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Item does not contain fulltext PURPOSE: Pemetrexed is a chemotherapeutic drug in the treatment of non-small cell lung cancer and mesothelioma. Optimized dosing of pemetrexed based on renal function instead of body surface area (BSA) is hypothesized to reduce pharmacokinetic variability in systemic exposure and could therefore improve treatment outcomes. The aim of this study is to compare optimized dosing to standard BSA-based dosing. METHODS: A multicenter randomized (1:1) controlled trial was performed to assess superiority of optimized dosing versus BSA-based dosing in patients who were eligible for pemetrexed-based chemotherapy. The individual exposure to pemetrexed in terms of area under the concentration-time curve (AUC) was determined. The fraction of patients attaining to a predefined typical target AUC (164 mg × h/L ± 25%) was calculated. RESULTS: A total of 81 patients were included. Target attainment was not statistically significant different between both arms (89% vs. 84% (p = 0.505)). The AUC of pemetrexed was similar between the optimized dosing arm (n = 37) and the standard of care arm (n = 44) (155 mg × h/L vs 160 mg × h/L (p = 0.436). CONCLUSION: We could not show superiority of optimized dosing of pemetrexed in patients with an adequate renal function does not show added value on the attainment of a pharmacokinetic endpoint, safety, nor QoL compared to standard of care dosing. CLINICAL TRIAL NUMBER: Clinicaltrials.gov identifier: NCT03655821. 01 januari 2023

Purpose Proton pump inhibitors (PPIs) are prescribed frequently and can cause potentially severe hypomagnesemia. Researchers assessed the prevalence of hypomagnesemia and the association between PPI use and hypomagnesemia in hospitalized older patients. Methods Researchers conducted a single-center, observational, retrospective cohort study with patients admitted to a geriatric ward at the Jeroen Bosch Hospital in the period between June 24, 2016, and August 30, 2020. Patients were included if they were 65 years of age or older, had a serum magnesium measurement, and a complete overview of patient’s current medication was present at the day of admission. The primary outcome was the occurrence of hypomagnesemia at hospital admission. Exposure to PPIs was the primary determinant investigated. Covariates were studied to identify risk factors and to adjust for potential confounding. The strength of the association between PPI and hypomagnesemia was evaluated with unconditional logistic regression, expressed as odds ratios (ORs) with 95% confidence intervals (CIs). Results The prevalence of hypomagnesemia was 21.9% in PPI users and 15.8% in non-PPI users. Overall, the use of PPIs was associated with hypomagnesemia (ORadj = 1.38, 95% CI 1.09-1.76). A trend for this association was most pronounced in male patients (ORadj = 1.88, 95% CI 1.27-2.79), smokers (ORadj = 3.95, 95% CI 1.52-10.28), and in patients using > 7 units alcohol a week (ORadj = 4.44, 95% CI 1.40-14.12). Conclusion Older patients who are taking a PPI have a higher risk of developing hypomagnesemia than nonusers; additional factors can contribute to the risk. Physicians should be aware of PPI-induced hypomagnesemia and routinely monitor serum magnesium levels in older patients.

Contains fulltext : 292912.pdf (Publisher’s version ) (Open Access) BACKGROUND: Expensive novel anticancer drugs put a serious strain on healthcare budgets, and the associated drug expenses limit access to life-saving treatments worldwide. OBJECTIVE: We aimed to develop alternative dosing regimens to reduce drug expenses. METHODS: We developed alternative dosing regimens for the following monoclonal antibodies used for the treatment of lung cancer: amivantamab, atezolizumab, bevacizumab, durvalumab, ipilimumab, nivolumab, pembrolizumab, and ramucirumab; and for the antibody-drug conjugate trastuzumab deruxtecan. The alternative dosing regimens were developed by means of modeling and simulation based on the population pharmacokinetic models developed by the license holders. They were based on weight bands and the administration of complete vials to limit drug wastage. The resulting dosing regimens were developed to comply with criteria used by regulatory authorities for in silico dose development. RESULTS: We found that alternative dosing regimens could result in cost savings that range from 11 to 28%, and lead to equivalent pharmacokinetic exposure with no relevant increases in variability in exposure. CONCLUSIONS: Dosing regimens based on weight bands and the use of complete vials to reduce drug wastage result in less expenses while maintaining equivalent exposure. The level of evidence of our proposal is the same as accepted by regulatory authorities for the approval of alternative dosing regimens of other monoclonal antibodies in oncology. The proposed alternative dosing regimens can, therefore, be directly implemented in clinical practice.

