Aims: The aim of this phase 1 trial was to assess the pharmacokinetics, safety, and tolerability of balcinrenone (previously AZD9977) in participants with severe renal impairment versus those with normal renal function. Methods: Participants with severe renal impairment (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m2) not on dialysis were compared with group-matched control participants with eGFR ≥90 mL/min/1.73 m2. Eligible participants received a single oral dose of 150 mg balcinrenone, and blood and urine samples were collected for analysis. Results: The total apparent balcinrenone clearance was 50% lower in the severe renal impairment group, resulting in a ~two-fold higher area under the curve (AUC) and a 1.4-fold higher maximum observed plasma concentration in the severe renal impairment group versus the control group. The terminal half-life and plasma protein binding were similar in both groups. Balcinrenone was safe and well tolerated in all participants. All adverse events reported were of mild-to-moderate severity and not considered related to balcinrenone. Conclusions: Balcinrenone exposure was approximately two-fold higher in participants with severe renal impairment compared with the group-matched control participants. Based on obtained results, the AUC exposure is predicted to be <50% higher in patients with an eGFR of 20 mL/min/1.73 m2 compared with those with an eGFR of 60 mL/min/1.73 m2. In light of these findings, no dose adjustment based on eGFR is needed in two ongoing studies that target these patients (MIRO-CKD [NCT06350123] and BalanceD-HF [NCT06307652]).

Short title of the paper … Aims: The FDA Adverse Event Reporting System (FAERS) database was used to study vortioxetine-associated adverse events (ADEs) in a real-world setting to provide recommendations for the safety management of vortioxetine in clinical use. Methods: The FAERS database was retrospectively queried to extract reports related to vortioxetine between the third quarter of 2013 and the second quarter of 2024. To identify and evaluate potential ADEs in patients treated with vortioxetine, various frequentist analytical methods were used, including reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN) and multi-item gamma Poisson shrinker (MGPS). Results: Vortioxetine was identified as a “prime suspect” drug in 13097 reports. At the system organ class level, vortioxetine was associated with an increased risk of psychiatric disorders (ROR = 5.36, 95% CI = 5.22–5.50) and gastrointestinal disorders (ROR = 1.89, 95% CI = 1.84–1.95). In addition, 162 preferred terms that simultaneously met the criteria of all four algorithms were identified. Among them, anxiety, nausea, vomiting, dry mouth, constipation, pruritus, sedation, and sexual dysfunction were consistent with common ADEs described in clinical trials. The median time to onset of vortioxetine-associated ADEs was 7 days (interquartile range = 1–31 days) and most ADEs occurred within the first month of vortioxetine treatment. Conclusions: This study validated common adverse events and also identified some potential emerging safety issues related to vortioxetine use in real-world clinical practice. Keywords: Vortioxetine, major depressive disorder, pharmacovigilance, adverse events, FDA Adverse Event Reporting System(FAERS)

Background and Aim: Alkaptonuria (AKU) is a rare metabolic disorder characterised by the accumulation of homogentisic acid (HGA). Deposition of HGA in the aortic valve leading to progressive aortic stenosis is a serious complication. Nitisinone has been shown to improve morbidity and slow disease progression in AKU but the effects of this treatment on aortic stenosis progression have not yet been described. This review extrapolated from the data set of SONIA 2, a 4-year multi-centre randomised controlled trial investigating the effect of nitisinone on AKU disease activity, but specifically examined measures of aortic stenosis disease progression. Methods: Data were obtained from echocardiograms performed on 138 patients over 48 months of follow-up. A linear mixed effects regression model was used to ascertain the difference in the maximal trans-aortic valve pressure gradient (Pmax) at baseline and 48 months between the treatment and control groups. Results: At baseline, 18/138 patients (13.0%) had aortic stenosis of varying degrees of severity and 25/138 (18.1%) had aortic sclerosis. The difference in Pmax between the control (N=69) and treatment (N=69) groups at baseline was 0.063mmHg [95% CI: -0.054mmHg to 0.18mmHg) and did not reach statistical significance (p=0.23). At the end of the 4-year treatment period, the difference in Pmax was 0.10mmHg [95% CI: -0.0007mmHg to 0.20mmHg] and was statistically significant (p=0.05). Conclusion: Nitisinone slowed progression of aortic stenosis in patients with AKU. This supports the argument for timely initiation of nitisinone to reduce the incidence and severity of aortic valvular disease in AKU patients.

