severe toxicity in DPYD variant allele carriers. We advise to apply FP dose reductions according to current guidelines in DPYD variant allele carriers starting CRT.