Pemetrexed is a chemotherapeutic drug in the treatment of non-small cell lung cancer and mesothelioma. Optimized dosing of pemetrexed based on renal function instead of body surface area (BSA) is hypothesized to reduce pharmacokinetic variability in systemic exposure and could therefore improve treatment outcomes. The aim of this study is to compare optimized dosing to standard BSA-based dosing.A multicenter randomized (1:1) controlled trial was performed to assess superiority of optimized dosing versus BSA-based dosing in patients who were eligible for pemetrexed-based chemotherapy. The individual exposure to pemetrexed in terms of area under the concentration-time curve (AUC) was determined. The fraction of patients attaining to a predefined typical target AUC (164 mg × h/L ± 25%) was calculated.A total of 81 patients were included. Target attainment was not statistically significant different between both arms (89% vs. 84% (p = 0.505)). The AUC of pemetrexed was similar between the optimized dosing arm (n = 37) and the standard of care arm (n = 44) (155 mg × h/L vs 160 mg × h/L (p = 0.436).We could not show superiority of optimized dosing of pemetrexed in patients with an adequate renal function does not show added value on the attainment of a pharmacokinetic endpoint, safety, nor QoL compared to standard of care dosing.Clinicaltrials.gov identifier: NCT03655821.

Purpose Pemetrexed is a widely used cytostatic agent with an established exposure–response relationship. Although dosing is based on body surface area (BSA), large interindividual variability in pemetrexed plasma concentrations is observed. Therapeutic drug monitoring (TDM) can be a feasible strategy to reduce variability in specific cases leading to potentially optimized pemetrexed treatment. The aim of this study was to develop a limited sampling schedule (LSS) for the assessment of pemetrexed pharmacokinetics. Methods Based on two real-life datasets, several limited sampling designs were evaluated on predicting clearance, using NONMEM, based on mean prediction error (MPE %) and normalized root mean squared error (NRMSE %). The predefined criteria for an acceptable LSS were: a maximum of four sampling time points within 8 h with an MPE and NRMSE ≤ 20%. Results For an accurate estimation of clearance, only four samples in a convenient window of 8 h were required for accurate and precise prediction (MPE and NRMSE of 3.6% and 5.7% for dataset 1 and of 15.5% and 16.5% for dataset 2). A single sample at t = 24 h performed also within the criteria with MPE and NRMSE of 5.8% and 8.7% for dataset 1 and of 11.5% and 16.4% for dataset 2. Bias increased when patients had lower creatinine clearance. Conclusions We presented two limited sampling designs for estimation of pemetrexed pharmacokinetics. Either one can be used based on preference and feasibility.

Contains fulltext : 251211.pdf (Publisher’s version ) (Open Access) Neutropenia is a dose-related treatment-limiting and costly adverse event of pemetrexed. We postulate that individualized dosing reduces the incidence of neutropenia. The aims of this study were (i) to investigate the costs of pemetrexed-related neutropenia and (ii) to determine the pharmacoeconomic benefits of individualized dosing of pemetrexed in terms of budget impact, yearly cost savings, and reduction in severe neutropenia. Retrospective data on the treatment of grade 3 or higher neutropenia during pemetrexed-based chemotherapy were collected from three Dutch hospitals to determine the mean healthcare consumption during a neutropenic episode. Subsequently, Monte Carlo simulations were performed using a validated pharmacokinetic/pharmacodynamic model to predict the neutropenia incidence during four cycles for standard dosing of pemetrexed and individualized dosing. The mean costs per neutropenia and the expected neutropenia incidence were combined to calculate the budget impact and cost savings. We found that the average costs per pemetrexed-associated neutropenic episode to be €1,490 (US $1,674). The neutropenia incidence for the standard and individualized pemetrexed dosing strategies were 12.7% and 9.9%, respectively. This resulted in total expected neutropenia-related costs of ~ €3.0 million (US $3.372 million) and €2.4 million (US $2.697 million), respectively. Taking the number of patients eligible for pemetrexed treatment into account, individualized dosing could result in saving €686,000 (US $770,995) on a yearly basis in the Netherlands alone. Individualized dosing of pemetrexed can decrease the incidence of neutropenia and thus result in a significant decrease in neutropenia-related costs and decreased risk of hospitalization or even death while maintaining therapeutic exposure.

Contains fulltext : 249097.pdf (Publisher’s version ) (Open Access) Pemetrexed is a cytotoxic drug for first-line treatment of lung cancer. It is often combined with other anticancer drugs such as cisplatin or carboplatin. In clinical practice, hyperhydration regimens are applied to overcome cisplatin-related nephrotoxicity. As pemetrexed is almost completely eliminated from the body by the kidneys, hyperhydration can result in augmented clearance. Furthermore, administration of large quantities of fluid may increase the volume of distribution of pemetrexed. Pharmacokinetics and, thus, efficacy and toxicity may be influenced by hyperhydration. This has not yet been properly studied. We performed a population pharmacokinetic analysis to assess hyperhydration as a covariate for pemetrexed clearance and for volume of distribution A relevant change was defined as >25% increase in clearance or volume of distribution. In our extensive dataset of 133 individuals, we found that hyperhydration did not significantly or relevantly explain variability in pemetrexed clearance (unchanged, P = .196) or volume of distribution (+7% change, P = .002), despite a power of >99% to detect a relevant change. Therefore, dose adjustments of pemetrexed are not required during hyperhydration with cisplatin.