Aim: Polypharmacy, defined as the concurrent use of multiple medications, poses significant health risks, particularly among aging populations. While polypharmacy is a recognized concern, limited research has investigated its spatial distribution or the demographic and socioeconomic factors influencing its prevalence. This study aimed to examine the spatial patterns of polypharmacy across Japan and identify regional characteristics associated with higher polypharmacy rates. Methods: An ecological study was conducted across 335 local health units in Japan using data from national health, demographic, and geographic databases. Polypharmacy was defined as prescriptions containing seven or more drugs, and the standardized polypharmacy ratio (SPR) was calculated by age-group population. Spatial autocorrelation of SPR was assessed using Moran’s I statistic. Clustering analysis incorporating SPR and regional variables identified distinct high-risk areas. Results: The prediction model for polypharmacy prescriptions achieved an R² of 0.98, indicating high accuracy, though SPR remained heterogeneous. Significant spatial autocorrelation was observed for both polypharmacy prescriptions (Moran’s I = 0.4; P < 0.001) and SPR (Moran’s I = 0.24; P < 0.001), highlighting regional clustering. Clustering analysis identified four groups by polypharmacy risk (Critical, High, Moderate, and Low). High-SPR areas were associated with higher population density, a greater proportion of younger adults (ages 20–60), and increased levels of education, income, and tertiary industry workers. Conclusion: Polypharmacy in Japan exhibits significant spatial clustering, with higher rates in urbanized regions driven by demographic and socioeconomic factors. Region-specific interventions addressing these unique characteristics are essential for improving polypharmacy management.

Thiopurines are a class of immunosuppressant and anti-neoplastic agents. They are widely used in the treatment of inflammatory bowel disease, hematological malignancies, and autoimmune diseases, but can cause significant toxicity. Inherited gene mutations are now recognized as independent risk factors for severe adverse drug reactions to thiopurines even at tenfold dose reductions. We present a case of thiopurine toxicity resulting in severe myelosuppression, hepatotoxicity, and alopecia in an individual with homozygous *3/*3 loss-of-function alleles in the NUDT15 gene. Our case highlights important differences in gene mutation frequencies between races that can help guide pharmacogenomic testing.

BACKGROUND: Botulinum toxin type A (BoNT-A) is widely used for its efficacy in treating a variety of neuromuscular disorders. However, data on its safety and adverse events (AEs) in real-world settings remain limited. The Food and Drug Administration Adverse Event Reporting System (FAERS) database provides an invaluable resource for evaluating the safety of BoNT-A. METHODS: We used four methods to evaluate the disproportionality of AEs associated with BoNT-A: the Reporting Odds Ratio (ROR), the Proportional Reporting Ratio (PRR), the Bayesian Confidence Propagation Neural Network (BCPNN), and the Multi-item Gamma Poisson Shrinker (MGPS). RESULTS: Among the 17,307,196 case reports in the FAERS database, there were 69,644 reports where BoNT-A was listed as the ”Primary Suspect” for AEs. AEs caused by BoNT-A affected 27 system organ classes (SOCs). Based on the four algorithms, 290 significant disproportionalities at the Preferred Term (PT) level were retained. Unexpected AEs such as skin wrinkles, hyperacusis, Guillain-Barre syndrome, mediastinitis, and infective aneurysm were identified, which are not mentioned in the product insert. CONCLUSION: This study provides an overview of AEs in the real-world use of BoNT-A, revealing its broad safety profile. Although the majority of AEs were mild to moderate, there is a need to remain vigilant for serious AEs and to monitor them in clinical practice.

Background: The perspectives of patients and healthcare professionals regarding deprescribing in surgical wards within hospital settings are unknown. Objective: To explore current practices, attitudes, and the enablers and barriers to deprescribing in hospital for older surgical inpatients from the perspectives of doctors, pharmacists, patients and carers. Methods: A mixed methods study was performed. Two surveys were administered Australia-wide (revised Patients’ Attitudes Towards Deprescribing questionnaire for patients/carers and Deprescribing Self-Efficacy Survey for doctors/pharmacists). Interviews, focus groups and observations of ward rounds were conducted with participants from five Australian hospitals. Quantitative data were analysed descriptively, while qualitative data were examined using a combined inductive and deductive approach, with results triangulated. Results: There were 109 survey participants (58 doctors/pharmacists and 51 patients/carers), 28 interview/focus group participants (15 doctors/pharmacists and 13 patients/carers) and eight ward round participants. Doctors and pharmacists reported low to moderate levels of confidence in deprescribing. While most patients and carers were satisfied with their medications, they expressed a willingness to consider deprescribing. Five themes were identified from the interviews, focus groups and ward round observations; 1) deprescribing is not a priority, 2) medication review occurs in response to triggers, 3) knowledge about deprescribing is limited, 4) deprescribing requires a team effort and 5) trust, rapport and communication are essential for successful deprescribing. Conclusions: Doctors working on surgical wards are unlikely to proactively deprescribe medications. A collaborative patient-centred approach involving geriatricians, clinical pharmacologists and pharmacists, along with educational interventions may facilitate deprescribing for surgical patients.

