Prescribing medicines to older people-How to consider the impact of ageing on human organ and body functions

Ageing is associated with several changes in human organs, which result in altered medication pharmacokinetics and pharmacodynamics. Ageing is also associated with changes in human body functions, such as impaired vision, hearing, swallowing, motor and cognitive functions, which can affect the adequate intake and administration of drugs. As a consequence, older people, and especially patients older than 75 years, are the main users of many drugs and they frequently use 5 drugs or more long-term (i.e. polypharmacy). All this increases the complexity of adequate drug intake, administration and adherence. However, there is a lack of evidence on the considerations that should be taken into account to ensure appropriate drug prescribing to older people. This review article summarizes the most clinically relevant changes in human organ and body functions and the consequential changes in pharmacokinetics and pharmacodynamics in older people, along with possible dosing consequences or alternatives for drugs frequently prescribed to this patient population. Recommendations are given on how ageing could be considered in clinical drug development, drug authorization and appropriate prescribing

Prevalence and predictors of inappropriate prescribing in outpatients with severe mental illness

Background: Potentially inappropriate prescribing (PIP) is frequent in geriatrics and results in an increased risk for adverse effects, morbidity, mortality and reduced quality of life. Research on PIP in psychiatry has mainly focused on elderly patients and inpatients. Objectives: To determine the prevalence and the predictors of PIP of psychotropic medication in outpatients with severe mental illness. Design: This study is part of the Muva study, a pragmatic open Stepped Wedge Cluster Randomized Trial of a physical activity intervention for patients (age ⩾ 16 years) with severe mental illness. Methods: A structured medication interview, questionnaires on social functioning, quality of life and psychiatric symptoms, and BMI and waist circumference measurements were performed followed by a structured medication review. Patients were divided into groups: PIP versus no PIP. Between-group differences were calculated and a multivariate binary logistic regression was performed to examine predictors for PIP. A receiver operating characteristics analysis was performed to determine the area under the curve (AUC). Results: In 75 patients, an average of 5.2 medications of which 2.5 psychotropic medication was used. 35 (46.7%) patients were identified with PIP. Unindicated long-term benzodiazepine use was the most frequently occurring PIP (34.1%). Predictors of PIP were female gender [odds ratio (OR) = 4.88, confidence interval (CI) = 1.16–20.58, p = 0.03], number of medications (OR = 1.41, CI = 1.07–1.86, p = 0.02) and lower social functioning (OR = 1.42, CI = 1.01–2.00, p = 0.05). The AUC was 0.88 for the combined prediction model. Conclusion: The prevalence of PIP of psychotropic medication in outpatients with severe mental illness is high. It is therefore important to identify, and where possible, resolve PIP by frequently performing a medication review with specific attention to females, patients with a higher number of medications and patients with lower social functioning. Trial registration: This trial was registered in The Netherlands Trial Register (NTR) as NTR NL9163 on 20 December 2020 (https://trialsearch.who.int/Trial2.aspx?TrialID=NL9163)

Medical Residents’ Informal Learning from Pharmacists in the Clinical Workplace

UNLABELLED: Workplace-based interactions between residents and pharmacists, though relatively underexplored, might contribute substantially to learning. This international study sought to investigate the affordances residents use for informal learning about medications, their interactions with pharmacists and patterns of resident-pharmacist engagement, as well as residents' perceived impact of these interactions on their learning. Contextual differences between US and Dutch residency training and electronic health record (EHR) may impact informal learning about medications. We conducted a cross-sectional, online, 25-item survey study, including closed-format and open-response questions among current resident physicians (post-graduate years 1-6, from a variety of residency programs n  = 803) from the University of California San Francisco, the University of Minnesota, and the University Medical Center Utrecht. Responses from 173 residents in both countries revealed that these physician trainees were afforded opportunities to engage in a wide variety of pharmacotherapy-related activities but engaged differently with social and environmental resources for support. Residents from the United States (US) utilized pharmacists and Up-To-Date, whereas Dutch residents preferentially utilized the online Dutch medication information site and EHR-embedded medication resources. US residents interacted with pharmacists significantly more frequently than Dutch residents. Pharmacists provided residents with a wide range of useful information, much of which is integrated into the medication resources in the Dutch EHR-based decision-support system. While US residents reported overwhelmingly that informal interactions with pharmacists contribute to their learning about medications, Dutch residents' responses did not confirm this. Intentionally designing residents' training to include opportunities for interactions with pharmacists could potentially positively impact residents' informal workplace learning. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40670-023-01784-1

