DosEmi study protocol: a phase IV, multicentre, open-label, crossover study to evaluate non-inferiority of pharmacokinetic-guided reduced dosing compared with conventional dosing of emicizumab in people with haemophilia A.

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 REGISTRATION NUMBER: EUCTR2021-004039-10-NL at https://trialsearch.who.int. PROTOCOL VERSION: V.4.1 on 28 October 2022 (DosEmi protocol_V4.1; NL81112.041.22).

Influence of allopurinol on thiopurine associated toxicity: A retrospective population-based cohort study.

AIMS: Thiopurines are important for treating inflammatory bowel disease, but are often discontinued due to adverse effects. Concomitant use of allopurinol might lower the risk of these unwanted effects, but large studies in the general population are lacking. The aims of this study were to evaluate rates of hepatotoxicity, myelotoxicity, pancreas toxicity and therapy persistence in adult thiopurine users with or without allopurinol. METHODS: A retrospective population-based cohort study was conducted within current thiopurine users (Clinical Practice Research Datalink). Among these patients, co-use of allopurinol was compared to non-use. Hazard ratios (HRs) for hepatotoxicity, myelotoxicity and pancreatitis were derived using time-dependent Cox proportional hazards models, and were adjusted for potential confounders. Persistence of thiopurine use was evaluated using Log-rank statistics. RESULTS: Patients using thiopurines (n = 37 360) were identified of which 1077 were concomitantly taking allopurinol. A 58% decreased risk of hepatotoxicity was observed in those concomitantly taking allopurinol (HR 0.42; 95% CI 0.30-0.60; NNT 46). Rate of myelotoxicity (HR 0.96; 95% CI 0.89-1.03) was not influenced. Risk of pancreatitis was increased (HR 3.00; 95% CI 1.01-8.93; NNH 337), but was only seen in those with active gout (suggesting confounding by indication). Finally, allopurinol co-users were able to maintain thiopurine therapy over twice as long as those not on allopurinol (3.9 years vs. 1.8 years, P < 0.0001). CONCLUSION: In thiopurine users, allopurinol is associated with a 58% reduced risk of hepatotoxicity. In addition, thiopurine persistence was prolonged by 2.1 years in allopurinol users. These data support the use of allopurinol in individuals requiring thiopurine therapy.

A semi-mechanistic model based on glutathione depletion to describe intra-individual reduction in busulfan clearance.

AIM: To develop a semi-mechanistic model, based on glutathione depletion and predict a previously identified intra-individual reduction in busulfan clearance to aid in more precise dosing. METHODS: Busulfan concentration data, measured as part of regular care for allogeneic hematopoietic cell transplantation (HCT) patients, were used to develop a semi-mechanistic model and compare it to a previously developed empirical model. The latter included an empirically estimated time effect, where the semi-mechanistic model included theoretical glutathione depletion. As older age has been related to lower glutathione levels, this was tested as a covariate in the semi-mechanistic model. Lastly, a therapeutic drug monitoring (TDM) simulation was performed comparing the two models in target attainment. RESULTS: In both models, a similar clearance decrease of 7% (range -82% to 44%), with a proportionality to busulfan metabolism, was found. After 40 years of age, the time effect increased with 4% per year of age (0.6-8%, P = 0.009), causing the effect to increase more than a 2-fold over the observed age-range (0-73 years). Compared to the empirical model, the final semi-mechanistic model increased target attainment from 74% to 76%, mainly through better predictions for adult patients. CONCLUSION: These results suggest that the time-dependent decrease in busulfan clearance may be related to gluthathione depletion. This effect increased with older age (>40 years) and was proportional to busulfan metabolism. The newly constructed semi-mechanistic model could be used to further improve TDM-guided exposure target attainment of busulfan in patients undergoing HCT.

What does it cost to redispense unused medications in the pharmacy? A micro-costing study.

