Aim: To measure the prevalence of polypharmacy and describe the prescribing of potentially inappropriate medication (PIM) in older people with polypharmacy in primary care. Methods: A multi-country retrospective cohort study across six countries: Belgium, France, Germany, Italy, Spain, UK. We used anonymized longitudinal patient level information from general practice databases hosted by IQVIA. Patients ≥65 years were included. Polypharmacy was defined as having 5-9, and ≥10 distinct drug classes (ATC Level 3) prescribed during a 6-month period. PIM defined: opioids, antipsychotics, proton pump inhibitors (PPI), benzodiazepines (ATC Level 5). We included country experts on the health care context to interpret findings. Results: Age and gender distribution was similar across the six countries (mean age 75-76 years; 54-56% female). The prevalence of polypharmacy of 5-9 drugs was 22.8% (UK) to 58.3% (Germany); ≥10 drugs from 11.3% (UK) to 28.5% (Germany). In the polypharmacy population prescribed ≥5 drugs, opioid prescribing ranged from 11.5% (France) to 27.5% (Spain). Prescribing of PPI was highest with almost half of patients receiving a PPI, 42.3% (Germany) to 65.5% (Spain). Benzodiazepine prescribing showed a marked variation between countries, 2.7% (UK) to 34.9% (Spain). The health care context information explained possible underreporting for PIM. Conclusion: We have found a high prevalence of polypharmacy with more than half of the older population being prescribed ≥5 drugs in four of the six countries. Whilst polypharmacy may be appropriate in many patients, worrying high usage of PIM (PPIs and benzodiazepines) supports current efforts to improve polypharmacy management across Europe.

Infants bear a significant malaria burden but are usually excluded from participating in early dose optimisation studies that inform dosing regimens of antimalarial therapy. Unlike older children, infants’ exclusion from early-phase trials has resulted in limited evidence to guide accurate dosing of antimalarial treatment for uncomplicated malaria or malaria preventive treatment in this vulnerable population. Subsequently, doses used in infants are often extrapolated from older children or adults, with the potential for under or overdosing. Population pharmacokinetic-pharmacodynamic (PK-PD) modelling, a quantitative methodology that applies mathematical and statistical techniques, can aid the design of clinical studies in infants that collect sparse pharmacokinetic data as well as support the analysis of such data to derive optimised antimalarial dosing in this complex and at-risk yet understudied subpopulation. In this review, we reflect on what PK-PD modelling can do in programmatic settings of most malaria-endemic areas and how it can be used to inform antimalarial dose optimisation for preventive and curative treatment of uncomplicated malaria in infants. We outline key developmental physiological changes that affect drug exposure in early life, the challenges of conducting dose optimisation studies in infants, and examples of how PK-PD modelling has previously informed antimalarial dose optimisation in this subgroup. Additionally, we have discussed the limitations and gaps of PK-PD modelling when used for dose optimisation in infants and best practices for using population PK-PD methods in this subgroup.

Aim The reference nutrient intake for vitamin D in people aged ≥4 years is 10 μg/day (400 IU/day) in the UK, but the recommended daily allowance is 15 μg/day (600 IU/day) for people aged 1-70 years in the US. Here, we aim to compare the 25-hydroxyvitamin D3 (25(OH)D3) serum concentration profiles between the two doses. Methods With adult trial data, we constructed a physiologically based pharmacokinetics (PBPK) model of serum concentrations of vitamin D3 and 25(OH)D3 using nonlinear mixed effects (NLME) modelling. We used this model to forecast the mean, 5% and 95% percentiles for serum 25(OH)D3 concentrations. Results Our final model uses bodyweight to adjust volume of each compartment and maximum clearance of 25(OH)D. No other covariate was identified. The model accurately predicted data from trials of a broad range of dose regimens. We simulated subjects of the average UK male and female weights with baseline 25(OH)D < 25 nmol/L. Simulation suggests circulating 25(OH)D concentrations in >5% of men and women taking 10 μg/day for a year might fail to reach 50 nmol/L, while those on 15 μg/day were predicted to attain this threshold. Conclusion The two doses generate significant difference in serum 25(OH)D3 concentrations. This needs to be considered for choosing the right dose for the public health guideline.

