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Background and Objective: High variability in tacrolimus pharmacokinetics directly after lung transplantation (LuTx) may increase the risk for acute kidney injury (AKI) and transplant rejection. The primary objective was to compare pharmacokinetic variability in patients receiving tacrolimus orally versus intravenously early after LuTx. Methods: Pharmacokinetic and clinical data from 522 LuTx patients transplanted between 2010 and 2020 in two university hospitals were collected to compare orally administered tacrolimus to intravenous tacrolimus early post-transplantation. Tacrolimus blood concentration variability, measured as intrapatient variability (IPV%) and percentage of time within the therapeutic range (TTR%), was analyzed within the first 14 days after LuTx. Secondary outcomes were AKI, acute rejection, length of stay in the intensive care unit (ICU), and mortality in the ICU and during hospital admission. Results: We included 224 patients in the oral and 298 in the intravenous group. The mean adjusted IPV% was 10.8% (95% confidence interval [CI] 6.9–14.6; p < 0.001) higher in the oral group (27.2%) than the intravenous group (16.4%). The mean TTR% was 7.3% (95% CI − 11.3 to − 3.4; p < 0.001) lower in the oral group (39.6%) than in the intravenous group (46.9%). The incidence of AKI was 46.0% for oral and 42.6% for intravenous administration (adjusted odds ratio [OR] 1.2; 95% CI 0.8–1.8; p = 0.451). The frequencies of clinically diagnosed acute rejection in the oral and intravenous groups were nonsignificant (24.6% vs 17.8%; OR 1.5 [95% CI 1.0–2.3; p = 0.059]). ICU and hospital mortality rate and ICU length of stay were similar. Conclusions: Administering tacrolimus orally directly after LuTx leads to a higher variability in blood concentrations compared to intravenous administration. There was no difference in the occurrence of AKI or transplant rejection.

Background: To assess the causal relationship between a medicinal product and a reported event, relevant information needs to be present. Information elements for assessing cases of exposure to medicinal products during pregnancy were predefined and used in a new tool to assess the quality of information. However, the extent in which the presence or absence of these predefined information elements is associated with the overall clinical quality of these cases, as evaluated by pharmacovigilance experts, remains uncertain. Objective: We aimed to validate a novel method to assess the clinical quality of information in real-world pregnancy pharmacovigilance case reports. Methods: The clinical quality of case reports regarding medicinal product exposure and pregnancy-related outcomes was appraised from spontaneous reports, literature, Teratology Information Services (UK and Switzerland), The Dutch Pregnancy Drug Register, the Gilenya pregnancy registry and the Enhanced PV programme of Novartis. Assessment was done by means of the novel standardised tool based on the presence and relevance of information, and by expert judgement. The novel tool was validated compared to the expert assessment as the gold standard expressed as the area under the receiver operating characteristic curves, after which the sensitivity and specificity were calculated using cross-tabulations. Inter-rater variability was determined by means of weighted Cohen’s kappa. Results: One hundred and eighty-six case reports were included. The clinical quality score as assessed by the novel method was divided into three categories with cut-off values of 45% (poor to intermediate) and 65% (intermediate to excellent). Sensitivity was 0.93 and 0.96 for poor to intermediate and intermediate to excellent, respectively. Specificity was respectively 0.52 and 0.73. Inter-rater variability was 0.65 (95% confidence interval 0.53–0.78) for the newly developed approach, and 0.40 (95% confidence interval 0.28–0.52) f

PURPOSE: In clinical practice, a discrepancy may exist between the prescribed amount of a drug and the commercially available pack sizes in the pharmacy, potentially contributing to drug waste. This study aimed-as an example of this phenomena-to quantify leftover of amoxicillin suspension prescribed to children, due to discrepancies between physician-prescribed and pharmacy-dispensed amounts.METHODS: We performed a retrospective cohort study including amoxicillin suspension dispensations for patients aged 0-12 years between 2017 and 2019 utilizing the Dutch PHARMO database. Leftover amount of amoxicillin was estimated by assessing the discrepancy between the prescribed and dispensed amounts. Extrapolated amoxicillin weight and economic spillage estimates for the Netherlands were determined. The impact of two theoretical interventions on leftover amount was assessed: (1) introducing vials with half the volume of the current 100 and 30 mL vials and (2) a combination of the first intervention with a maximum of 10% round-down by the dispensing pharmacy of the prescribed dose.RESULTS: We included 79 512 amoxicillin suspension dispensations for 62 252 patients. The mean leftover amount of amoxicillin suspension per dispensing was 27%. The yearly amount of amoxicillin leftover was 49.8 kg in the study cohort, equivalent to yearly 633 kg and €621 000 when extrapolated to the Netherlands. Employing the first theoretical intervention reduced the mean leftover per dispensing to 20%, reducing the yearly leftover to 31.6 kg amoxicillin in the study cohort, and to 400 kg and €400 000 extrapolated. The second theoretical intervention further reduced leftover to 17%, reducing the yearly leftover to 24.3 kg amoxicillin in the study cohort, and to 300 kg and €300 000 extrapolated.CONCLUSION: Approximately a quarter of amoxicillin suspension remains as leftover per dispensing. Applying different theoretical intervention shows the potential for a significant red