BACKGROUND: Redispensing unused medications that have been returned to outpatient pharmacies by patients may reduce waste and healthcare costs. However, little is known regarding the extra costs associated with this process, nor the price level of medications for which this is economically beneficial. The objective of this study was to assess costs associated with redispensing unused medications in the pharmacy and the price level at which redispensing becomes cost-beneficial. METHODS: A micro-costing study was conducted in four Dutch outpatient pharmacies for medications requiring room-temperature storage and requiring refrigeration. First, the pharmacy's necessary additional process steps and resources for redispensing were identified. Second, time required for each process step was simulated. Third, required resources were quantified by calculating labour, purchasing and overhead costs. Lastly, a model with different scenarios was constructed to calculate the price of a medication package at which redispensing becomes cost-beneficial. RESULTS: Three main additional process steps for redispensing were identified: (1) pack medications with product quality indicators before dispensing, (2) assess quality of medications returned to the pharmacy (temperature storage, package integrity, expiry date) and (3a) restock medications fulfilling quality criteria or (3b) dispose of medications not fulfilling criteria. Total time required for all steps up to restock one medication package was on average 5.3 (SD ±0.3) and 6.8 (SD ±0.3) minutes for medications stored at room-temperature and under refrigeration, respectively, and associated costs were €5.54 and €7.61. Similar outcomes were found if a medication package would ultimately be disposed of. The price level primarily depended upon the proportion of dispensed packages returned unused to the pharmacy and fulfilling the quality criteria: if 5% is returned, of which 60% fulfils quality criteria, the price level was €101 per package for medications requiring room-temperature storage and €215 per package for those requiring refrigeration. However, if 10% is returned, of which 60% fulfils the quality criteria, the price level decreases to €53 and €109, respectively (arbitrary proportions). CONCLUSIONS: Redispensing unused medications in the pharmacy is at least cost-beneficial if applied to expensive medications.

Pharmacists' Activities to Reduce Medication Waste: An International Survey.

Aim: To identify activities that pharmacists undertake to reduce medication waste, and to assess the extent to which these activities are implemented, their importance for waste-reduction and feasibility for broad implementation. Methods: A two-phase survey was conducted among community and hospital pharmacists working in different developed countries. Phase one used an open-ended questionnaire to identify activities undertaken by pharmacists. Answers were thematically analysed to construct a list of medication waste-reducing activities. In phase two, a questionnaire was disseminated among pharmacists from different countries, to assess if these activities are implemented (yes/no), their importance and feasibility (1 to 5 ranking scale). Results: In phase one, 53 pharmacists participated and 14 activities were identified. These were categorized into the pharmaceutical supply chain: prescribing, dispensing (pharmacy/patient-related) and leftover stage. In phase two, 89 pharmacists participated. Most activities were implemented by a minority of pharmacists. Reducing medication amounts in stock was most frequently implemented (dispensing stage pharmacy-related; 86%), followed by collecting unused medications (leftover stage; 77%) and performing a medication review (dispensing stage; 68%). Waste-reducing activities in the dispensing stage activities were both considered most important and feasible (ranked 4). Overall, most activities scored higher on importance than on feasibility. Conclusions: Pharmacists have various opportunities to reduce medication waste throughout the pharmaceutical supply chain, however, not all are broadly implemented. Pharmacists consider waste-reducing activities important, but they are less certain about the feasibility for implementation in practice.

Association of busulfan exposure with survival and toxicity after haemopoietic cell transplantation in children and young adults: a multicentre, retrospective cohort analysis.

