Background Recombinant factor IX Fc fusion protein (rFIX-Fc) is an extended half-life (EHL) factor concentrate administered to haemophilia B patients. So far, a population pharmacokinetic (PK) model has only been published for patients ≥12 years of age. Aim Assess the predictive performance of the published rFIX-Fc population PK model for patients of all ages and develop a model that describes rFIX-Fc PK using real world data. Methods We collected prospective and retrospective data from patients with haemophilia B (FIX activity level ≤5 IU/dL) treated with rFIX-Fc and included in the OPTI-CLOT TARGET study (NTR7523) or United Kingdom (UK)-EHL Outcome Registry (NCT02938156). Predictive performance was assessed by comparing predicted with observed FIX activity levels. A novel population PK model was constructed using nonlinear mixed-effects modelling. Results Real world data was obtained from 37 patients (median age: 16 years, range 2-71) of whom 14 were <12 years of age. Observed FIX activity levels were significantly higher than levels predicted using the published model, with a median prediction error (PE) of -48.8%. The novel model showed a lower median PE (3.4%) and better described rFIX-Fc PK, especially for children <12 years of age. In the novel model, an increase in age was correlated with a decrease in clearance (p<0.01). Conclusion The published population PK model significantly underpredicted FIX activity levels. The novel model better describes rFIX-Fc PK, especially for children <12 years of age. This study underlines the necessity to strive for representative population PK models, thereby avoiding extrapolation outside the studied population.

Aim The prevalence of undocumented medical treatments among children is a significant issue, as well as many EU countries lack access to newly developed children friendly medicines. Consequently, there is a pressing need for supplementary resources that can facilitate informed decision-making regarding children’s medication. We therefore aim to describe the process of establishing a children’s Drug and Therapeutics Committee (cDTC), as well as the preparing and implementation of recommendations for children in the Capital region of Denmark Method Following the guidelines outlined by the World Health Organization a cDTC was established. Recommendations for pediatric medication practice were constructed from assessments of medication use patterns among children in the Capital Region between 2019 and 2021. The recommendations were meticulously crafted based on evaluation of the current marketing authorization landscape and existing best available evidence. Results In 2019, the Capital Region established the first cDTC supported by expert councils and an editorial board. A total of 2.429 purchase item numbers covering 1.222.846 defined daily doses and 592.088 purchased packages covering 10.200.000 defined daily doses were identified in the secondary and primary sectors, respectively. Three comprehensive lists covering recommendations for newborns and children were published between 2021 and 2020 totaling 331 recommended pharmaceutical products. The recommendations primarily intended for use in the secondary healthcare sector were implemented through the revision of 38 pediatric- and 6 neonatal product ranges throughout Capital region. Conclusion Recommendation lists for children governed by a cDTC provide a rational auxiliary tool that can be immediately implemented in the clinic.

Abstract Aims Bruton’s tyrosine kinase inhibitors (BTKIs), including first-generation ibrutinib, second-generation acalabrutinib, and zanubrutinib may have certain mechanisms of action (MOAs) related to adverse effects (AEs) on the cardiovascular system. We aimed to evaluate the cardiac AEs of BTKIs reported to the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) and to compare the differences in cardiovascular toxicity of ibrutinib, acalabrutinib, and zanubrutinib. Methods Only primary suspect drugs from the FAERS database were extracted from January 2013 to December 2022 across all indications of FDA-approved BTKIs. Disproportionality was measured by reporting odds ratios (RORs) and information components (ICs). An additional disproportionality analysis was also performed from January 2020 to December 2022. Results A total of 10,353 cases involving ibrutinib, acalabrutinib and zanubrutinib were included. Ibrutinib was significantly associated with the incidence of cerebrovascular accidents, myocardial infarction and other thrombotic events. Acalabrutinib was associated with new signals, including cardiac failure, ventricular extrasystoles, pulmonary edema and angina pectoris, and hypertension and myocardial infarction were found in additional analyses. Furthermore, acalabrutinib was characterized by a much earlier onset of cardiovascular events. Only atrial fibrillation was associated with zanubrutinib use. Acalabrutinib and zanubrutinib had lower ROR values for cardiac AEs, and fewer signals for these two drugs compared with ibrutinib. Conclusion This study indicated that new AEs were not clearly noted on the label for acalabrutinib. It is suggested that the cardiovascular risks of BTKIs remain a concern and worth attention as next-generation BTKIs are discovered and developed.