Background: The availability of ready-to-administer (RTA) syringes for intravenous (IV) drugs facilitates rapid and safe administration in emergency and intensive care situations. Hospital pharmacies can prepare RTA syringes through aseptic batchwise filling. Due to excess production of these RTA syringes for sufficient availability for patient care and their limited (microbiological) shelf-life, waste is unavoidable, which contributes to environmental pollution. RTA prefilled sterilized syringes (PFSSs) have much longer shelf-lives than aseptically prepared RTA syringes and might contribute to reducing drug waste. Aim: This study aimed to evaluate the difference in drug waste between RTA syringes that were prepared through aseptic batchwise filling and RTA PFSSs in the Intensive Care Unit (ICU). Methods: We measured drug waste of RTA syringes over an 8-year time period from August 2015 to May 2023 in the 32-bed ICU of the University Medical Center Utrecht. We distinguished between RTA syringes prepared through aseptic batchwise filling by our hospital pharmacy (“RTA aseptic syringes”, shelf-life of 31 days) and RTA PFSSs (shelf-life of 18 months). An intervention group of three drug products that were replaced by PFSSs was compared to a control group of five drug products that were not replaced by PFSSs during the study period. We then defined four different periods within the total study period, based on quarantine time of the RTA aseptic syringes and time of PFSS introduction: 1) no quarantine, 2) 3-day quarantine, 3) 7-day quarantine and 4) PFSS introduction. Our primary endpoint was the number of RTA syringes that was wasted, expressed as the percentage of the total number of syringes dispensed to the ICU in each of these four periods. We used a Kruskall-Wallis test to test if waste percentages differed between time periods in the control and intervention groups, with a post-hoc Dunn's test for pairwise comparisons. Furthermore, we applied two interrupted ti

BACKGROUND: Many patients with inflammatory bowel disease (IBD) have transitioned from an infliximab originator to a biosimilar. However, some patients retransition to the originator (i.e. stop biosimilar and reinitiate the originator). Whether this sign of potential unsatisfactory treatment response is specifically related to the infliximab biosimilar or the patient and/or the disease including patients' beliefs on the biosimilar is unclear.OBJECTIVES: We aimed to compare the risk of and reasons for infliximab discontinuation between retransitioned patients and those remaining on biosimilar.DESIGN: Non-interventional, multicentre cohort study.METHODS: IBD patients who transitioned from infliximab originator to biosimilar between January 2015 and September 2019 in two Dutch hospitals were eligible for this study. Retransitioned patients (retransitioning cohort) were matched with patients remaining on biosimilar (biosimilar remainder cohort). Reasons for discontinuation were categorised as the unwanted response (i.e. loss of effect or adverse events) or remission. Risk of unwanted discontinuation was compared using Cox proportional hazards models.RESULTS: Patients in the retransitioning cohort ( n = 44) were younger (median age 39.9 versus 44.0 years), more often female (65.9% versus 48.9%) and had shorter dosing intervals (median 48.5 versus 56.0 days) than in the biosimilar remainder cohort ( n = 127). Infliximab discontinuation due to unwanted response was 22.7% in the retransitioning and 13.4% in the biosimilar remainder cohort, and due to remission was 2.3% and 9.4%, respectively. Retransitioned patients are at increased risk of discontinuing due to unwanted response compared with biosimilar remainder patients (adjusted HR 3.7, 95% CI: 1.0-13.9). Patients who retransitioned due to an increase in objective disease markers had higher discontinuation rates than patients who retransitioned due to symptoms only (66.7% versus 23.7%).