BACKGROUND: Intravenous busulfan combined with therapeutic drug monitoring to guide dosing improves outcomes after allogeneic haemopoietic cell transplantation (HCT). The best method to estimate busulfan exposure and optimum exposure in children or young adults remains unclear. We therefore assessed three approaches to estimate intravenous busulfan exposure (expressed as cumulative area under the curve [AUC]) and associated busulfan AUC with clinical outcomes in children or young adults undergoing allogeneic HCT. METHODS: In this retrospective analysis, patients from 15 centres in the Netherlands, USA, Canada, Switzerland, UK, Italy, Germany, and Australia who received a busulfan-based conditioning regimen between March 18, 2001, and Feb 12, 2015, were included. Cumulative AUC was calculated by numerical integration using non-linear mixed effect modelling (AUCNONMEM), non-compartmental analysis (AUC from 0 to infinity [AUC0-∞] and to the next dose [AUC0-τ]), and by individual centres using various approaches (AUCcentre). The main outcome of interest was event-free survival. Other outcomes of interest were graft failure or relapse, or both; transplantation-related mortality; acute toxicity (veno-occlusive disease or acute graft versus-host disease [GvHD]); chronic GvHD; overall survival; and chronic-GvHD-free event-free survival. We used propensity-score-adjusted Cox proportional hazard models, Weibull models, and Fine-Gray competing risk regressions for statistical analyses. FINDINGS: 790 patients were enrolled, 674 of whom were included: 274 (41%) with malignant and 400 (59%) with non-malignant disease. Median age was 4·5 years (IQR 1·4-10·7). The median busulfan AUCNONMEM was 74·4 mg × h/L (95% CI 31·1-104·6), which correlated with the standardised method AUC0-∞ (r2=0·74), but the latter correlated poorly with AUCcentre (r2=0·35). Estimated 2-year event-free survival was 69·7% (95% CI 66·2-73·0). Event-free survival at 2 years was 77·0% (95% CI 72·1-82·9) in the 257 patients with an optimum intravenous busulfan AUC of 78-101 mg × h/L compared with 66·1% (60·9-71·4) in the 235 patients at the low historical target of 58-86 mg × h/L and 49·5% (29·2-66·0) in the 44 patients with a high (>101 mg × h/L) busulfan AUC (p=0·011). Compared with the low AUC group, graft failure or relapse occurred less frequently in the optimum AUC group (hazard ratio [HR] 0·57, 95% CI 0·39-0·84; p=0·0041). Acute toxicity (HR 1·69, 1·12-2·57; p=0·013) and transplantation-related mortality (2·99, 1·82-4·92; p<0·0001) were significantly higher in the high AUC group (>101 mg × h/L) than in the low AUC group (<78 mg × h/L), independent of indication; no difference was noted between AUC groups for chronic GvHD (<78 mg × h/L vs ≥78 mg × h/L, HR 1·30, 95% CI 0·73-2·33; p=0·37). INTERPRETATION: Improved clinical outcomes are likely to be achieved by targeting the busulfan AUC to 78-101 mg × h/L using a new validated pharmacokinetic model for all indications. FUNDING: Research Allocation Program and the UCSF Helen Friller Family Comprehensive Cancer Center and the Mt Zion Health Fund of the University of California, San Francisco.

Associations Between Personality Traits and Adherence to Antidepressants Assessed Through Self-Report, Electronic Monitoring, and Pharmacy Dispensing Data: A Pilot Study.

Treatment with antidepressants is often compromised by substantial nonadherence. To understand nonadherence, specific medication-related behaviors and beliefs have been studied, but less is known about broader and temporally stable personality "traits." Furthermore, adherence has often been assessed by a single method. Hence, we investigated associations between the Big Five personality traits and adherence assessed by self-report, electronic drug use monitoring, and dispensing data. Using the Big Five Inventory, we assessed the personality traits "openness," "conscientiousness," "extraversion," "agreeableness," and "neuroticism" of patients treated with antidepressants who were invited through community pharmacies. Self-reported adherence was assessed with the Medication Adherence Rating Scale (score >24), electronic monitoring with medication event monitoring system (MEMS) devices (therapy days missed ≤ 10% and < 4 consecutive days missed), and dispensing data (medication possession ratio ≥ 80%). One hundred four women and 33 men participated (mean age, 51; standard deviation, 14). Paroxetine was most frequently prescribed (N = 53, 38%). Logistic regression analysis revealed that of the personality traits, the third and fourth quartiles of "conscientiousness" were associated with better self-reported adherence (odds ratio, 3.63; 95% confidence interval, 1.34-9.86 and odds ratio, 2.97; 95% confidence interval, 1.09-8.08; P ≤ 0.05). No relationships were found between personality traits and adherence assessed through electronic drug use monitoring or dispensing data. We therefore conclude that adherence to antidepressant therapy seems to be largely unrelated to personality traits.