Alignment of CanMEDS-based Undergraduate and Postgraduate Pharmacy Curricula in The Netherlands

In this article the design of three master programs (MSc in Pharmacy) and two postgraduate specialization programs for community or hospital pharmacist is described. After a preceding BSc in Pharmacy, these programs cover the full pharmacy education capacity for pharmacists in primary and secondary health care in the Netherlands. All programs use the CanMEDS framework, adapted to pharmacy education and specialization, which facilitates the horizontal integration of pharmacists' professional development with other health care professions in the country. Moreover, it is illustrated that crossing the boundary from formal (university) education to experiential (workplace) education is eased by a gradual change in time spent in these two educational environments and by the use of comparable monitoring, feedback, and authentic assessment instruments. A reflection on the curricula, based on the principles of theIntegrative Pedagogy Modeland theSelf-determination Theory, suggests that the alignment of these educational programs facilitates the development of professional expertise and professional identity of Dutch pharmacists

Impulse control disorders associated with dopaminergic drugs: A disproportionality analysis using vigibase

BACKGROUND: Dopamine receptor agonist drugs, which are used, for example, to treat Parkinson's disease (PD), increase the risk for impulse control disorders (ICDs), potentially resulting in devastating psychosocial consequences. It is unknown whether other drugs with dopaminergic properties also increase the risk for ICDs. This study assesses the disproportionality of reporting ICDs between drugs with dopaminergic properties and selected non-dopaminergic drugs. METHODS: A case/non-case disproportionality analysis was performed, using data from VigiBase (1968-2020). Reports on ICDs as suspected adverse drug reactions (ADRs) were cases (n=852), and those with ADRs other than ICDs were non-cases (n=281,720). Relative reporting frequencies were expressed as adjusted reporting odds ratios (aRORs). Within the dopamine receptor agonists, the relationship between reporting odds ratios and dopamine receptor occupancy was explored. RESULTS: A high disproportionality was found for reporting ICDs for all dopaminergic drugs (aROR 20.4 [95% CI 17.4-24.1]) compared to non-dopaminergic drugs. In pharmacotherapeutic subgroups, a high disproportionality was found for primary dopaminergic agents used in PD (aROR 52.1 [95% CI 44.1-61.5]), and to a lesser extent for ADHD psychostimulants and antidepressants (aROR 5.8 [95% 4.1-8.3] and aROR 3.9 [95% CI 2.9-5.6], respectively). There was no difference in reporting by consumers and healthcare professionals. The highest disproportionality was found for the dopamine receptor agonists pramipexole and ropinirole. CONCLUSIONS: A signal of disproportion in ICD occurrence was found among all investigated drugs with dopaminergic properties, highlighting the importance of counselling and monitoring for ICDs when prescribing dopaminergic drugs

Performance of a trigger tool for detecting adverse drug reactions in patients with polypharmacy acutely admitted to the geriatric ward

PURPOSE: Adverse drug reactions (ADRs) account for 10% of acute hospital admissions in older people, often under-recognised by physicians. The Dutch geriatric guideline recommends screening all acutely admitted older patients with polypharmacy with an ADR trigger tool comprising ten triggers and associated drugs frequently causing ADRs. This study investigated the performance of this tool and the recognition by usual care of ADRs detected with the tool. METHODS: A cross-sectional study was performed in patients ≥ 70 years with polypharmacy acutely admitted to the geriatric ward of the University Medical Centre Utrecht. Electronic health records (EHRs) were screened for trigger-drug combinations listed in the ADR trigger tool. Two independent appraisers assessed causal probability with the WHO-UMC algorithm and screened EHRs for recognition of ADRs by attending physicians. Performance of the tool was defined as the positive predictive value (PPV) for ADRs with a possible, probable or certain causal relation. RESULTS: In total, 941 trigger-drug combinations were present in 73% (n = 253/345) of the patients. The triggers fall, delirium, renal insufficiency and hyponatraemia covered 86% (n = 810/941) of all trigger-drug combinations. The overall PPV was 41.8% (n = 393/941), but the PPV for individual triggers was highly variable ranging from 0 to 100%. Usual care recognised the majority of ADRs (83.5%), increasing to 97.1% when restricted to possible and certain ADRs. CONCLUSION: The ADR trigger tool has predictive value; however, its implementation is unlikely to improve the detection of unrecognised ADRs in older patients acutely admitted to our geriatric ward. Future research is needed to investigate the tool's clinical value when applied to older patients acutely admitted to non-geriatric wards