Objective: Taking the practice of clinical pharmacists participating in enhanced recovery after surgery (ERAS) protocol of gastric cancer patients undergoing radical gastrectomy as an example, to explore the value of pharmacists in hospitalization cost control. Methods: 160 gastric cancer patients who underwent radical gastrectomy in Jiangsu Cancer Hospital from February 2023 to October 2023 were divided into control group and research group, with 80 cases in each group. The control group implemented the conventional ERAS protocol without the involvement of the clinical pharmacist. The research group was managed by a professional clinical pharmacist on the base of the conventional ERAS protocol. Results: (1) There were no significant differences in age, gender, site of surgical resection, and TNM stage between the two groups. (2) Compared with the control group, patients in the research group had shorter length of stay (LOS) (P < 0.001) and first postoperative ventilation time (P < 0.001), as well as fewer hospitalization cost (P = 0.005). (3) Albumin on postoperative day (POD) 30 and prealbumin on POD7 were significantly different between two groups (P = 0.029, P = 0.046). (4) The irrational prescription rate of antimicrobials (P < 0.001) and total nutrient admixture (P = 0.001) in the research group were significantly lower than those in the control group. Conclusion: This study shows that clinical pharmacists participating in perioperative ERAS program for gastric cancer can improve the nutritional status, promote the rehabilitation postoperative, shorten LOS, and increase the rate of rational drug use, thus reducing medical expenses

Aim: To assess the risk of major congenital malformations following first-trimester PSE exposure. Methods: A population-based retrospective cohort study was conducted on pregnancies of women aged 15-49 years, insured by Clalit Health Services in southern Israel, who gave birth or had elective pregnancy terminations due to suspected fetal malformation at Soroka Medical Center (1999-2017). The study focused on the drug Clarinase (120 mg PSE, 5 mg loratadine). Multivariate negative binomial regression models were used to evaluate the risk for major congenital malformations, adjusting for potential confounders. Results: Of 251,543 pregnancies, 313 (0.12%) were exposed to Clarinase in the first trimester. PSE exposure was not associated with major congenital malformations overall (adjusted Relative Risk [aRR] = 0.90, 95% CI 0.558-1.45; p=0.66) or by organ system (cardiovascular: aRR = 0.938, p=0.841; central nervous: aRR = 0.618, p=0.633; musculoskeletal: aRR = 1.800, p=0.155; gastrointestinal: aRR = 1.013, p=0.990; genitourinary: aRR = 0.704, p=0.547). Conclusion: First-trimester PSE exposure was not associated with major congenital malformations, either overall or by organ system.

Introduction: Suboptimal adherence to antipsychotics leads to poorer outcomes and relapse. The adherence behaviour of people may be influenced by several factors including the number of antipsychotics used and their formulation. This study aimed to identify longitudinal adherence patterns to oral and long-acting injectable (LAI) antipsychotics in monotherapy or polypharmacy through group-based trajectory modelling (GBTM). Methods: This was a retrospective cohort study that linked prescription and dispensing data of adult patients with a new antipsychotic prescribed between 2015-2019 in Catalonia (Spain). GBTM was used to classify patients following a similar longitudinal pattern of adherence. The response variable was adherence, estimated through the continuous medication availability measure (CMA), in each 30-day period during 12 months of follow-up. Baseline and treatment characteristics were used to characterize the trajectories identified. Results: Among the 7,730 patients included in the study, we identified seven clinically distinct trajectory groups of adherence to antipsychotics: “non-adherent” (19%), “low adherent” (9%), “early-decline” (6%), “mid-decline” (5%), “late-decline” (5%), “high adherent” (21%), and “fully adherent” (35%). Trajectories with better adherence were more likely to receive the prescription from a psychiatrist, receive LAIs and have previous exposure to other antipsychotics. Intermittent medication use patterns and high levels of polypharmacy were characteristics of the “low” and “high adherent” groups. Conclusions: The trajectories reflect three adherence behaviours: stable over time; patients who discontinue treatment and; patients with an intermittent refill pattern. Patients on polypharmacy should have more regular adherence monitoring and LAIs should be considered, as they appear to be associated with better adherence.