Risk of Hospitalization for Hypoglycemia in Older Patients with Diabetes Using Antipsychotic Drugs.

OBJECTIVE: Antipsychotics may disrupt metabolic regulation in patients with diabetes mellitus. The risk of hypoglycemia in older users of antipsychotics with diabetes is largely unknown. Therefore, we investigated the association between the use of antipsychotic drugs and hypoglycemia requiring hospital admission in older patients with diabetes. METHODS: In a nested case-control study using community pharmacy records linked to hospital admission data in the Netherlands (1998-2008), a cohort of 68,314 patients at least 65 years with diabetes was studied. Cases were patients from the study cohort with a first hospital admission for hypoglycemia; up to five comparison subjects were selected for each case. Exposure to antipsychotic drugs was the primary determinant of interest. Logistic regression analysis was performed to estimate the strength of the association between antipsychotic drug use and hypoglycemia, taking into account potential confounders. RESULTS: Eight hundred fifteen patients were admitted to hospital for hypoglycemia. Current use of antipsychotic drugs was associated with an increased risk of hypoglycemia compared with non-use (adjusted OR: 2.26; 95% CI: 1.45-3.52; Wald χ(2) = 13.08, df = 1, p ≤0.001), especially in the first 30 days of treatment (adjusted OR: 7.65; 95% CI: 2.50-23.41; Wald χ(2) = 12.72, df = 1, p ≤0.001) and with higher doses (adjusted OR: 8.20; 95% CI: 3.09-21.75; Wald χ(2) = 17.90, df = 1, p ≤0.001). CONCLUSION: Use of antipsychotic drugs by older patients with diabetes mellitus was associated with an increased risk of hospitalization for hypoglycemia. Our findings suggest that glucose levels should be monitored closely after initiation of antipsychotic drugs.

Completeness of patient records in community pharmacies post-discharge after in-patient medication reconciliation: a before-after study.

BACKGROUND: Transfer of discharge medication related information to community pharmacies could improve continuity of care. This requires for community pharmacies to accurately update their patient records when new information is transferred. An instruction manual that specifies how to document information regarding medication changes and clinical information (i.e. allergies/contraindications) could support community pharmacies. OBJECTIVE: To explore the effect of instruction manuals sent to community pharmacies on completeness of their patient records. SETTING: A before-after study was performed (July 2009-August 2010) in the St Lucas Andreas Hospital, a general teaching hospital in Amsterdam, The Netherlands. METHODS: Patients discharged from the cardiology and respiratory ward were included consecutively. The intervention consisted of a training session for community pharmacies regarding documentation problems and faxing an instruction manual to community pharmacies specifying how to document discharge information in their information system. Usual care consisted of faxing a discharge medication overview to community pharmacies without additional instructions. Two weeks after discharge the medication records of community pharmacies were collected by fax. These were compared with the initial discharge overviews regarding completeness of medication changes (i.e. explicit explanation that medication had been changed) and clinical information documentation. MAIN OUTCOME MEASURE OUTCOMES: were the number and percentage of completely documented medication changes (either needing to be dispensed or not) and clinical information items. The sample size was calculated at 107 patients per measurement period. Multivariable logistic regression was used for analysis. RESULTS: Two hundred and eighteen patients (112 before-106 after) were included. Completeness of medication changes documentation increased marginally after the intervention (46.6 vs 56.3 %, adjusted Odds Ratio 1.4 [95 % confidence interval 1.07-1.83]). Documentation increased when medication was actually dispensed by the community pharmacy. No significant improvements were seen for allergy and contraindication documentation. CONCLUSION: The intervention is insufficient to increase the completeness of documentation by community pharmacies as marginal improvements were achieved. Future studies should evaluate whether electronic infrastructures may help in achieving updated medication records to improve continuity of pharmaceutical care.

