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.

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.

Aims: Lenvatinib mesylate (LEN) is an orally administered tyrosine kinase inhibitor (TKI) used to treat various cancers, including hepatocellular carcinoma (HCC). LEN therapy for HCC is associated with a high incidence of adverse events, including hypertension (HTN). However, the risk factors associated with LEN therapy remain unclear. This study aimed to investigate the incidence of LEN-induced HTN (LENiHTN) and the relationship between the incidence of HTN and patient demographics in patients with HCC receiving LEN therapy. Methods: This was a single-centre, retrospective study of patients with HCC who received LEN therapy between 19 April 2018 and 30 September 2020. The observation period was from 1 week before the start to 1 month after the end of LEN administration. Results: In total, 75 patients with HCC were enrolled. LENiHTN of any grade was found in 74.7% of patients. The use of two or more antihypertensive agents before starting LEN was more common (P = 0.007); serum potassium (K), and albumin–bilirubin score (ALBI) were lower (P = 0.013 and 0.038, respectively); and albumin (Alb) was higher (P = 0.025). The cut-off values of K, Alb, and ALBI for HTN were estimated to be 4.1 mEq L-1, 3.1 g dL-1, and -1.736, respectively. In the multivariate analysis, K and ALBI were independent risk factors for LENiHTN. Conclusion: Low K and high ALBI were independent risk factors for LENiHTN. Systematic evaluation of HTN risk and early intervention for HTN prevention among high-risk patients can markedly enhance the efficacy and utilisation of LEN therapy.

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: Pharmacogenetics (PGx) is increasingly recognised as a strategy for medicines optimisation and prevention of adverse drug reactions. According to guidelines produced by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetic Working Group (DPWG), most medicines with drug-gene interactions (DGIs) are prescribed in primary care. This study aimed to estimate the prevalence of potential and actionable DGIs involving all medicines dispensed in Irish primary care. Methods: Dispensings of 46 drugs to General Medical Services (GMS) patients in the Health Service Executive Primary Care Reimbursement Service (HSE-PCRS) Irish pharmacy claims database from 01/01/21-31/12/21 were analysed to estimate the national prevalence of total dispensings and incidence of first time dispensings of drugs with potential DGIs according to the CPIC and/or DPWG guidelines. Phenotype frequency data from the UK Biobank and the CPIC were used to estimate the incidence of actionable DGIs. Results: One in five dispensings [12,443,637 of 62,754,498; (19.8%)] were medicines with potential DGIs; 1,878,255 of these dispensed for the first time. On application of phenotype frequencies and linked guideline based therapeutic recommendations, 2,349,055 potential DGIs i.e. (18.9%) required action, such as monitoring, guarding against maximum dose, drug or dose change. One in five [369,700 (19.7%)] first time dispensings required action, with 139,169 (7.4%) requiring a change in prescribing. Antidepressants, weak opioids and statins were most commonly identified as having actionable DGIs. Conclusions: There is a high prevalence of DGIs in primary care in the Irish setting, identifying the need and opportunity to optimise drug therapy through PGx testing.

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.

Great advances have been made in the knowledge of development and regulatory approval of medicinal product containing genetically Modified cells. Although a guideline has been available in the EU since 2012, the current updated version provides a useful guide to developers and professionals involved in the regulatory process of these medicines. This article presents the main issues communicated in that guidance, the regulators' insights and a commentary from the academic developers' point of view.

Long-acting injectable (LAI) cabotegravir and rilpivirine for HIV treatment and LAI cabotegravir for pre-exposure HIV prophylaxis are being rolled out in a multitude of countries worldwide. Due to the prolonged exposure, it can be challenging to undertake ‘traditional’ pharmacokinetic studies and current guidance is derived from their oral equivalents or physiologically-based pharmacokinetic studies. This review aims to consider pharmacokinetic characteristics of cabotegravir and rilpivirine and describe anticipated drug-drug interactions (DDIs) with frequent concomitant medications in African settings. Relevant comedications were identified from the WHO 2021 List of Essential Medicines. All original human and physiologically-based pharmacokinetic studies published in English on PubMed, discussing DDIs with LAI cabotegravir and rilpivirine prior to April 2023, were reviewed. The Liverpool HIV interaction database was also reviewed. LAI cabotegravir and rilpivirine have half-lives of 6-12 and 13-28 weeks, respectively. Cabotegravir is primarily metabolised by UDP-glucuronyltransferase (UGT)-1A1 and rilpivirine by cytochrome P450 (CYP)-3A4. LAI cabotegravir and rilpivirine themselves exhibit low risk of perpetrating interactions with comedications as they do not induce or inhibit the major drug metabolising enzymes. However, they are victims of DDIs relating to the induction of their metabolising enzymes by concomitantly administered medication. Noteworthy contraindicated comedications include rifamycins, carbamazepine, phenytoin, flucloxacillin and griseofulvin, which induce CYP3A4 and/or UGT1A1, causing clinically-significant reduced concentrations of rilpivirine and/or cabotegravir. In addition to virologic failure, subtherapeutic concentrations resulting from DDIs can lead to emergent drug resistance. Clinicians should be aware of potential DDIs and counsel people receiving LAI cabotegravir/rilpivirine appropriately to minimise risk.