Objective: Metamizole is quite an old drug with analgesic, antipyretic and spasmolytic properties. Recent findings have shown that it may induce several cytochrome P450 enzymes, especially CYP3A4 and CYP2B6. The clinical relevance of these properties is uncertain. We aimed to unravel potential pharmacokinetic interactions between metamizole and the CYP3A4 substrate quetiapine. Methods: Plasma concentrations of quetiapine from a large therapeutic drug monitoring database were analyzed. Two groups of 33 patients, either receiving quetiapine as a monotherapy (without CYP modulating co-medications) or with concomitantly applied metamizole were compared addressing a potential impact of metamizole on the metabolism of quetiapine being reflected in differences of plasma concentrations of quetiapine and dose-adjusted plasma concentrations (C/D). Results: Patients co-medicated with metamizole showed significantly lower plasma concentrations of quetiapine (median 45.2 ng/mL, Q1=15.5; Q3=90.5 vs. 92.0 ng/mL, Q1=52.3; Q3=203.8, p=0.003). Accordingly, plasma concentrations of quetiapine in the control group were more than twice of those in the metamizole group (+103% higher). The dose-adjusted plasma concentrations were 69 % lower in the co-medication group (p=0.001). Conclusions: The combination of metamizole and quetiapine leads to significantly lower drug concentrations of quetiapine, most likely via an induction of cytochrome P450 CYP3A4 by metamizole. Clinicians have to consider the risk of adverse drug reactions, especially treatment failure under quetiapine when adding metamizole.

Aim Prescribing of antidepressant and antipsychotic drugs in general populations has increased in the UK, but prescribing trends in people with type 2 diabetes (T2D) have not previously been investigated. The aim of this study was to describe time trends in annual prevalence of antidepressant and antipsychotic drug prescribing in adult patients with T2D. Methods Repeated annual cross-sectional analyses of a population-based diabetes registry, derived from primary and secondary care data in Scotland, from 2004 to 2021. For each cross-sectional calendar year time period, we calculated the prevalence of antidepressant and antipsychotic drug prescribing, overall and by sociodemographic characteristics and drug subtype. Results The number of patients with a T2D diagnosis in Scotland increased from 161,915 in 2004 to 309,288 in 2021. Prevalence of antidepressant and antipsychotic prescribing in patients with T2D increased markedly between 2004 and 2021 (from 20.0 per 100 person-years to 33.3 per 100 person-years and from 2.8 per 100 person-years to 4.7 per 100 person-years, respectively). We observed this pattern for all drug subtypes except for first-generation antipsychotics, prescribing of which remained largely stable. The degree of increase, as well as overall prevalence of prescribing, differed by age, sex, socioeconomic status, and subtype of drug class. Conclusion There has been a marked increase in the prevalence of antidepressant and antipsychotic prescribing in patients with T2D in Scotland. Further research should identify the reasons for this increase, including indication for use and the extent to which this reflects increases in incident prescribing rather than increased duration.

Aim: This study aimed to analyse the initiation adherence phase to lipid-lowering therapy for primary prevention of cardiovascular disease in a Spanish population aged 70 years or older. The secondary objective was to identify the determinants of initiation and early discontinuation. Methods: Observational study conducted in the CARhES (CArdiovascular Risk factors for HEalth Service research) cohort. People aged 70 and older with a first prescription of a lipid-lowering drug and without a previous Major Adverse Cardiovascular Event were selected (2018-2021). Data on sociodemographics, clinical conditions, drugs and use of health services were collected from clinical and administrative electronic databases. The study population was classified into: non-initiation, early discontinuation (i.e., discontinuation after the first dispensing) and initiation with more than one dispensing. Their characteristics were compared. Determinants of initiation and early discontinuation were explored. Results: Among the 15,019 people studied, 80.2% initiated the medication, 11.2% showed an early discontinuation and 8.6% were non-initiators. An older age or conditions such as dementia, diabetes or depression reduced the likelihood of initiation, while obesity and a high pharmacological burden increased it. People over 90 of age or those prescribed a statin in combination were more likely to have an early discontinuation. Conclusion: Non-initiation and early discontinuation are common among older people prescribed lipid-lowering drugs as primary prevention of cardiovascular disease by the first time. The presence of chronic pathologies other than cardiovascular ones should be considered when assessing whether or not to prescribe these drugs in the elderly.