Aims: Adavosertib, a WEE1 inhibitor, has been studied for safety and efficacy as monotherapy and in combination therapy. The phase 2b ADAGIO trial evaluated adavosertib monotherapy for uterine serous carcinoma with a recommended dose of 300 mg dosing on days 1 to 5 and days 8 to 12 of 21‑day cycle. However, reports of severe neutropaenia and dose reduction in approximately half of patients at 300 mg suggested potential tolerability concerns. Methods: We conducted a model-based benefit-risk analysis, including an exposure-safety analysis, pooling data from all AstraZeneca-sponsored monotherapy studies. The analysis focused on the relationship between adavosertib exposure and incidence of adverse events such as haematological and gastrointestinal toxicities. A preliminary exposure-efficacy analysis was conducted based on available efficacy data from the ADAGIO study. Results: A strong correlation is observed between adavosertib exposure and predicted probability of developing neutropenia. Also, baseline creatinine clearance (bCLCr) was identified as an independent factor for severe neutropaenia development. Patients with bCLCr ≥50 mL/min were less likely to experience severe neutropaenia than those with bCLCr <50 ml/min. The model shows that a dose reduction from 300 to 250 mg reduces the predicted probability of neutropaenia by 55% when compared at the 95th percentile exposure range at these doses. Contrary to exposure safety, exposure-efficacy relationship was similar across doses. Conclusion: The model-based approach identifies risk factors, aiding in the decision to use a 250 mg monotherapy dose. This regimen may manage hematological toxicities across studies. Reducing adavosertib doses minimizes risks, underscoring the need for dose adjustment

Background: Psoriasis is a chronic autoimmune disease with limited treatment options in India. Methotrexate is a conventional therapy, while Secukinumab, a human monoclonal antibody against IL-17, is a newer option. Objective: To compare the safety and efficacy of Secukinumab versus Methotrexate in Indian patients with moderate to severe plaque psoriasis. Methods: This open-labeled, randomized, case-controlled study included 14 patients (7 per group) with moderate to severe plaque psoriasis. Group A received Secukinumab, while Group B received Methotrexate. Efficacy was assessed by PASI score reduction at Day 90, and safety was evaluated by laboratory investigations and adverse event reporting. Results: Secukinumab showed improvement in PASI score reduction (PASI 75) compared to Methotrexate (p=0.281). Secukinumab was also found to be safer, with fewer adverse events and no significant changes in laboratory parameters. Conclusion: Secukinumab is a more effective and safer treatment option for moderate to severe plaque psoriasis in Indian patients compared to Methotrexate. Further studies are needed to confirm these findings and establish Secukinumab as a viable treatment option in India.

Aims: Endostatin is a type of human vascular endostatin with more stable and higher activity. This study sought to evaluate pharmacokinetics (PK), safety and preliminary efficacy between treatment with endostatin 4 hours intravenous infusion and 72 hours or 168 hours intravenous pump infusion in patients with advanced non-small cell lung cancer (NSCLC). Methods: A total of 24 patients with advanced NSCLC were randomly assigned to group A and B. All patients received a standard 21 days treatment cycle of platinum-based doublet chemotherapy (paclitaxel or pemetrexed) and endostatin. Endostatin was administered at 7.5 mg/m2/day for 4 hours from day 1 to day 14 of cycle 1. Starting from day 1 of cycle 2, endostatin was administered at 105 mg/m2/cycle for 72 hours (group A) or 168 hours (group B), respectively. The total treatment duration was 4 cycles, with the option to extend up to 6 cycles. Results: The PK exposure per cycle of endostatin 4 hours infusion and 72 hours or 168 hours pump infusion were comparable between group A and group B. The majority of adverse events during pump infusion were consistent with those observed during infusion and no endostatin-related serious adverse events were reported. The overall objective response rate (ORR) was 37.5%. Conclusion: The PK exposure between intravenous infusion and intravenous pump infusion at the same total cycle dose is similar. Both 72 hours and 168 hours intravenous pump infusion endostatin were well tolerated, and no new unexpected safety signals were observed.