BackgroundElderly patients are at increased risk for Adverse Drug Events (ADEs). Proactively screening elderly people visiting the emergency department for the possibility of their hospital admission being drug-related helps to improve patient care as well as prevent potential unnecessary medical costs. Existing routine ADE assessment heavily relies on a rule-based checking process. Recently, machine learning methods have been shown to be effective in automating the detection of ADEs, however, most approaches used only either structured data or free texts for their feature engineering. How to better exploit all available EHRs data for better predictive modeling remains an important question. On the other hand, automated reasoning for the preventability of ADEs is still a nascent line of research.MethodsClinical information of 714 elderly ED-visit patients with ADE preventability labels was provided as ground truth data by Jeroen Bosch Ziekenhuis hospital, the Netherlands. Methods were developed to address the challenges of applying feature engineering to heterogeneous EHRs data. A Dual Autoencoders (2AE) model was proposed to solve the problem of imbalance embedded in the existing training data.ResultsExperimental results showed that 2AE can capture the patterns of the minority class without incorporating an extra process for class balancing. 2AE yields adequate performance and outperforms other more mainstream approaches, resulting in an AUPRC score of 0.481.ConclusionsWe have demonstrated how machine learning can be employed to analyze both structured and unstructured data from electronic health records for the purpose of preventable ADE prediction. The developed algorithm 2AE can be used to effectively learn minority group phenotype from imbalanced data.

Background Medication is frequently thrown away after a patient’s discharge from hospital, with undesirable economic and environmental consequences. Because of the rising costs of healthcare, interventions to reduce medication wastage (and associated costs) are warranted. Using Patient’s Own Medication during hospitalisation might decrease medication wastage and associated costs. Objective To study the economic impact of patient’s own medication use on medication waste and hospital staff’s time spent during hospitalisation. Setting In seven Dutch hospitals, of which university, teaching, general, and specialised hospitals, eight different hospital wards, surgical and medical, were selected. Method In this prospective pre-post intervention study data on the economic value of medication waste and time spent by healthcare professionals were collected for a 2 months period each. The economic value of medication waste was defined as the value (€) of wasted medication per 100 patient days. For each ward, time spent on medication process activities was measured 10 times per staff member. The average time spent (in hours) on medication process steps (multiple activities) per staff member per 100 patients and associated salary costs were calculated for both periods. Main outcome measure The primary outcome of the study was the total economic value (€) of wasted medication per 100 patient days. Results Implementation of Patient’s Own Medication decreased the economic value of wasted medication by 39.5% from €3983 to €2411 per 100 patient days. The mean time spent on the total medication process was reduced with 5.2 h per 100 patients (from 112.7 to 104.4 h per 100 patients). We observed a shift in professional activities, as physicians and nurses spent less time on the medication process, whereas pharmacy technicians had a greater role in it. When time spent was expressed as salary; €1219 could be saved per 100 patients. Conclusions This study showed that ‘Patient’s Own Medication' implementation may have a positive economic impact, as the value of medication waste decreases, hospital staff devoted less time on the medication process, and staff deployment is more efficient.

The antipsychotic drug clozapine is associated with weight gain. The proposed mechanisms include blocking of serotonin (5-HT2a/2c ), dopamine (D2 ) and histamine (H1 ) receptors. Clozapine is metabolized by cytochrome P450 1A2 (CYP1A2) to norclozapine, a metabolite with more 5-HT2c -receptor and less H1 blocking capacity. We hypothesized that norclozapine serum levels correlate with body mass index (BMI), waist circumference and other parameters of the metabolic syndrome. We performed a retrospective cross-sectional study in 39 patients (female n = 8 (20.5%), smokers n = 18 (46.2%), average age 45.8 ± 9.9 years) of a clozapine outpatient clinic in the Netherlands between 1 January 2017 and 1 July 2020. Norclozapine concentrations correlated with waist circumference (r = 0.354, P = .03) and hemoglobin A1c (HbA1c) (r = 0.34, P = .03). In smokers (smoking induces CYP1A2), norclozapine concentrations correlated with waist circumference (r = 0.723, P = .001), HbA1c (r = 0.49, P = .04) and BMI (r = 0.63, P = .004). Elucidating the relationship between norclozapine and adverse effects of clozapine use offers perspectives for interventions and treatment options.

