Body weight gain in clozapine-treated patients: Is norclozapine the culprit?

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.

Hyperhydration with cisplatin does not influence pemetrexed exposure.

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.

The effect of Patient's Own Medication use on patient's self-reported medication knowledge during hospitalisation: a pre-post intervention study.

BACKGROUND: Improving patient's medication knowledge and consequently medication use is essential for optimal treatment outcomes. As patient knowledge about medication is currently suboptimal, interventions to optimise medication knowledge are necessary. Implementation of Patient's Own Medication (POM) in which patients bring their outpatient medication to the hospital, and nurses administer these during admission, may increase medication knowledge. The aim of this study is to explore the impact of POM use on self-reported medication knowledge of hospitalised patients compared to standard care. Patient's sense of medication safety, attitude to the provision of information, and to inpatient medication use were studied in both standard care and during POM use too. METHOD: In this nationwide intervention study perceived medication knowledge was assessed with a questionnaire pre and post implementing POM use. The questionnaire assessed perceived medication knowledge at admission and discharge, medication safety during hospitalisation, the provision of information during hospitalisation and at discharge, and inpatient medication use during hospitalisation. Patients' answers were categorised into positive and negative/neutral. The proportion of patients with adequate medication knowledge, in the standard care and POM use group at hospital admission and discharge, were calculated and compared with adjustment for potential confounders. RESULTS: Among the 731 patients (393 received standard care and 338 POM) who completed the questionnaire (80.2%), POM use seemed to be positively associated with self-reported knowledge on how to use medication at discharge (adjusted OR: 3.22 [95% CI 2.01-5.16]). However, for the other two knowledge related statements POM use was not associated. Medication knowledge at admission was the most important variable associated with perceived medication knowledge at discharge. The majority perceived POM use to be safer (52.9% of standard care patients versus 74.0% POM users; P <  0.01), POM users knew better which medicines they still used during hospitalisation (85.8% versus 92.3% resp.; P = 0.01), and most patients preferred POM use regardless of having experienced it (68.2% versus 82.2% resp.; P <  0.01). CONCLUSION: POM use positively affects patient's medication knowledge about how to use medication and patients' perception of medication safety. With POM use more patients have a positive attitude towards the provision of information. The majority of patients prefer POM use. In conclusion, POM use seems a valuable intervention and requires further investigation.

Inhibition of CYP2D6 with low dose (5 mg) paroxetine in patients with high 10-hydroxynortriptyline serum levels-A prospective pharmacokinetic study.

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 (<200 µg/L) concentrations, and the degree of phenoconversion, expressed as the change in ratio nortriptyline/hydroxynortriptyline concentrations before and after paroxetine addition, are prospectively observed and described. After paroxetine addition, 12 patients (80%) had therapeutic nortriptyline and safe hydroxynortriptyline concentrations. Hydroxynortriptyline concentrations decreased in all patients. The average nortriptyline/hydroxynortriptyline concentrations ratio increased from 0.32 to 0.59. This study shows that 5 mg paroxetine addition is able to lower high hydroxynortriptyline serum levels to safe ranges.

Prospective validation of a model-informed precision dosing tool for vancomycin in intensive care patients.

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.

Association Between Urinary Tract Infections and Antipsychotic Drug Use in Older Adults.

Antipsychotic drugs are frequently prescribed to older adults, but they may be associated with serious adverse effects. The objective was to investigate the association between use of antipsychotics in older adults and the risk of urinary tract infections (UTIs).This study was designed as a cohort study.Data were obtained from the Clinical Practice Research Datalink from January 1, 2000, to September 29, 2016.Primary care patients 65 years or older in the United Kingdom with a first prescription for an oral antipsychotic were included in the study.Incidence of UTIs was calculated for periods with and without exposure to antipsychotic drugs in one cohort. Cox proportional hazard regression analysis with Andersen-Gill extension for recurrent events was used to calculate hazard ratios (HRs) with 95% confidence interval (CI).During the study period, 191,827 individuals with a first prescription for an oral antipsychotic drug were identified. Current use of antipsychotics was associated with an increased risk of UTI compared with past use (adjusted HR, 1.31; 95% CI, 1.28-1.34). This effect was strongest in the first 14 days of use (adjusted HR, 1.83; 95% CI, 1.73-1.95) and in individuals who used more than one antipsychotic drug concomitantly (adjusted HR, 1.64; 95% CI, 1.45-1.87). The risk was slightly higher for typical antipsychotics than for atypical antipsychotics. Stratification by sex showed that risk estimates were slightly higher in men than in women.Use of antipsychotics was associated with an increased risk of UTIs in both men and women, particularly in the first weeks after the start of treatment.