A document by Olivia Liu. Click on the document to view its contents.

Aims This randomized controlled pilot study aimed to assess the differences in the frequency, type, and severity of prescribing errors made by medical students when assessed in an electronic prescribing system (EPS) compared to traditional prescribing methods (e.g., writing/typing out a prescription). Methods Fourth year medical students in the period of November 1st to July 31st, 2023, were asked to participate in this single center prospective, randomized, controlled intervention study. Participants performed a prescribing assessment in either an EPS (intervention group) or in a more traditional prescribing platform (control group). The prescriptions were checked for errors, graded, and categorized. Differences in prescribing errors, error categories, and severity were analyzed. Results Out of 334 students, 84 participated in the study. Nearly all participants (98.8%) made one or more prescribing errors, primarily involving inadequate information errors. In the intervention group, more participants made prescribing errors involving the prescribed amount (71.4% vs. 19.0%; P<0.01), but fewer involving administrative errors (2.4% vs. 19.0%; P=0.03). Prescribing-method-specific errors were identified in 4.8% and 40.5% of the intervention and control group, respectively, with significant differences in overlapping errors as well. Conclusions This study shows the importance of training electronic prescribing (e-prescribing) competencies in medical curricula, in addition to traditional prescribing methods. It identifies prescribing-method-specific prescribing errors and emphasizes the need for further research to define e-prescribing competencies. Additionally, the need for an accessible real-life-like e-prescribing environment tailored to educators and students is essential for effective learning and incorporation of e-prescribing into medical curricula.

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

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 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.

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.

Aim: The pharmacokinetics of doravirine have been studied in clinical trials, but not in real-world settings. Our study aims to characterize and identify factors influencing doravirine pharmacokinetics (a CYP3A4 substrate) in real-world people with HIV (PWH). Methods: A total of 174 doravirine concentrations measured in 146 PWH followed up in the therapeutic drug monitoring (TDM) program at the University Hospital of Lausanne (Switzerland) between 2019 and 2023 were included in the analysis. Population pharmacokinetic analysis and Monte Carlo simulations to investigate the clinical significance of the covariates retained in the final model were performed using NONMEM. Results: A one-compartment model with first-order absorption and linear elimination best described doravirine pharmacokinetics. Potent CYP3A4 inhibitors and, to a lesser extent age, were the only tested covariates to significantly impact doravirine clearance (CL). Potent CYP3A4 reduced CL by 50%, and a 30% decrease in CL was observed in an 80-year-old compared to a 55-year-old PWH. The effect of potent CYP3A4 inhibitors was prominent, explaining 59% of between-subject variability in CL. Model-based simulations predicted 2.8-fold and 1.6-fold increases in median steady-state trough and maximum doravirine concentrations, respectively, when a potent CYP3A4 inhibitor was co-administered. Conclusion: Our findings show that potent CYP3A4 inhibitors and age influence doravirine pharmacokinetics. However, given the good tolerability of doravirine, dosing adjustment of doravirine is probably not mandatory in those situations. TDM remains useful essentially in specific clinical situations, such as hepatic impairment, suspected non-adherence or pregnancy.

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.

A reexamination of clinical principles of long-term opioid therapy (LTOT) for chronic pain is long overdue amid the ongoing opioid crisis. Most patients on LTOT report ineffectiveness (poor pain control, function, and health), but still find deprescribing challenging. Although prescribed as analgesics, opioids more likely provide pain relief primarily through reward system actions (enhanced relief and motivation) and placebo effect and less through anti-nociceptive effects. The unavoidable physiologic LTOT dependence can automatically lead to a paradoxical worsening of pain, disability, and medical instability (maladaptive opioid dependence) without addiction due to allostatic opponent neuroadaptations involving reward/anti-reward and nociceptive/anti-nociceptive systems. This opioid induced chronic pain syndrome (OICP) can persist/progress whether LTOT dose is maintained at the same level, increased, decreased, or discontinued. Current conceptualization of LTOT as a straightforward long-term analgesic therapy appears incongruous in view of the complex mechanisms of opioid action, LTOT dependence and OICP. LTOT can be more appropriately conceptualized as therapeutic induction and maintenance of an adaptive LTOT dependence for functional improvement irrespective of analgesic benefits. Adaptive LTOT dependence should be ideally used for a limited time to achieve maximum functional recovery and deprescribed while maintaining functional gains. Patients on LTOT should be regularly reevaluated to identify if maladaptive LTOT dependence with OICP has diminished any functional gains or lead to ineffectiveness. Ineffective LTOT (with maladaptive LTOT dependence) should be modified to make it safer and more effective. An adequately functional life without opioids is the ideal healthy long-term goal for both LTOT initiation and LTOT modification.