Variability between nursing homes in prevalence of antipsychotic use in patients with dementia.

BACKGROUND: Antipsychotic drugs (APD) are widely prescribed for people with dementia residing in long term care facilities (LTCFs). Concern has been expressed that such prescribing is largely inappropriate. The objective of this study is to examine if differences in facility-level prevalence of APD use in a sample of LTCFs for patients with dementia can be explained by patient and facility-related characteristics. METHODS: A point prevalence study was conducted using data from the VU University Resident Assessment Instrument (VURAI) database from nursing homes and residential care facilities in the Netherlands. Patients were selected who had a diagnosis of dementia. LTCF and patient characteristics were extracted from the VURAI; facility-level resident satisfaction surveys were provided by the National Institute for Public Health. RESULTS: In total, 20 LTCFs providing care for 1,090 patients with dementia were investigated. Overall, 31% of patients used an APD. In facilities with a high prevalence of APD use behavioral symptoms were present in 62% of their patients. In facilities with medium APD use behavioral problems remained frequent (57%), and in facilities with low prevalence of APD use 54% of the patients had behavioral symptoms. Facilities with a high prevalence of APD use were often large, situated in urban communities, and scored below average on staffing, personal care, and recreational activities. CONCLUSIONS: There was considerable variation between the participating LTCFs in the prevalence of APD use. Variability was related to LTCF characteristics and patient satisfaction. This indicates potential inappropriate prescribing because of differences in institutional prescribing culture.

Bridging differences in outcomes of pharmacoepidemiological studies: design and first results of the PROTECT project.

BACKGROUND: Observational pharmacoepidemiological (PE) studies on drug safety have produced discrepant results that may be due to differences in design, conduct and analysis. PURPOSE: The pharmacoepidemiology work-package (WP2) of the Pharmacoepidemiological Research on Outcomes of Therapeutics by a European ConsorTium (PROTECT) project aims at developing, testing and disseminating methodological standards for design, conduct and analysis of pharmacoepidemiological studies applicable to different safety issues using different databases across European countries. This article describes the selection of the safety issues and the description of the databases to be systematically studied. METHODS: Based on two consensus meetings and a literature search, we selected five drug-adverse event (AE) pairs to be evaluated in different databases. This selection was done according to pre-defined criteria such as regulatory and public health impact, and the potential to investigate a broad range of methodological issues. RESULTS: The selected drug-AE pairs are: 1) inhaled long-acting beta-2 agonists and acute myocardial infarction; 2) antimicrobials and acute liver injury; 3) antidepressants and/or benzodiazepines and hip fracture; 4) anticonvulsants and suicide/suicide attempts; and 5) calcium channel blockers and malignancies. Six European databases, that will be used to evaluate the drug-AE pairs retrospectively, are also described. CONCLUSION: The selected drug-AE pairs will be evaluated in PE studies using common protocols. Based on consistencies and discrepancies of these studies, a framework for guiding methodological choices will be developed. This will increase the usefulness and reliability of PE studies for benefit-risk assessment and decision-making.

The association between CYP2D6 genotype and switching antipsychotic medication to clozapine.