Deprescribing in Newly Admitted Psychogeriatric Nursing Facility Patients.

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.

Drug therapy management in patients with renal impairment: how to use creatinine-based formulas in clinical practice.

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.

Fluctuation of the renal function after discharge from hospital and its effects on drug dosing in elderly patients--study protocol.

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.

Impact of Drug Recalls on Patients in The Netherlands: A 5-Year Retrospective Data Analysis.

Drug recalls occur frequently and have the potential to impact considerable numbers of patients and healthcare providers. However, in the absence of a comprehensive overview the extent of conducted recalls and their impact on patients remains unknown. To address this, we developed a comprehensive overview of drug recalls affecting patients. We compiled this overview based on the drug recall registrations from the Jeroen Bosch Hospital (JBZ), the University Medical Center Utrecht (UMCU), and the Royal Dutch Pharmacists Association (KNMP). A retrospective data analysis was conducted to identify drug recalls that affected patients. Specifically, we defined these as drug recalls that required patients to actively switch their drug to a different batch or brand of the same drug or to switch to a drug within the same or a different class of drugs. To quantify the impact, we used real-world drug dispensing data. Between January 1, 2017, and December 31, 2021, we identified 48 drug recalls that necessitated patients to make active changes to their medications an estimated 855,000 times. Most of the affected patients (292,000) were required to switch to a different brand of the same drug, whereas in 95,000 cases patients had to switch to a drug from another drug class. Our study suggests that a significant number of patients are affected by drug recalls. Future efforts are needed to elucidate patients' experiences and preferences regarding drug recalls, which could provide valuable insights to aid decision-making by relevant (national) authorities concerning drug recalls.

Sulfamethoxazole-Trimethoprim-Induced Hyperkalemia in Hospitalized Patients Using Potassium-Sparing Drugs: An Observational Study.

The objective of this analysis is to investigate the risk of hyperkalemia in hospitalized patients using sulfamethoxazole-trimethoprim (Co-trimoxazole) and a potassium-sparing drug (potassium-sparing diuretic or renin-angiotensin system [RAS]-inhibitor). Researchers conducted a nested case control study within a cohort of hospitalized patients using a potassium-sparing diuretic and/or a RAS-inhibitor from the PHARMO Database Network. Researchers estimated the odds ratios (ORs) and 95% confidence intervals (CI) for the risk of hyperkalemia in patients receiving both Co-trimoxazole and a potassium-sparing drug compared with patients only receiving a potassium-sparing drug. Among a cohort of 25,849 patients, researchers identified 2054 cases of hyperkalemia during hospitalization in patients also using a potassium-sparing drug. Using Co-trimoxazole in addition to a potassium-sparing drug was associated with an increased risk of hyperkalemia in hospitalized patients (ORadj = 1.65, 95% CI 1.26-2.16) compared with using only a potassium-sparing drug. There was a trend of a more pronounced association between hyperkalemia and the co-use of Co-trimoxazole and potassium-sparing drugs in patients with an estimated GFR of 15-29 mL/min (ORadj = 3.15, 95% CI 1.29-7.70). The number needed to harm for hyperkalemia induced by adding Co-trimoxazole to patients receiving a potassium-sparing drug is 19.5. Using the combination of Co-trimoxazole with a potassium-sparing drug in hospitalized patients increases the risk of hyperkalemia compared with using only a potassium-sparing drug. Physicians and other prescribers should be aware of hyperkalemia and routinely monitor serum potassium levels in hospitalized patients using this combination of drugs.

The use of artificial intelligence to optimize medication alerts generated by clinical decision support systems: a scoping review.

OBJECTIVE: Current Clinical Decision Support Systems (CDSSs) generate medication alerts that are of limited clinical value, causing alert fatigue. Artificial Intelligence (AI)-based methods may help in optimizing medication alerts. Therefore, we conducted a scoping review on the current state of the use of AI to optimize medication alerts in a hospital setting. Specifically, we aimed to identify the applied AI methods used together with their performance measures and main outcome measures. MATERIALS AND METHODS: We searched Medline, Embase, and Cochrane Library database on May 25, 2023 for studies of any quantitative design, in which the use of AI-based methods was investigated to optimize medication alerts generated by CDSSs in a hospital setting. The screening process was supported by ASReview software. RESULTS: Out of 5625 citations screened for eligibility, 10 studies were included. Three studies (30%) reported on both statistical performance and clinical outcomes. The most often reported performance measure was positive predictive value ranging from 9% to 100%. Regarding main outcome measures, alerts optimized using AI-based methods resulted in a decreased alert burden, increased identification of inappropriate or atypical prescriptions, and enabled prediction of user responses. In only 2 studies the AI-based alerts were implemented in hospital practice, and none of the studies conducted external validation. DISCUSSION AND CONCLUSION: AI-based methods can be used to optimize medication alerts in a hospital setting. However, reporting on models' development and validation should be improved, and external validation and implementation in hospital practice should be encouraged.