Clinical pharmacists are health care practitioners who have advanced education and training in comprehensive medication management. Clinical pharmacists participate in the management of specific medications or individual disease states and collaborate with other health care team. Despite the clinical pharmacist participate in healthcare team, there are several cases of challenge in the interprofessional relationship with other healthcare team especially related drug management. The role of clinical pharmacists could be improved by increasing interprofessional communication between doctors and clinical pharmacist in the healthcare system. Previous studies reported that physicians were comfortable with pharmacists detecting and preventing prescription errors, but were uncomfortable with them recommending drug therapy to patients. Acceptance of pharmacists' suggestions by prescribers is a necessary component of the evaluation of clinical pharmacy services.

The C-reactive protein (CRP) can guide the antibiotic prescription for infectious diseases which are likely viral. We identified all patients, aged 15 years or older, being registered in the database between January, 1, 2000 and December, 31, 2019 and newly diagnosed with upper respiratory tract infections (URTIs), COPD- or asthma-related exacerbations. From the date of these diagnoses, patients were followed up until occurrence of antibiotic prescription (for these indications) up to December 31, 2019. The association between the prescription of CRP and the outcome was investigated using a nested case-control analysis. In a cohort of 469,684 patients being diagnosed for URTI (83%), COPD- (11%) and asthma (7%)-related exacerbations, 28688 (6.11%) were prescribed with antibiotics because of the aforementioned indications. Of note, 98% of cases were not tested with CRP. Those receiving antibiotics showed a greater propensity to be previously tested for CRP than related controls. Our findings indicate that most of the antibiotic prescriptions for the investigated conditions did not report prior evaluation of CRP values. Nevertheless, it seems that some GPs properly used CRP before deciding for an antibiotic therapy. Further information and incentives in using CRP test should be therefore sustained in primary care.

Aims: Omalizumab is an anti-immunoglobulin E (IgE) monoclonal antibody that was first approved by the United States (US) Food and Drug Administration (FDA) for the treatment of allergic asthma in 2003. The pivotal trials supporting the initial approval of omalizumab used dosing determined by patient’s baseline IgE and body weight, with the goal of reducing the mean free IgE level to approximately 25 ng/mL or less. While the underlying parameters supporting the dosing table remained the same, subsequent studies and analyses have resulted in approved alternative versions of the dosing table, including the European Union (EU) asthma dosing table, which differs in weight bands and maximum allowable baseline IgE and omalizumab dose. In this study, we leveraged modeling and simulation approaches to predict and compare the free IgE reduction and forced expiratory volume in 1 second (FEV1) improvement with omalizumab dosing based on the US and EU asthma dosing tables. Methods: Previously established population pharmacokinetic-IgE and IgE-FEV1 models were used to predict and compare post-treatment free IgE and FEV1 based on the US and EU dosing tables. Clinical trial simulations (with virtual asthma populations) and Monte Carlo simulations were performed to provide both breadth and depth in the comparisons. Results/Conclusions: The US and EU asthma dosing tables were predicted to result in generally comparable free IgE suppression and FEV1 improvement. However, this has not been clinically validated with respect to the registrational endpoint of reduction in annualized asthma exacerbations.

A document by Dhrita Khatri. Click on the document to view its contents.