PURPOSE: Genetic variation in the cytochrome P450 2D6 (CYP2D6) enzyme is responsible for interindividual differences in the metabolism of many antipsychotic drugs, but the clinical relevance of polymorphisms in CYP2D6 for response to antipsychotic treatment is relatively unknown. In the Netherlands, clozapine is prescribed only when patients are non-responsive to or intolerant of at least two different antipsychotics. The aim of our study was to determine the association of the CYP2D6 genotype with switching to clozapine, which served as a surrogate outcome marker for treatment response to antipsychotics. METHODS: CYP2D6 genotype was assessed in patients who had been switched to clozapine and compared with antipsychotic users whose treatment regimen included no more than two different antipsychotic drugs and no clozapine. We also performed the analysis in patients who only used CYP2D6-dependent antipsychotics. RESULTS: A total of 528 patients were included in the study (222 cases, 306 controls). No statistically significant differences were found in the distribution of the polymorphisms among the case and control groups, both in all patients and in only those patients using CYP2D6-dependent antipsychotics. However, a trend was observed, suggesting an inverse association between CYP2D6 genotype and the switch to clozapine. (9.5 vs. 5.1 % poor metabolisers and 1.3 vs. 2.6 % ultrarapid metabolisers in cases vs. controls, respectively). CONCLUSIONS: Although the results of our study suggest that the CYP2D6 phenotype is not a major determining factor for patients to be switched to clozapine treatment, larger studies are warranted with a focus on the clinical consequences of the CYP2D6 ultrarapid metaboliser and poor metaboliser phenotypes.

Anticonvulsant treatment of asphyxiated newborns under hypothermia with lidocaine: efficacy, safety and dosing.

BACKGROUND: Lidocaine is an antiarrythmicum used as an anticonvulsant for neonatal seizures, also during therapeutic hypothermia following (perinatal) asphyxia. Hypothermia may affect the efficacy, safety and dosing of lidocaine in these patients. OBJECTIVE: To study the efficacy and safety of lidocaine in newborns with perinatal asphyxia during moderate hypothermia, and to develop an effective and safe dosing regimen. METHODS: Hypothermic newborns with perinatal asphyxia and lidocaine for seizure control were included. Efficacy was studied using continuous amplitude-integrated electroencephalography. Safety was assessed using continuous cardiac monitoring. An optimal dosing regimen was developed with simulations using data from a pharmacokinetic model. Plasma samples were collected during hypothermia on consecutive mornings. RESULTS: A total of 22 hypothermic and 26 historical normothermic asphyxiated newborns with lidocaine were included. A response of 91% on epileptiform activity on the amplitude-integrated EEG was observed for lidocaine add-on therapy. No relationship between lidocaine or MEGX plasma concentrations and heart frequency could be identified. None of the newborns experienced cardiac arrythmias. Hypothermia reduced lidocaine clearance by 24% compared with normothermia. A novel dosing regimen was developed an initial bolus loading dose of 2 mg/kg, for patients with body weight 2.0-2.5 kg followed by consecutive continuous infusions of 6 mg/kg/h (for 3.5 h), 3 mg/kg/h (for 12 h), 1.5 mg/kg/h (for 12 h), or for patients with body weights 2.5-4.5 kg 7 mg/kg/h (for 3.5 h), 3.5 mg/kg/h (for 12 h), 1.75 mg/kg/h (for 12 h), before stopping. CONCLUSIONS: Lidocaine can be assumed to be an effective antiepileptic drug during hypothermia in asphyxiated neonates.

Body weight-dependent pharmacokinetics of busulfan in paediatric haematopoietic stem cell transplantation patients: towards individualized dosing.