Introduction: A key reason for the failure of anti-tuberculosis (TB) treatment is missed doses (instances where medication is not taken). Adverse drug reactions (ADRs) are one cause of missed doses, but the global evidence for this, their relative contribution to missed doses versus other causes, the patterns of missed doses due to ADRs, and the specific ADRs associated with missed doses have not been appraised. We sought to address these questions through a scoping review. Methods: MEDLINE, Embase and Web of Science were searched on 3 November 2021 using terms around active TB, missed doses and treatment challenges. Studies reporting both ADR and missed dose data were examined. (PROSPERO: CRD42022295209). Results: Searches identified 108 eligible studies. 88/108 (81%) studies associated ADRs with an increase in missed doses. 33/61 (54%) studies documenting the reasons for missed doses gave ADRs as a primary reason. No studies examined patterns of missed doses due to ADRs. 41/108 (38%) studies examined associations between 68 types of ADR (across 15 organ systems) and missed doses. Nuance around ADR-missed doses relations regarding drug susceptibility testing profile and missed dose originator was found. Conclusions: There is extensive evidence that ADRs are a key driver for missed doses of anti-TB treatment. Some papers examined specific ADRs, none evaluated the patterns of missed doses due to ADRs, demonstrating a knowledge deficit. Knowing why doses both are and are not missed due to ADRs is essential in providing targeted interventions to improve treatment outcomes.

Introduction Randomised controlled trials show a reduction in acute kidney injury, renal impairment, and acute renal failure after initiation of a sodium glucose cotransporter-2 inhibitor. Observational literature on the association is conflicting, however important to understand for populations with a higher risk of medication-related adverse renal events. We aimed to systematically review the literature to summarize the association between sodium glucose cotransporter-2 inhibitor use and acute kidney injury, renal impairment, and acute renal failure in three at-risk groups: older people aged >65 years, people with heart failure, and people with reduced renal function. Methods Data Sources: A systematic search of Embase (1974–29/03/21) and PubMed (1946–29/03/21) was performed. Study Selection: RCTs and observational studies were included if they reported numbers of acute kidney injury or acute renal failure in people using sodium glucose cotransporter-2 inhibitors, compared to other diabetic therapies. Studies needed to report results by level of renal function, heart failure status, or age. Results Of 858 results, 6 studies were included. The absolute risk of acute kidney injury or acute renal failure was higher in people >65 years compared to those <65 years, higher in people with heart failure (vs. without), and higher in people with reduced kidney function (vs. preserved kidney function), but insufficient evidence to determine if the relative effect of sodium glucose cotransporter-2 inhibitors on this risk was similar for each group. Conclusion At risk cohorts are associated with a higher incidence of acute kidney problems in users of sodium glucose cotransporter-2 inhibitors.

Aim To evaluate the performance of ChatGPT in key areas of clinical pharmacy practice, including prescription review, patient medication education, adverse drug reaction (ADR) recognition, ADR causality assessment, and drug counseling. Methods Quantitative and qualitative analyses were conducted to assess the accuracy and quality of ChatGPT in comparison to those of the clinical pharmacist. Results The results indicate that ChatGPT is excellent in drug counseling and weak in prescription review, patient medication education, ADR recognition, and ADR causality. Conclusions While ChatGPT holds promise in clinical pharmacy practice as a supplementary tool, the ability of ChatGPT to handle complex problems needs further improvement and refinement.