INTRODUCTION: Emicizumab effectively prevents bleeding in people with haemophilia A (PwHA), but is a burden for national healthcare budgets and consequently may limit access. According to the drug label, dosing of emicizumab is based on body weight with fixed intervals of 7, 14 or 28 days, which leads to mean plasma concentrations of 55 µg/mL (SD 15 µg/mL). However, a moderate variability of concentrations and a minimal effective concentration of 30 µg/mL have been suggested in studies. Therefore, a dose of emicizumab that targets a trough concentration of 30 µg/mL is hypothesised to be equally effective as conventional dosing in the prevention of bleeding.METHODS AND ANALYSIS: We designed a phase IV, multicentre, open-label, crossover study to evaluate non-inferiority of bleed control of ≥6 months on conventional dosing in comparison to ≥6 months on dose intervention. This dose intervention consists of reducing the dose of emicizumab to target a trough concentrations of 30 µg/mL using individual pharmacokinetic (PK) parameters. Ninety-five PwHA aged >1 years who received conventional dosing of emicizumab for ≥12 months with good bleeding control during the last 6 months will be recruited from all Dutch haemophilia treatment centres. The study is powered to detect a clinically relevant decrease (risk difference) of 15% in the proportion of patients without treated bleeds during follow-up. Secondary endpoints are spontaneous joint or muscle bleeds, and annualised treated bleeding rates (using negative binomial regression). Cost-effectivity between conventional dosing and individualised PK-guided dosing of emicizumab will be compared.ETHICS AND DISSEMINATION: The DosEmi study was approved by the Medical Ethics Review Committee NedMec of the University Medical Center of Utrecht, The Netherlands. Study results will be communicated through publications in international scientific journals and presentations at (inter)national conferences.TRIAL R

OBJECTIVE: Combining text mining (TM) and clinical decision support (CDS) could improve diagnostic and therapeutic processes in clinical practice. This review summarizes current knowledge of the TM-CDS combination in clinical practice, including their intended purpose, implementation in clinical practice, and barriers to such implementation.MATERIALS AND METHODS: A search was conducted in PubMed, EMBASE, and Cochrane Library databases to identify full-text English language studies published before January 2022 with TM-CDS combination in clinical practice.RESULTS: Of 714 identified and screened unique publications, 39 were included. The majority of the included studies are related to diagnosis (n = 26) or prognosis (n = 11) and used a method that was developed for a specific clinical domain, document type, or application. Most of the studies selected text containing parts of the electronic health record (EHR), such as reports (41%, n = 16) and free-text narratives (36%, n = 14), and 23 studies utilized a tool that had software "developed for the study". In 15 studies, the software source was openly available. In 79% of studies, the tool was not implemented in clinical practice. Barriers to implement these tools included the complexity of natural language, EHR incompleteness, validation and performance of the tool, lack of input from an expert team, and the adoption rate among professionals.DISCUSSION/CONCLUSIONS: The available evidence indicates that the TM-CDS combination may improve diagnostic and therapeutic processes, contributing to increased patient safety. However, further research is needed to identify barriers to implementation and the impact of such tools in clinical practice.

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common, disabling side effect in non-small cell lung cancer (NSCLC) patients treated with platinum-based therapy. There is increasing evidence for associations between genetic variants and susceptibility to CIPN. The aim of this study was to further explore genetic risk factors for CIPN by investigating previously reported genetic associations. Methods: A multicenter prospective follow-up study (PGxLUNG, NTR NL5373610015) in NSCLC patients (stage II-IV) treated with first-line platinum-based (cisplatin or carboplatin) chemotherapy was conducted. Clinical evaluation of neuropathy (CTCAE v4.03) was performed at baseline and before each cycle (four cycles, every three weeks) of chemotherapy and at three and six months after treatment initiation. The relationship between 34 single nucleotide polymorphisms (SNPs) in 26 genes and any grade (grade ≥ 1) and severe (grade ≥ 2) CIPN was assessed by using univariate and multivariate logistic regression modelling. Results: In total, 320 patients were included of which 26.3% (n = 84) and 8.1% (n = 26) experienced any grade and severe CIPN, respectively. The GG-genotype (rs879207, A > G) of TRPV1, a gene expressed in peripheral sensory neurons, was observed in 11.3% (n = 36) of the patients and associated with an increased risk of severe neuropathy (OR 5.2, 95%CI 2.1–12.8, adjusted p-value 0.012). A quarter (25%, n = 9/36) of the patients with the GG-genotype developed severe neuropathy compared to 6% (n = 17/282) of the patients with the AG- or AA-genotype. Multivariate logistic regression analysis showed statistically significant associations between the GG-genotype (ORadj 4.7, 95%CI 1.8–12.3) and between concomitant use of paclitaxel (ORadj 7.2, 95%CI 2.5–21.1) and severe CIPN. Conclusions: Patients with the GG-genotype (rs879207) of TRPV1 have an almost 5-fold higher risk of developing severe neuropathy when treated with platinum-based therapy. Future st