AIM: Chagas disease (ChD) is a neglected disease affecting approximately 7 million individuals in Latin America. Benznidazole (BZ) is the most commonly used treatment. Therefore, understanding the adverse effects of BZ is crucial for devising targeted monitoring and interventions to enhance patient management. METHODS: A retrospective cohort study of patients with ChD treated with BZ to identify and characterize BZ adverse drug reactions (ADRs). RESULTS: 518 patients were enrolled: 449 children (median age: 4yrs, range 1mo-17.75yrs) and 69 adults (median age: 25yrs, range 18-59). A 75% of pediatric patients received a median dose of BZ of 6.6 mg/kg/day (IQR25–75 = 5.7-7.3) for at least 60 days. Adult patients received a median BZ dose of 5.6 mg/kg/day (IQR25–75 = 5.2-6.1) for a median duration of 31 days (IQR25–75 = 30-60). Overall, 152/518 (29.34%) patients developed BZ-related ADRs, with an incidence of 116/449 (25.83%) in children and 36/69 (52.17%) in adults (OR = 0.32, CI95 = 0.19 to 0.54, p < 0.001). The study identified 240 ADRs, primarily mild to moderate, but severe ADRs occurred in 1.11% of children and 1.45% of adults. The skin was the most affected system in both groups. A 10.23% of patients abandoned treatment (53/518). Adults discontinued treatment more frequently than children (OR = 3.36 CI95 = 1.7 to 6.4, p < 0.001). CONCLUSION: Our study supports the safety of BZ for ChD in children and adults. Avoiding BZ treatment due to safety concerns does not seem to be supported by the evidence.

Purpose: To assess the ChatGPT-4 (ChatGPT) large language model (LLM) on tasks relevant to community pharmacy. Methods: ChatGPT was assessed with community pharmacy-relevant test cases involving drug information retrieval, identifying labeling errors, prescription interpretation, decision making under uncertainty and multi-disciplinary consults. Drug information on rituximab, warfarin, and St. John’s wort was queried. The decision-support scenarios consisted of a subject with swollen eyelids, and a maculopapular rash in a subject on lisinopril and ferrous sulfate. The multi-disciplinary scenarios required integration of medication management with nutrition and physical therapy. Results: The responses from ChatGPT-4 for rituximab, warfarin, and St. John’s wort were satisfactory and cited drug databases and drug-specific monographs. ChatGPT identified labeling errors related to incorrect medication strength, form, administration route, unit conversion, and directions. For the patient with inflamed eyelids, the course of action developed by GPT-4 was comparable to the pharmacist’s approach. For the patient with the maculopapular rash, both the pharmacist and ChatGPT placed a drug reaction to either lisinopril or ferrous sulfate at the top of the differential. ChatGPT provided customized vaccination requirements for travel to Brazil, guidance on management of drug allergies, and recovery from a knee injury. ChatGPT provided satisfactory medication management and wellness information for a diabetic on metformin and semaglutide. Conclusions: LLMs have the potential to become a powerful tool in community pharmacy. However, testing in validation studies across diverse pharmacist queries, drug classes, and populations, and engineering to secure patient privacy will be needed to enhance LLM utility.

Aim: To investigate if interventions to discontinue or down-titrate heart failure (HF)-pharmacotherapy are feasible and associated with risks in older people. Methods: A systematic review and meta-analysis were conducted according to PRISMA 2020 guidelines. Electronic databases were searched from inception to March 8th 2023. Randomised controlled trials (RCTs) and observational studies included people with HF, aged >50 years and who discontinued or down-titrated HF-pharmacotherapy. Outcomes were feasibility (whether discontinuation or down-titration of HF-pharmacotherapy was sustained at follow-up) and associated risks (mortality, hospitalisation, adverse drug withdrawal effects [ADWE]). Random-effects meta-analysis was performed when heterogeneity was not substantial (Higgins I2<70%). Sub-analysis by frailty status was conducted. Results: Six RCTs (536-participants) and 27 observational studies (810,499-participants) across six therapeutic classes were included, for 3-260 weeks follow-up. RCTs were conducted in patients presenting with stable HF. Down-titrating a renin-angiotensin system inhibitor (RASI) in patients with chronic kidney disease was 76% likely than continuation (Risk Ratio [RR] 1.76, 95%CI 1.14-2.73), with no difference in mortality (RR 0.64, 95%CI 0.30-1.64). Discontinuation of beta-blockers were feasible compared to continuation in preserved ejection fraction (RR 1.00, 95%CI 0.68-1.47). Participants were 25% likely to re-initiate discontinued diuretics (RR 0.75, 95%CI 0.66-0.86). Digoxin discontinuation was associated with 5.5-fold risk of hospitalisation compared to continuation. Worsening HF was the commonest ADWE. One observational study measured frailty but did not report outcomes by frailty status. Conclusions: The appropriateness and associated risks of down-titrating or discontinuing HF-pharmacotherapy in people aged >75 years is uncertain. Evaluation of outcomes by frailty status necessitates investigation.