Trastuzumab and first-line taxane chemotherapy in metastatic breast cancer patients with a HER2-negative tumor and HER2-positive circulating tumor cells:a phase II trial

Purpose: HER2 overexpressing circulating tumor cells (CTCs) are observed in up to 25% of HER2-negative metastatic breast cancer patients. Since targeted anti-HER2 therapy has drastically improved clinical outcomes of patients with HER2-positive breast cancer, we hypothesized that patients with HER2 overexpressing CTCs might benefit from the addition of trastuzumab to chemotherapy. Methods: In this single-arm, phase II trial, patients with HER2-positive CTCs received trastuzumab as addition to first-line treatment with taxane chemotherapy. Patients with detectable CTCs but without HER2 overexpression that received taxane chemotherapy only, were used as control group. The primary outcome measure was progression-free rate at 6 months (PFR6), with a target of 80%. In November 2022, the study was terminated early due to slow patient accrual. Results: 63 patients were screened, of which eight patients had HER2-positive CTCs and were treated with trastuzumab. The median number of CTCs was 15 per 7.5 ml of blood (range 1–131) in patients with HER2-positive CTCs, compared to median 5 (range 1–1047) in the control group. PFR6 was 50% in the trastuzumab group and 54% in the taxane monotherapy group, with no significant difference in median PFS (8 versus 9 months, p = 0.51). Conclusion: No clinical benefit of trastuzumab was observed, although this study was performed in a limited number of patients. Additionally, we observed a strong correlation between the number of evaluable CTCs and the presence of HER2-positive CTCs. We argue that randomized studies investigating agents that are proven to be solely effective in the HER2-positive patient group in patients with HER2-positive CTCs and HER2-negative tissue are currently infeasible. Several factors contribute to this impracticality, including the need for more stringent thresholds, and the rapidly evolving landscape of cancer treatments.</p

Trastuzumab and first-line taxane chemotherapy in metastatic breast cancer patients with a HER2-negative tumor and HER2-positive circulating tumor cells:a phase II trial

Purpose: HER2 overexpressing circulating tumor cells (CTCs) are observed in up to 25% of HER2-negative metastatic breast cancer patients. Since targeted anti-HER2 therapy has drastically improved clinical outcomes of patients with HER2-positive breast cancer, we hypothesized that patients with HER2 overexpressing CTCs might benefit from the addition of trastuzumab to chemotherapy. Methods: In this single-arm, phase II trial, patients with HER2-positive CTCs received trastuzumab as addition to first-line treatment with taxane chemotherapy. Patients with detectable CTCs but without HER2 overexpression that received taxane chemotherapy only, were used as control group. The primary outcome measure was progression-free rate at 6 months (PFR6), with a target of 80%. In November 2022, the study was terminated early due to slow patient accrual. Results: 63 patients were screened, of which eight patients had HER2-positive CTCs and were treated with trastuzumab. The median number of CTCs was 15 per 7.5 ml of blood (range 1–131) in patients with HER2-positive CTCs, compared to median 5 (range 1–1047) in the control group. PFR6 was 50% in the trastuzumab group and 54% in the taxane monotherapy group, with no significant difference in median PFS (8 versus 9 months, p = 0.51). Conclusion: No clinical benefit of trastuzumab was observed, although this study was performed in a limited number of patients. Additionally, we observed a strong correlation between the number of evaluable CTCs and the presence of HER2-positive CTCs. We argue that randomized studies investigating agents that are proven to be solely effective in the HER2-positive patient group in patients with HER2-positive CTCs and HER2-negative tissue are currently infeasible. Several factors contribute to this impracticality, including the need for more stringent thresholds, and the rapidly evolving landscape of cancer treatments.</p