De geschatte glomerulaire filtratiesnelheid (eGFR) is een belangrijk onderdeel van medicamenteus therapiemanagement bij patienten met een verminderde nierfunctie. Als de patient met een verminderde nierfunctie een geneesmiddel nodig heeft, kan een niet-renaal uitgescheiden middel een effectief en veiliger alternatief vormen voor een renaal uitgescheiden geneesmiddel. Wanneer toch een renaal uitgescheiden geneesmiddel nodig is, zult u eerst moeten nagaan of de eGFR een realistische weergave is van de nierfunctie. Daarna bepaalt u de dosering van het geneesmiddel in relatie tot: 1) het therapeutisch venster van het geneesmiddel, 2) de snelheid waarmee het doel van de farmacotherapie bereikt dient te worden en 3) de mogelijkheid tot het monitoren van bijwerkingen en de effectiviteit. Deze overwegingen zijn ook van belang bij chronische farmacotherapie, waarbij u de dosering in de loop van de tijd gradueel moet aanpassen aan de afname van de nierfunctie. Bij geneesmiddelen met een smalle therapeutische breedte moet u bij voorkeur een lagere dosering voorschrijven als de indicatie dat toelaat.

Item does not contain fulltext Pemetrexed is a cytostatic antifolate drug and a cornerstone in the treatment of lung cancer. Although generally well tolerated, a substantial part of the patient population experiences dose-limiting or even treatment-limiting toxicities. These include mucositis, skin problems, fatigue, renal toxicity, and neutropenia. Several studies confirmed that pemetrexed pharmacokinetics can serve as a prognostic factor for the development of toxicity, especially for neutropenia. Preventing and managing toxicity of pemetrexed can help to ensure durable treatment. Several evidence-based strategies are already implemented in clinical care. With the introduction of standard vitamin supplementation and dexamethasone, the incidence of hematological toxicity and skin reactions substantially decreased. In the case of high risk for toxicity, granulocyte colony-stimulating factor can be used to prevent severe hematological toxicity. Moreover, high-dose folinic acid can resolve severe pemetrexed-induced toxicity. There are several experimental options to prevent or manage pemetrexed-related toxicity, such as the use of standard folinic acid, hemodialysis, antidotes such as thymidine, hypoxanthine, and glucarpidase, and the use of therapeutic drug monitoring. These strategies still need clinical evaluation before implementation, but could enable treatment with pemetrexed for patients who are at risk for toxicity, such as in renal impairment.

Background Pemetrexed is used for the treatment for non-small cell lung cancer and mesothelioma. Patients with renal impairment are withheld treatment with this drug as it is unknown what dose is well tolerated in this population. Objective The purpose of our study was to investigate the pharmacokinetics (PK) of pemetrexed in patients with renal impairment. Methods A population PK analysis of pemetrexed was performed using non-linear mixed-effects modelling with phase I data obtained from the manufacturer. Additionally, the impact of renal function on pemetrexed PK was assessed with a simulation study using the developed PK model and a previously developed PK model lacking the phase I data. Results The dataset included 548 paired observations of 47 patients, with a wide range of estimated glomerular filtration rates (eGFR; 14.4–145.6 mL/min). Pemetrexed PK were best described by a three-compartment model with eGFR (calculated using the Chronic Kidney Disease–Epidemiology Collaboration [CKD-EPI] formula) as a linear covariate on renal pemetrexed clearance. Using the developed model, we found that renal clearance accounts for up to 84% (95% confidence interval 69–98%) of total pemetrexed clearance, whereas the manufacturer previously reported a 50% contribution of renal clearance. Conclusion Renal function is more important for the clearance of pemetrexed than previously thought and this should be taken into account in patients with renal impairment. Furthermore, a third compartment may contribute to prolonged exposure to pemetrexed during drug washout. Supplementary Information The online version contains supplementary material available at 10.1007/s40262-020-00972-1.

Contains fulltext : 229200.pdf (Publisher’s version ) (Open Access) AIMS: Vancomycin is an important antibiotic for critically ill patients with Gram-positive bacterial infections. Critically ill patients typically have severely altered pathophysiology, which leads to inefficacy or toxicity. Model-informed precision dosing may aid in optimizing the dose, but prospectively validated tools are not available for this drug in these patients. We aimed to prospectively validate a population pharmacokinetic model for purpose model-informed precision dosing of vancomycin in critically ill patients. METHODS: We first performed a systematic evaluation of various models on retrospectively collected pharmacokinetic data in critically ill patients and then selected the best performing model. This model was implemented in the Insight Rx clinical decision support tool and prospectively validated in a multicentre study in critically ill patients. The predictive performance was obtained as mean prediction error and relative root mean squared error. RESULTS: We identified 5 suitable population pharmacokinetic models. The most suitable model was carried forward to a prospective validation. We found in a prospective multicentre study that the selected model could accurately and precisely predict the vancomycin pharmacokinetics based on a previous measurement, with a mean prediction error and relative root mean squared error of respectively 8.84% (95% confidence interval 5.72-11.96%) and 19.8% (95% confidence interval 17.47-22.13%). CONCLUSION: Using a systematic approach, with a retrospective evaluation and prospective verification we showed the suitability of a model to predict vancomycin pharmacokinetics for purposes of model-informed precision dosing in clinical practice. The presented methodology may serve a generic approach for evaluation of pharmacometric models for the use of model-informed precision dosing in the clinic.