Aim: Coagulation factor XI (FXI) plays a crucial role in the intrinsic coagulation pathway, and inhibitors targeting it may mitigate the risk of hemorrhage compared to anticoagulants currently on the market. SKB336, a novel selective inhibitor of FXI/FXIa, has been shown to prolong the activated partial thromboplastin time (APTT) in in-vitro and in-vivo studies. This study aimed to determine the safety, tolerability, pharmacokinetics, and pharmacodynamics of SKB336 in healthy subjects. Methods: In this randomized, single-blinded, placebo-controlled, and dose-escalation phase I study, 60 healthy subjects were allocated to six cohorts (0.1 mg/kg, 0.3 mg/kg, 0.6 mg/kg, 1.25 mg/kg, 2.5 mg/kg, and 4 mg/kg) and received SKB336 injection or placebo in a 4:1 ratio. The safety, tolerability, pharmacokinetics, and immunogenicity were measured up to 85 days post-dose. Exploratory analysis consisted of FXI activity and APTT. Results: SKB336 was well tolerated in all six cohorts, without any hemorrhagic events, reported deaths, or serious adverse events. No significant dose-dependent correlation was observed with the incidence of adverse events. Dose-dependent increases in the Cmax and AUC were observed. The mean t1/2 was 21.3–33.5 days, indicating a potential monthly dosing frequency. The maximum inhibition rate of FXI activity for all six cohorts reached 0, 17%, 28%, 48%, 54%, and 59%, respectively. The maximum APTT ratio to baseline reached 1.09-, 1.26-, 1.47-, 1.77, 1.91-, and 2.00-fold, respectively. Conclusion: SKB336 was generally tolerated, without any bleeding events in healthy volunteers. Besides, SKB336 presented a persistent dose-dependent prolongation of APTT and duration of FXI inhibition.

A document by Tirhani Maluleke. Click on the document to view its contents.

Here, we reported a rare case of linear porokeratosis (LP) treated topically with atorvastatin nanoemulgel for 12 weeks. The patient reported no obvious skin irritation and was delighted with the outcome. We evaluated the efficacy of topical atorvastatin as a monotherapy in this LP patient and reviewed the relevant studies on the application of topical statins/cholesterol in treating LP.

Aim Tragic incidents in Phase I trials have been cited to suggest that trials put participants at high levels of risk. This meta-analysis aimed to evaluate risks to Phase I trial participants at the Fortrea Clinical Research Unit (FCRU) (UK) between 2016-2021. Methods Sixty-Five FCRU Phase I trials enrolling 3194 participants were included (99% healthy volunteers). Analysed trials tested active drugs, had finalised clinical study reports (CSRs), and standardised AE reporting procedures. Data on drug type, study design, participant numbers, and AEs were extracted from CSRs. A chi-square test of homogeneity tested mild, moderate, and severe AE probability distributions between placebo and active groups. A negative binomial regression examined relationships of administration route (parenteral vs non-parenteral), drug type (small molecule vs biologic), and trial type (First in Human (FIH) vs non-FIH) to number of AEs reported. Results Over 55% of participants reported at least one AE. 5051 AEs were reported; classified as mild (90.1%), moderate (9.4%), severe (0.4%), or unknown (0.1%). Proportion of AEs by severity category was similar between active and placebo groups (χ2(2)=3.942, p=0.139). Fifteen serious AEs were reported. Parenteral administration and biological drugs had no significant effect on AE incidence. FIH trials were a significant predictor of lower AE risk. Conclusion AEs were commonly reported in these Phase I trials. Trial features perceived to increase AE risks (parenteral administration, biologic drugs) did not and AE risk in FIH trials was lower compared with non-FIH trials. The trials analysed posed a low risk of serious harm to participants.

Background Voriconazole (VCZ) is a first-line treatment drug for invasive fungal disease, with narrow therapeutic window and significant inter-individual variability. VCZ is primarily metabolized by liver, which declines with age. For elderly patients, physiological and pathological factors lead to more pronounced fluctuations in VCZ plasma concentrations. Thus, it is crucial to establish a model that accurately predicts VCZ plasma concentration in elderly patients. Methods A retrospective study was performed incorporating 32 variables, including population pharmacokinetics (PPK) parameters derived from the PPK model. Recursive Feature Elimination with Cross-Validation was used for feature selection. Multiple algorithms were selected and combined into an ensemble model, and the model was interpreted by Shapley Additive exPlanations. Results The predictive performance of machine learning was greatly improved after inclusion of PPK parameters. The composition of XGBoost, RF, and CatBoost (1:1:8) with the highest R2 (0.828) was determined as the final ensemble model. Feature selection greatly simplified the model from 31 variables to 9 variables without compromising its performance. The R2, mean square error, mean absolute error, and accuracy (± 30%) of external validation were 0.633, 1.094, 2.286, and 71.05%, respectively. Conclusions Our study is the first to include PPK parameters as new factors for machine learning modeling to predict VCZ plasma concentrations in elderly patients. The model underwent optimization through feature selection. Our model provides a reference for individualized dosing of VCZ in clinical practice, enhancing the efficacy and safety of VCZ treatment in elderly patients. Keywords: voriconazole, elderly patients, machine learning, population pharmacokinetics, precision medicine