BACKGROUND AND OBJECTIVES: The wide variability in pharmacokinetics of busulfan in children is one factor influencing outcomes such as toxicity and event-free survival. A meta-analysis was conducted to describe the pharmacokinetics of busulfan in patients from 0.1 to 26 years of age, elucidate patient characteristics that explain the variability in exposure between patients and optimize dosing accordingly. PATIENTS AND METHODS: Data were collected from 245 consecutive patients (from 3 to 100 kg) who underwent haematopoietic stem cell transplantation (HSCT) in four participating centres. The inter-patient, inter-occasion and residual variability in the pharmacokinetics of busulfan were estimated with a population analysis using the nonlinear mixed-effects modelling software NONMEM VI. Covariates were selected on the basis of their known or theoretical relationships with busulfan pharmacokinetics and were plotted independently against the individual pharmacokinetic parameters and the weighted residuals of the model without covariates to visualize relations. Potential covariates were formally tested in the model. RESULTS: In a two-compartment model, body weight was the most predictive covariate for clearance, volume of distribution and inter-compartmental clearance and explained 65%, 75% and 40% of the observed variability, respectively. The relationship between body weight and clearance was characterized best using an allometric equation with a scaling exponent that changed with body weight from 1.2 in neonates to 0.55 in young adults. This implies that an increase in body weight in neonates results in a larger increase in busulfan clearance than an increase in body weight in older children or adults. Clearance on the first day was 12% higher than that of subsequent days (p < 0.001). Inter-occasion variability on clearance was 15% between the 4 days. Based on the final pharmacokinetic-model, an individualized dosing nomogram was developed. CONCLUSIONS: The model-based individual dosing nomogram is expected to result in predictive busulfan exposures in patients ranging between 3 and 65 kg and thereby to a safer and more effective conditioning regimen for HSCT in children.

Pharmacogenetics in randomized controlled trials: considerations for trial design.

Pharmacogenetic analyses of clinical trials aim to either detect whether a subgroup of patients identified by genetic characteristics responds differently to the treatment or to verify whether a proposed genotype-guided treatment is beneficial over standard care. This article describes three different trial designs, differing in the timing of randomization and genotyping. Each design has its own advantages, and the objectives and conditions under which each one is most suited are discussed.

The decision to continue or discontinue treatment: experiences and beliefs of users of selective serotonin-reuptake inhibitors in the initial months--a qualitative study.

BACKGROUND: Little is known about patients' views on taking selective serotonin-reuptake inhibitors (SSRIs) and their decision-making processes regarding either continuation or discontinuation within a few months of initiating therapy. OBJECTIVE: To explore the experiences and beliefs of SSRI users in relation to initiation and execution of treatment, with the intention to identify patterns leading to discontinuation or continuation of treatment. METHODS: Semistructured qualitative interview study. Eighteen patients, older than 18 years, were interviewed 3 months after starting SSRI treatment prescribed by a general practitioner (GP), 9 of whom had discontinued (discontinuers) and 9 of whom continued treatment (continuers). RESULTS: Two main patterns lead to either discontinuation or continuation of use. Continuers were satisfied with the GP's role during initiation and execution of SSRI treatment and fully trusted their decision. Continuers' attitudes toward treatment were predominantly positive; they seemed to have little doubt about the necessity of using an SSRI and hardly considered discontinuing for fear of relapse. Discontinuers, on the other hand, seemed to be less involved in decision making and often appeared to have little confidence in their GPs. Most discontinuers felt that they lacked knowledge, and their attitude toward taking SSRIs was rather negative. Discontinuers often were unconvinced about the necessity of using an SSRI and appeared to have a strong desire to discontinue treatment. CONCLUSION: Lack of shared decision making between patient and GP, limited counseling during treatment, lack of knowledge, and patients' negative attitudes toward SSRI use and the disease itself, hampered the acceptance of the SSRI and brought on the decisional conflict to discontinue treatment. Health care professionals could be more supportive during the initial months of SSRI treatment by eliciting patients' considerations for continuing or discontinuing treatment.

Preventable hospital admissions related to medication (HARM): cost analysis of the HARM study.