The antidepressant nortriptyline is metabolized by cytochrome P450 2D6 (CYP2D6) to the less active and more cardiotoxic drug metabolite, 10-hydroxynortriptyline. High serum levels of this metabolite (>200 μg/L) may lead to withdrawal of nortriptyline therapy. Adding CYP2D6 inhibitors reduce the metabolic activity of CYP2D6 (phenoconversion) and so decrease the forming of hydroxynortriptyline. In this study, 5 mg paroxetine is administered to patients with high hydroxynortriptyline concentrations (>200 μg/L). The shift in number of patients to therapeutic nortriptyline (50-150 μg/L) and safe hydroxynortriptyline (

Purpose The use of estimated glomerular filtration rate (eGFR) in daily clinical practice. Methods eGFR is a key component in drug therapy management (DTM) in patients with renal impairment. eGFR is routinely reported by laboratories whenever a serum creatinine testing is ordered. In this paper, we will discuss how to use eGFR knowing the limitations of serum creatinine-based formulas. Results Before starting a renally excreted drug, an equally effective drug which can be used more safely in patients with renal impairment should be considered. If a renally excreted drug is needed, the reliability of the eGFR should be assessed and when needed, a 24-h urine creatinine clearance collection should be performed. After achieving the best approximation of the true GFR, we suggest a gradual drug dose adaptation according to the renal function. A different approach for drugs with a narrow therapeutic window (NTW) is recommended compared to drugs with a broad therapeutic window. For practical purposes, a therapeutic window of 5 or less was defined as a NTW and a list of NTW drugs is presented. Considerations about the drug dose may be different at the start of the therapy or during the therapy and depending on the indication. Monitoring effectiveness and adverse drug reactions are important, especially for NTW drugs. Dose adjustment should be based on an ongoing assessment of clinical status and risk versus the benefit of the used regimen. Conclusion When determining the most appropriate dosing regimen serum creatinine-based formulas should never be used naively but always in combination with clinical and pharmacological assessment of the individual patient. Electronic supplementary material The online version of this article (doi:10.1007/s00228-016-2113-2) contains supplementary material, which is available to authorized users.

Objective To determine whether advised changes as a result of structured medication reviews in psychogeriatric patients were implemented and if the implemented changes were maintained. Design Prospective cohort study. Setting Three nursing facilities in The Netherlands. Patients, participants Newly admitted psychogeriatric residents. Intervention After admission, a structured medication review was performed by a pharmacist and physician resulting in a treatment plan that was approved by the patient's legal representative and implemented. Main outcome measure(s) The percentage of advised changes approved (= approval rate) and the percentage of implemented medication changes still present 90 days after approval (= 90-day implementation rate). Results A total of 45 patients were included who used a total number of 333 drugs (mean ± standard deviation 7.4 ± 3.3 drugs). Changes were advised to 159 medications used by 42 patients. Of these changes, 150 were approved (approval rate 94.3%). Finally, 105 were implemented, and 89 were still implemented after 90 days (90-day implementation rate 84.8%). Overall, 59.7% of the advised changes concerned deprescribing (stopping or dose reduction). The proportion of advised changes implemented was similar for symptommodifying and risk-modifying drugs, namely, almost 85%. Overall, 55.3% of the recommended changes to deprescribe concerned 10 drug groups. Conclusion Medication could be successfully deprescribed from psychogeriatric patients after structured medication reviews performed by pharmacists and nursing facility physicians. More than 50% of the advised changes to deprescribe involved 10 drug groups, which raises the question whether the structured medication review can be performed more efficiently by focusing on the most common problems.

Objectives To improve the current standalone pharmacy clinical decision support system (CDSS) by identifying and quantifying the benefits and limitations of the system. Methods Alerts and handling of the executed clinical rules were extracted from the CDSS from the period September 2011 to December 2011. The number of executed clinical rule alerts, number of actions on alerts, and the reason why alerts were classified as not relevant were analyzed. The alerts where considered clinically relevant when the pharmacist needed to contact the physician. Results The 4065 alerts have been separated into: 1137 (28.0%) new alerts, 2797 (68.8%) repeat alerts and 131 (3.2%) double alerts. When the alerts were analyzed, only 3.6% were considered clinically relevant. Reasons why alerts were considered as not to be relevant were: (a) the dosage was correct or already adjusted, (b) the drug was (temporarily) stopped and (c) the monitored laboratory value or drug dosage had already reverted to be within the reference limits. The reasons for no action were linked to three categorical limitations of the used system: ‘algorithm alert criteria’, ‘CDSS optimization’, and ‘data delivery’. Conclusion This study highlighted a number of ways in which the CDSS could be improved. These different aspects have been identified as important for developing an efficient CDSS.