The aims of the current review were to identify, in the context of people with acquired communication disorders: factors which influence medication adherence, current interventions targeting medication adherence, and how medication adherence is currently measured. This study was conducted and reported in accordance with both PRISMA and SWiM guidelines. Two authors independently screened the results of a literature search, assessed risk of bias, and extracted relevant data. Eight studies were identified for inclusion. Four of the studies presented information relating to current interventions which target medication adherence for people with acquired communication disorders. Four of the studies investigated factors which influence medication adherence for people with acquired communication disorders. Seven of these eight studies outlined methods used for measuring medication adherence. The results of this review indicate that patient related factors are most associated with medication non-adherence in a population with acquired communication disorders, followed by socio-economic factors and medication-related factors. Despite the recognised importance of medication adherence, no gold standard of assessment or intervention currently exist for this population. Half of the included studies replaced patients with communication difficulties with caregiver proxies, thus reducing opportunities for patients to participate meaningfully in research. The term “acquired communication disorders” encompasses a range of conditions with diverse aetiologies, presentations, and needs, and future research should be tailored to specific patient groups most at risk of medication non-adherence, namely those with aphasia and cognitive-communication impairments. Patients should be empowered to participate in future research to ensure the literature accurately represents their lived experience.

Aim: Population pharmacokinetics (PK) models may be effective to improve antibiotic exposure with individualized dosing. The aim of the study is to assess cefazolin exposure using a population PK model in critically ill children. Methods: We conducted a single center observational study including children under 18 years old who had cefazolin plasma monitoring before and after the model implementation. First concentration at steady state of each cefazolin course was analyzed. Optimal exposure was defined by concentrations values ranged from free concentration over 4 times the MIC for 100% of the dosing interval to total trough or plateau concentration under 100 mg/L. Results: Fifty-eight patients were included, of whom 39 and 19 children received conventional dosing or model-informed dosing, respectively. Median [range] age was 2.3 [0.1-17] years old and median weight was 14.2 [2.9-72] kg. There were more continuous infusions (CI) in the model group than in the conventional group (n=19/19 (100%) vs n=23/39 (59%)). Compared to conventional dosing, model-informed dosing provided more optimal exposure (n=17/39 (44%) vs n= 15/19 (79%), p=0.01) and less underexposure (n= 18/39 (46%) vs n= 2/19 (10%), p=0.008), without increasing overexposure (n= 4/39 (10%) vs n= 2/19 (11%), p=1). Moreover, the time to reach a 50% decrease of C Reactive Protein levels was significantly shorter in the model group than the conventional group (3 [0.5-13] vs 4 [1-34]; p=0.045. Conclusions: Use of individualized cefazolin model-informed dosing improves critically ill children’s exposure. Further studies are needed to assess the clinical benefit of cefazolin PK model application.