OBJECTIVE: Adverse drug events (ADEs) can cause serious harm to patients and can lead to hospitalization or even death. ADEs are a burden not only to patients and their relatives, but also to society and have the potential to involve high costs. To provide more information on the economic burden of preventable adverse drug events of outpatients, we performed a cost study on the data collected in the Hospital Admissions Related to Medication (HARM) study. In this study we examined the frequency, preventability, and risk factors for hospital admissions related to medication. METHODS: The average costs for a preventable medication-related hospital admission were calculated by summing the direct medical costs and the production losses of all the preventable admissions, taking into account the different types of hospitals (academic and general) and the age of the admitted patients. RESULTS: The average medical costs for one preventable medication-related hospital admission were €5461. The average production loss costs for one admission were €1712 for a person younger than 65 years of age. Combining the medical costs and the costs of production losses resulted in average costs of €6009 for one, potentially preventable, medication-related hospital admission for all ages. CONCLUSIONS: The costs of potentially preventable hospital admissions related to medication are considerable. Therefore, patient safety interventions to prevent ADEs and hospital admissions may be cost-effective or even cost saving.

The relationship between benzodiazepine use and traffic accidents: A systematic literature review.

In many countries, benzodiazepines are the most commonly used and misused psychoactive medicinal drugs. Results of epidemiological studies investigating the association between benzodiazepine use and traffic accidents seem to be inconclusive or inconsistent at first sight. However, the outcome of epidemiological studies may be influenced by several methodological factors like study design, study population, exposure measurement, outcome definitions and possible confounders. Our objective was to conduct a systematic literature review of epidemiological studies that investigated the association between benzodiazepine use and traffic accidents, including related outcomes like culpability and injury or accident severity. We searched EMBASE, PubMed and Forensic Science Abstracts 3/0 (FORS) for references included in these databases at 1 June 2009 using the term 'benzodiazepines' in combination with 'driving performance' or 'accident risk' or 'traffic accident'. For inclusion in this review, the study design had to be comparative, include road users involved in accidents and provide specific data about benzodiazepines. Sixty-six studies were included in the review. The study populations varied from the general (driving) population, accident-involved road users with or without injury and persons admitted to a hospital to fatally injured accident-involved drivers. Exposure assessment was performed by using toxicological results, prescription data or questionnaires. The divergent study populations and comparison groups and the variety of methods used to express the outcome of interest hampered comparison between results. Evidence is growing that exposure to benzodiazepines is related to increased accident risk. The literature indicates that the greatest accident risk is associated with the use of long half-life benzodiazepines, increasing dosage and the first few weeks of use of benzodiazepines. Clear evidence of increased culpability associated with benzodiazepine use is scarce. More research has to be done to elucidate the relationship between benzodiazepine use and injury severity.

Patients' perceptions and illness severity at start of antidepressant treatment in general practice.

OBJECTIVES: Patients' perceptions are important to consider when trying to understand why patients often do not follow prescriptions for antidepressant treatment. This study aimed to investigate the influence of patients' perceptions and illness severity at the start on antidepressant-medication-taking behaviour. METHODS: Eighteen community pharmacies in the Netherlands participated in this 6-month follow-up study. One hundred and ten patients presenting a first antidepressant prescription, prescribed by a general practitioner (GP), were included. A questionnaire was completed at inclusion, after 6 and 26 weeks. KEY FINDINGS: Of all 110 patients, eight (7.3%) did not initiate drug taking, 32 (29.1%) discontinued use, six (5.5%) switched to different antidepressant medication, and 64 (58.2%) continued on the same antidepressant during follow-up. Compared to continuers, non-initiators had lower belief scores for impact of illness (P = 0.044), perceived norm GP (P < 0.001), intention to take medication (P < 0.001), and attitude towards medication (P = 0.004). Furthermore, non-initiators were less severely depressed (P = 0.024). Discontinuers and continuers did not differ in illness severity at inclusion. However, discontinuers more often reported a non-specific reason for use, such as fatigue and sleeping problems (P = 0.014). Compared to continuers, switchers had higher illness severity scores at inclusion (depression, P = 0.041; anxiety, P = 0.050). During follow-up depression and anxiety severity improved for all treatment groups and reached the same level of severity at 6 months. CONCLUSIONS: Patients' illness and treatment perceptions and illness severity influence their decisions about antidepressant drug taking. Patients' care could be improved by eliciting patients' beliefs about illness and treatment and assessing illness severity before prescribing.