In this report we describe a 53-year-old woman with advanced non-small cell lung cancer, treated with pemetrexed and cisplatin combination therapy, followed by pemetrexed monotherapy. The patient developed severe muscle spasms at least twice, shortly after administration of pemetrexed monotherapy. A possible explanation for this observation is that in combination with cisplatin therapy, the patient was hyperhydrated before administration to promote renal excretion and reduce toxicity. Pemetrexed is also renally excreted, which supports the finding that toxicity did not occur when the patient was hyperhydrated. After discontinuation of pemetrexed the symptoms did not reoccur. All aspects of this case point to a possible relationship between pemetrexed and an adverse drug reaction (ADR). We conclude that muscle spasms are a rare, but possibly dose-related ADR of pemetrexed-based therapy.

SUMMARY Purpose Hypoglycaemia is a limiting factor for glycaemic management of diabetes with intensive insulin and/or oralantidiabetic drug (OAD) regimen. Case reports suggest that antidepressants may interferewithblood glucose metabolism inpatients with diabetes mellitus potentially increasing the risk of clinically relevant hypoglycaemia. Comorbid depressiontreatedwithantidepressantscouldthereforefurthercomplicateglycaemiccontrol.Wehavecarriedoutanestedcase–controlstudy among diabetic patients to assess the risk of hypoglycaemia requiring hospitalisation associated with the use ofantidepressants.Methods Diabetic patients treated with insulin and/or OADs were selected from the Dutch Pharmo system. Exposure toantidepressants was the primary determinant investigated. Use of antidepressants was further subclassified based on thereceptor binding profile to investigate whether specific pharmacological properties could explain a potential influence onglucose homeostasis. Conditional logistic regression was used to estimate odds ratios and to adjust for confounding factors.Results Fromthebasecohort(40600patients),549(1.35%)caseswereidentifiedand1897controlswereselected.Currentuseofanyantidepressantwasnotassociatedwithasignificantlyhigherriskofhypoglycaemiarequiringhospitalisation(OR:1.36(95%CI:0.84–2.20)).Atrendforahigherriskonhypoglycaemiawasidentifiedforantidepressantswithhighaffinityforthe serotonin reuptake transporter. The risk on severe hypoglycaemia was increased after 3 years of use (OR: 2.75 (95%CI:1.31–5.77)).Conclusions Itisimportantfordiabeticpatientsusingantidepressantsformorethan3yearstopayattentionforsymptomsof hypoglycaemia and strict blood glucose self-monitoring. Copyright # 2008 John Wiley & Sons, Ltd.key words—antidepressive agents; diabetes mellitus; hypoglycaemia; adverse drug reactions; drug safetyReceived 19 May 2007; Accepted 7 January 2008

Purpose Anecdotal evidence suggests that antidepressants (ADs) may complicate glycaemic control. The objective of this longitudinal study was to investigate the influence of ADs on glycaemic control within diabetes patients. Methods From the pharmacy registry database PHARMO, we selected insulin users who did not use oral antidiabetics. The study population comprised: 133 patients with at least 12 months insulin use before and 6 months during an AD episode, including 56 patients with an additional 6 months of insulin use after the AD episode; 180 patients with 24 months insulin use without an AD episode. Glycaemic control was measured as the amount of insulin used, which was calculated intra-individually in 3-month periods. We stratified for selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs). Results Mean age (s.d.) of the subjects was 53.9 (19) years; 46.9% were men. Overall, the amount of insulin used did not change during or after AD use. No-AD users showed an increase of 16% in amount of insulin used over a period of 2 years (p

Objectives Depression is common in patients with diabetes, and the use of antidepressants may impair glycaemic control. We assessed the association between antidepressant use and hyper- and hypoglycaemia. Methods Based on spontaneous reports listed in the World Health Organization (WHO) Adverse Drug Reaction Database, a case-control study was conducted. The study base consisted of all adverse drug reactions (ADRs) ascribed to antidepressants, antipsychotics and benzodiazepines between 1969 and 2005. Cases were defined as reported ADRs classified as hyper- or hypoglycaemia and separated in different study populations. All other reports were considered as controls. Exposure to antidepressants was the primary determinant investigated. Benzodiazepines and antipsychotics were chosen as reference groups. Potential confounding factors, namely, age, gender, use of antidiabetic medication, use of hyper- or hypoglycaemia-inducing comedication and reporting year, were determined on the index date. Multivariate logistic regression was used to evaluate the strength of the association, which was expressed as reporting odds ratios (RORs) with 95% confidence intervals (95% CI). Results Overall, the use of antidepressants was associated with hyperglycaemia [ROR 1.52 (95% CI: 1.20–1.93)] and of hypoglycaemia [ROR 1.84 (95% CI: 1.40–2.42)]. The association with hyperglycaemia was most pronounced for antidepressants with affinity for the 5-HT2c receptor, histamine-1 receptor and norepinephrinic (NE) reuptake transporter. The association with hypoglycaemia was most pronounced for antidepressants with affinity for the serotonin reuptake transporter. Conclusion The results of this study strengthen the findings in individual case reports that the use of antidepressants is associated with disturbances in glucose homeostasis.