L-carnitine is an essential co-factor for mitochondrial fatty acid metabolism which is an important source of energy in cardiac and skeletal muscle. Physiological concentrations of L-carnitine are maintained in man by exogenous dietary intake and endogenous synthesis. Valproic acid is a fatty acid used for numerous therapeutic indications ranging from epilepsy to bipolar disorder. The metabolism of valproic acid produces both therapeutic and toxic metabolites. Whilst it has a good safety profile, adverse effects of valproic acid in chronic use include hepatotoxicity ranging from transient elevation of liver enzymes to fulminant liver failure and hyperammonaemia with resultant encephalopathy. There is evidence supporting the use of L-carnitine in treating hyperammonaemia and hepatotoxicity following chronic therapeutic use and after acute overdose of valproic acid, but the optimal dose and route of administration is unknown. Following exogenous oral administration of L-carnitine, the bioavailability ranges from 14-18%. After bolus intravenous administration of L-carnitine in doses ranging from 20 to 100 mg/kg, the volume of distribution is 0.2-0.3 L/kg and the fraction excreted unchanged in urine is 0.73-0.95 suggesting that renal clearance of L-carnitine is dose-dependent due to saturable renal re-absorption at supra-physiological concentrations. Based on the pharmacokinetics of L-carnitine, we advocate the administration of L-carnitine for valproic-acid induced hyperammonaemia or hepatotoxicity as an intravenous loading dose of 5 mg/kg followed by a continuous intravenous infusion instead of the oral or intravenous boluses which are currently advocated.

Prescribing errors (PEs) can lead to patient harm. Prediction tools are available to detect patients at risk but are not ideal. We investigated whether doctors can identify hospitalized patients at risk of medication-related harm by assessing the prevalence of PEs. This matched case-control study was carried out on three clinical wards (Internal Medicine, Upper GI Surgery, and Otolaryngology & Oncology) in an academic hospital in the Netherlands. A total of 387 patients with 5191 prescriptions were included. A multidisciplinary in-hospital pharmacotherapeutic stewardship team detected 799 PEs affecting 279 patients (72.1%). Most (58.8%) PEs occurred during hospitalization. Doctors identified 40 patients (cases) as needing a clinical medication review (CMR). These patients were matched by age (10 years) and the number of prescriptions at the time of CMR (1), 1:1 with patients not selected for CMRs (controls). There were no significant differences in age, number of prescriptions, sex, renal function, or documented allergies or intolerances between the matched cases and controls or between controls and other patients who did not received a CMR. The incidence of PEs was higher among cases than controls, and more cases than controls had one or more PEs (97.5% versus 72.5% (OR=14.8, 95% CI [1.8 – 121.1], p=0.002)). The rate of PEs was three times higher in cases than in controls (IRR=3.0, 95% [2.3 – 4.0], p<0.001). In conclusion, clinical ward doctors can effectively identify patients with PEs thus at risk of medication-related harm. This may be a new and interesting selecting strategy for targeted PE-mitigating interventions.

Aims: This study aimed to investigate exposure-response (ER) relationships in efficacy and safety for mirvetuximab soravtansine (MIRV) which is a first-in-class antibody-drug conjugate approved for the treatment of folate receptor-α positive platinum-resistant ovarian cancer. Methods: MIRV was characterized in 4 clinical studies. Exposure metrics for MIRV, its payload and a metabolite were derived from a population pharmacokinetic model. Efficacy was analyzed in MIRV-treated patients (N=215) in a recent confirmatory, randomized, chemotherapy-controlled MIRASOL trial, and safety was evaluated in patients pooled across all 4 clinical studies (N=757). Results: In the MIRASOL trial, MIRV demonstrated significant benefit over chemotherapy in progression-free survival (PFS), objective response rate (ORR), and overall survival (OS). The most common adverse events (AEs) included ocular disorders, peripheral neuropathy, and pneumonitis. For PFS, ORR and OS, the trough concentration of MIRV was the predictor consistently found in ER models for efficacy. In contrast, for ocular AEs (as well as the time to onset of ocular AEs) and peripheral neuropathy, the area under the concentration-time curve (AUC) was identified as the exposure metric in ER models for safety. No exposure parameters were found to correlate with pneumonitis. Covariates in all models did not show clinically meaningful impact on efficacy or safety. Logistic regression models for ORR and ocular AEs based on AUC were used to justify the clinical dose regimen approved for MIRV. Conclusions: The trough concentration of MIRV correlated with efficacy whereas the AUC was associated with major AEs. The ER relationships supported the selected therapeutic dose regimen.