Adoption of antithrombotic stewardship and utilization of clinical decision support systems-A questionnaire-based survey in Dutch hospitals.

Antithrombotics require careful monitoring to prevent adverse events. Safe use can be promoted through so-called antithrombotic stewardship. Clinical decision support systems (CDSSs) can be used to monitor safe use of antithrombotics, supporting antithrombotic stewardship efforts. Yet, previous research shows that despite these interventions, antithrombotics continue to cause harm. Insufficient adoption of antithrombotic stewardship and suboptimal use of CDSSs may provide and explanation. However, it is currently unknown to what extent hospitals adopted antithrombotic stewardship and utilize CDSSs to support safe use of antithrombotics. A semi-structured questionnaire-based survey was disseminated to 12 hospital pharmacists from different hospital types and regions in the Netherlands. The primary outcome was the degree of antithrombotic stewardship adoption, expressed as the number of tasks adopted per hospital and the degree of adoption per task. Secondary outcomes included characteristics of CDSS alerts used to monitor safe use of antithrombotics. All 12 hospital pharmacists completed the survey and report to have adopted antithrombotic stewardship in their hospital to a certain degree. The median adoption of tasks was two of five tasks (range 1-3). The tasks with the highest uptake were: drafting and maintenance of protocols (100%) and professional's education (58%), while care transition optimization (25%), medication reviews (8%) and patient counseling (8%) had the lowest uptake. All hospitals used a CDSS to monitor safe use of antithrombotics, mainly via basic alerts and less frequently via advanced alerts. The most frequently employed alerts were: identification of patients using a direct oral anticoagulant (DOAC) or a vitamin K antagonist (VKA) with one or more other antithrombotics (n = 6) and patients using a VKA to evaluate correct use (n = 6), both reflecting basic CDSS. All participating hospitals adopted antithrombotic stewardship, but the adopted tasks vary. CDSS alerts used are mainly basic in their logic.

Ineffectiveness and adverse events of nitrofurantoin in women with urinary tract infection and renal impairment in primary care.

PURPOSE: To determine whether treatment with nitrofurantoin in women with urinary tract infection (UTI) and renal impairment in primary care is associated with a higher risk of ineffectiveness and/or serious adverse events than in women without renal impairment. METHODS: A cohort of 21,317 women treated with nitrofurantoin and a cohort of 7,926 women treated with trimethoprim, identified from the Pharmo Record Linkage System, were analysed. The primary outcome was ineffectiveness of treatment of nitrofurantoin defined as the start of a second antibacterial within 1 month after the start of nitrofurantoin. The secondary outcome was the occurrence of serious adverse events of nitrofurantoin leading to hospitalization within 90 days. A cohort of trimethoprim users was used to determine if the associations found for nitrofurantoin were mainly related to nitrofurantoin itself. The association between renal impairment and the risk of these outcomes was determined with Cox regression and expressed as hazard ratios (HRs). RESULTS: Overall, the incidence density for ineffectiveness was 5.4 per 1,000 person-days, and moderate renal impairment was not associated with ineffective treatment [HR 1.1, 95 % confidence interval (CI) 0.74-1.51]. The overall incidence density for adverse events was 0.02 per 1,000 person-days. In patients with renal impairment (<50 ml/min/1.73 m²) the risk of pulmonary adverse events leading to hospitalization was significantly increased (HR 4.1, 95 % CI 1.31-13.09) CONCLUSIONS: Nitrofurantoin treatment was not associated with a higher risk of ineffectiveness in women with UTI and moderate renal impairment (30-50 ml/min/1.73 m²). However, we did find a significant association between renal impairment (<50 ml/min/1.73 m²) and pulmonary adverse events leading to hospitalization.

Renal function-based versus standard dosing of pemetrexed: a randomized controlled trial.

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.

A Systematic Evaluation of Cost-Saving Dosing Regimens for Therapeutic Antibodies and Antibody-Drug Conjugates for the Treatment of Lung Cancer.

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.

Proton Pump Inhibitors and Hypomagnesemia in Older Inpatients: An Observational Study.

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.

The Pharmacoeconomic Benefits of Pemetrexed Dose Individualization in Patients With Lung Cancer.

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.