Contains fulltext : 155294.pdf (Publisher’s version ) (Open Access) BACKGROUND: Chronic kidney disease (CKD) is associated with an increased mortality rate, risk of cardiovascular events and morbidity. Impaired renal function is common in elderly patients, and their glomerular filtration rate (GFR) should be taken into account when prescribing renally excreted drugs. In a hospital care setting the GFR may fluctuate substantially, so that the renal function group and therefore the recommended dose, can change within a few days. The magnitude and prevalence of the fluctuation of renal function in daily clinical practice and its potential effects on appropriateness of drug prescriptions after discharge from the hospital is unknown. METHODS/DESIGN: This is a prospective observational study. Patients >/= 70 years with renal impairment (eGFR < 60 ml/min/1.73 m(2)) admitted to a geriatric ward are eligible to participate. Participants undergo blood sample collection to measure serum creatinine level at three time points: at discharge from hospital, 14 days, and 2 months after discharge. At these time points the actual medication of the participants is assessed and the number of incorrect prescriptions according to the Dutch guidelines in relation to their estimated renal function is measured. In addition, for a hypothetical selection of drugs, the need for drug dose adaptation in relation to renal function is measured. The outcome of interest is the percentage of patients that changes from renal function group after discharge from hospital compared to the renal function at discharge. In addition, the percentages of patients whose actual medications are incorrectly prescribed and for the hypothetical selection of drugs that would have required dose adaptation will be determined at discharge, 14 days and 2 months after discharge. For each outcome, risk factors which may lead to increased risk for fluctuation of renal function and/or incorrect drug prescribing will also be identified and analysed. DISCUSSION: This study will provide data on changes in renal function in elderly patients after discharge from the hospital with a focus on the medications used. The benefits for healthcare professionals comprise of the creation, adjustment or confirmation of recommendations for the monitoring of the renal function after discharge from hospital of elderly patients.

Contains fulltext : 153158.pdf (Publisher’s version ) (Open Access) BACKGROUND: The Modification of Diet in Renal Disease (MDRD) formula is widely used in clinical practice to assess the correct drug dose. This formula is based on serum creatinine levels which might be influenced by chronic diseases itself or the effects of the chronic diseases. We conducted a systematic review to determine the validity of the MDRD formula in specific patient populations with renal impairment: elderly, hospitalized and obese patients, patients with cardiovascular disease, cancer, chronic respiratory diseases, diabetes mellitus, liver cirrhosis and human immunodeficiency virus. METHODS AND FINDINGS: We searched for articles in Pubmed published from January 1999 through January 2014. Selection criteria were (1) patients with a glomerular filtration rate (GFR) < 60 ml/min (/1.73m2), (2) MDRD formula compared with a gold standard and (3) statistical analysis focused on bias, precision and/or accuracy. Data extraction was done by the first author and checked by a second author. A bias of 20% or less, a precision of 30% or less and an accuracy expressed as P30% of 80% or higher were indicators of the validity of the MDRD formula. In total we included 27 studies. The number of patients included ranged from 8 to 1831. The gold standard and measurement method used varied across the studies. For none of the specific patient populations the studies provided sufficient evidence of validity of the MDRD formula regarding the three parameters. For patients with diabetes mellitus and liver cirrhosis, hospitalized patients and elderly with moderate to severe renal impairment we concluded that the MDRD formula is not valid. Limitations of the review are the lack of considering the method of measuring serum creatinine levels and the type of gold standard used. CONCLUSION: In several specific patient populations with renal impairment the use of the MDRD formula is not valid or has uncertain validity.