Performance of a trigger tool for detecting adverse drug reactions in patients with polypharmacy acutely admitted to the geriatric ward

Key summary pointsAim To investigate the performance of an adverse drug reaction (ADR) trigger tool in patients with polypharmacy acutely admitted to our geriatric ward. Findings The ADR trigger tool had a positive predictive value (PPV) of 41.8%. Usual care recognised 83.5% of ADRs considered as possible, probable or certain, increasing to 97.1% when restricted to probable and certain ADRs. Message It is unlikely that implementation of the ADR trigger tool will improve detection of unrecognised ADRs in older patients acutely admitted to our geriatric ward.Purpose Adverse drug reactions (ADRs) account for 10% of acute hospital admissions in older people, often under-recognised by physicians. The Dutch geriatric guideline recommends screening all acutely admitted older patients with polypharmacy with an ADR trigger tool comprising ten triggers and associated drugs frequently causing ADRs. This study investigated the performance of this tool and the recognition by usual care of ADRs detected with the tool. Methods A cross-sectional study was performed in patients >= 70 years with polypharmacy acutely admitted to the geriatric ward of the University Medical Centre Utrecht. Electronic health records (EHRs) were screened for trigger-drug combinations listed in the ADR trigger tool. Two independent appraisers assessed causal probability with the WHO-UMC algorithm and screened EHRs for recognition of ADRs by attending physicians. Performance of the tool was defined as the positive predictive value (PPV) for ADRs with a possible, probable or certain causal relation. Results In total, 941 trigger-drug combinations were present in 73% (n = 253/345) of the patients. The triggers fall, delirium, renal insufficiency and hyponatraemia covered 86% (n = 810/941) of all trigger-drug combinations. The overall PPV was 41.8% (n = 393/941), but the PPV for individual triggers was highly variable ranging from 0 to 100%. Usual care recognised the majority of ADRs (83.5%), increasing to 97.1% when restricted to possible and certain ADRs. Conclusion The ADR trigger tool has predictive value; however, its implementation is unlikely to improve the detection of unrecognised ADRs in older patients acutely admitted to our geriatric ward. Future research is needed to investigate the tool's clinical value when applied to older patients acutely admitted to non-geriatric wards

Pharmacogenetics and phenoconversion: the influence on side effects experienced by psychiatric patients

Introduction: Preventing side effects is important to ensure optimal psychopharmacotherapy and therapeutic adherence among psychiatric patients. Obtaining the pharmacogenetic profile of CYP2C19 and CYP2D6 can play an important role in this. When the genotype-predicted phenotype shifts because of the use of co-medication, this is called phenoconversion. The aim was to study the influence of the pharmacogenetic (PGx) profile and phenoconversion on side effects experienced by psychiatric patients. Methods: A retrospective cohort study was performed using data from 117 patients from a psychiatric outpatient clinic. Patients were genotyped with a psychiatric PGx panel and side effects were evaluated using the Udvalg for Kliniske Undersølgelser side effects rating scale (UKU). Results: Of all patients, 10.3% and 9.4% underwent phenoconversion (any shift in predicted phenotype) for CYP2C19 and CYP2D6 respectively. No significant associations were found between the phenotype and UKU-score. 75% of the patients with an Intermediate metabolizer (IM) or Poor metabolizer (PM) phenoconverted phenotype of CYP2C19 experienced nausea and vomiting compared to 9.1% of the Normal metabolizer (NM) and Ultrarapid metabolizer (UM) patients (p = 0.033). 64% of the patients with an IM or PM phenoconverted phenotype of CYP2D6 experienced the side effect depression compared to 30.4% NMs and UMs (p = 0.020). CYP2D6 IM and PM patients had a higher concentration-dose ratio than NM patients (p < 0.05). Discussion: This study underlines the importance to consider phenoconversion when looking at a patient’s genotype. This is important for a better prediction of the phenotype and preventing possible side effects under a specific psychopharmacotherapy