Item does not contain fulltext RATIONALE, AIMS AND OBJECTIVES: Renal dysfunction is highly prevalent in HIV-infected patients and may require dose adjustment of renally excreted antiretroviral drugs. The Modification of Diet in Renal Disease (MDRD)-4 formula is frequently used in daily practice to estimate patients' renal function. The aim of this systematic review was to assess the validity of the MDRD-4 formula in HIV-infected patients. METHOD: A systematic search in Pubmed and EMBASE was done to identify studies which compared MDRD-4 with measured glomerular filtration rate (mGFR) in HIV-infected patients. RESULTS: Five studies were included, which provided data from 464 HIV-infected patients with mean mGFR ranging from 87 to 118 ml/min/1.73 m(2). In all studies, results from the MDRD-4 gave an underestimation of the mGFR. Mean bias ((MDRD-4) - mGFR) ranged from -6 to -11 ml/min/1.73 m(2) across studies. The accuracy expressed in terms of P 30 ranged from 64 to 89 %. CONCLUSIONS: The MDRD-4 formula is as valid in HIV-positive as in HIV-negative patients. Because the available studies comprised mainly HIV-infected patients with mildly impaired to good renal function (GFR >/= 60 ml/min/1.73 m(2)), more research is needed to validate the MDRD-4 formula in HIV-infected patients with moderate to severe renal impairment.

Item does not contain fulltext OBJECTIVE To compare the clinical relevance of medication alerts in a basic and in an advanced clinical decision support system (CDSS). DESIGN: A prospective observational study. MATERIALS AND METHODS: We collected 4023 medication orders in a hospital for independent evaluation in two pharmacotherapy-related decision support systems. Only the more advanced system considered patient characteristics and laboratory test results in its algorithms. Two pharmacists assessed the clinical relevance of the medication alerts produced. The alert was considered relevant if the pharmacist would undertake action (eg, contact the physician or the nurse). The primary analysis concerned the positive predictive value (PPV) for clinically relevant medication alerts in both systems. RESULTS: The PPV was significantly higher in the advanced system (5.8% vs 17.0%; p

Drug effects are not solely determined by the pharmacological properties of the active substance, but also depend heavily on the way it is used in practice by health professionals and patients. Non-adherence to instructions for use seems to have contributed to the withdrawal of drugs such as troglitazon, mibefradil, and most recently cerivastatin [1–3]. Hepatotoxicity andmyopathy are two rare but serious side-effects of statins. Myopathy can lead to a life threatening rhabdomyolysis. Product labelling of statins advises to monitor hepatic function and creatinine kinase (CK) concentrations (especially in patients who are experiencing muscle pain), because this may prevent progress of these drug-induced complications. The objective of the present study was to estimate the incidence of CK and hepatic function measurements in a cohort of patients starting with a statin, and to evaluate whether this was influenced by the withdrawal of cerivastatin. From eight community pharmacies located in Tilburg, the Netherlands and surroundings, patients starting with a statin during the period December 2000–April 2001 (period 1), or during the period August 8, 2001–October 2001(period 2) were selected. Period 2 was chosen after the withdrawal of cerivastatin. Date of filling the prescription was the index date. Age, gender, statin, prescribed dosage, and relevant concomitant drug use were obtained for all patients. From the regional clinical chemistry laboratory, which performs measurements for in-as well as outpatients, the number of hepatic function and CK measurements was determined during a 3 month follow-up period after the index date. Five hundred and thirty patients were included. Any clinical chemistry measurement during follow-up was performed in54.2% (287) of all patients; CK levels were checked in 13.0% (69) of the patients while hepatic functiontests were performed in 22.3% (118) of all patients. There was no difference in these frequencies before, and after the withdrawal of cerivastatin (Table 1). Table 1 Incidence of CK, hepatic function or any clinical chemistry measurement during 3 months of follow-up Gender, age, standardized dosage, interacting concomitant drug use, and CK-inducing concomitant drug use did not cause significant deviations of these outcomes. Only 5.3% (1) of the patients starting with cerivastatin was checked for CK compared with 13.3% (68) of the patients using other statins (RR 0.40 (95% CI 0.06, 2.70)). In contrast, any clinical chemistry measurement and hepatic function were determined more frequently in cerivastatin starters compared with other statin starters: RR 1.48 (95% CI 1.16, 1.90) respectively RR 3.04 (95% CI 2.08, 4.47). This study shows that, in daily medical practice, adherence to drug prescribing guidelines to perform clinical chemistry measurements is limited. The withdrawal of cerivastatin has not led to an increase in hepatic function-and CK measurements. Cerivastatin was taken off the market because available evidence (mainly case reports) suggested a higher frequency of serious side-effects in comparison with other statins [4]. It is remarkable that CK was less frequently checked in patients using cerivastatin while hepatic function was more frequently measured in this study. It is important to recognize that the population was limited to 530 patients with only 19 starters of cerivastatin. The strength of this study was the conductance in daily practice. The risk of losing patients during follow-up was minimized because in The Netherlands outpatients usually visit the same pharmacy [5], and all clinical chemistry testing was concentrated in one laboratory. Overall it is important to realize that a drug is not a chemical entity alone but comes along with instructions for patients and prescribers in order to optimize the benefit-harm balance. Strategies for adherence to such instructions should be developed and implemented.