Aims Information on breastfeeding and the safety of biologics in infants is lacking due to difficulties in case collection. We evaluated a method for determining the concentration of biologics in breast milk using a dry filter method that can simplify the collection, storage, and transport of breast milk. Methods To generate dried filter paper (DFP) samples, approximately 30 L of breast milk was placed onto a Whatman 903 card and punched out. After extraction, the supernatant was measured using an enzyme-linked immunosorbent assay. Three concentrations of each drug were prepared in liquid breast milk (LBM) and DFP samples for stability testing, which confirmed that samples were stable up to 28 days after storage at 2–8 ºC or -20 ºC for LBM and at 25±5 ºC for DFP. LBM and DFP samples were provided by lactating mothers using biologics during lactation. Drug concentrations were compared. Results Breast milk was provided by 12 lactating mothers (tocilizumab, n=4; abatacept, n=2; etanercept, n=1; golimumab, n=1; sarilumab, n=1; and belimumab, n=3). The accuracy and precision of measurements for the six drugs were within acceptable limits. After 28 days, concentrations remained at more than 90% under all storage conditions. The quantitative values of the provided LBM and DFP samples were similar. The maximum relative infant dose ranged from 0.09% to 1.12%, which was an acceptable range. Conclusion A method for determining the concentration of biologics using DFP is expected to help improve pharmacotherapy for lactating women.

The potential of using chatGPT in pharmacometrics was explored in this study, with a focus on developing a pharmacokinetic (PK) model for standard half-life factor VIII. Our results demonstrated that chatGPT can be utilized to accurately obtain typical PK parameters from literature, generate a population PK model in R, and develop an interactive Shiny application to visualize the results. ChatGPT’s language generation capabilities enabled the development of R codes with minimal programming knowledge and helped identify and fix errors in the code. While chatGPT presents several advantages, such as its ability to streamline the development process, its use in pharmacometrics also has limitations and challenges, including the accuracy and reliability of AI-generated data, the lack of transparency and interpretability of AI. Overall, our study demonstrates the potential of using chatGPT in pharmacometrics, but researchers must carefully evaluate its use for their specific needs.

Objective Methotrexate (MTX) is the cornerstone in the treatment of rheumatoid arthritis (RA) patients. However, adherence to MTX therapy is not optimal, and instruments to assess medication non-adherence are warranted. To date there is no consensus on the best method to determine adherence to MTX. The aim of this study was to assess the correlation between adherence assessed with a Medication Event Monitoring System (MEMS) versus pill count, MTX-polyglutamate (PG) concentration and Compliance-Questionnaire-Rheumatology (CQR) in patients with established RA. Second, the correlations between these methods and the Disease Activity Scores of 28 joints (DAS28) were examined. Methods Adult RA patients currently treated with MTX were included. Multivariable linear and logistic regression were used, with adherence assessed with MEMS as dependent variable versus pill count, MTX-PG concentrations, CQR as independent variables, and DAS28 versus each of the four adherence measurements. Covariates were included, such as comedication, age and use of corticosteroids. Results 190 consecutive RA patients were included. Pill count was correlated with adherence assessed with MEMS (linear regression, β = .690, p = <.001), whereas CQR and MTX-PGs were not. Logistic regression confirmed the correlation between dichotomized adherence and pill count only (β = 5.64, p= <.001). No other correlations were found, neither for all adherence outcomes and DAS28. Conclusion Measuring adherence with MEMS is correlated with pill count, whereas other methods were not correlated with MEMS, nor with DAS28. Pill count can be used to estimate adherence to MTX therapy, in case MEMS is not achievable.

Tamoxifen is the most used hormonal therapy for estrogen receptor positive breast cancer. CYP2D6 is the main enzyme in the metabolic pathway of tamoxifen to endoxifen. Variations in endoxifen plasma concentrations are associated with CYP2D6 polymorphisms. This study aimed to determine the association between the CYP2D6 polymorphisms and endoxifen plasma concentrations in a cohort of Zimbabwean breast cancer patients (n = 40). TaqMan genotyping and copy number assays were done to determine CYP2D6 genotypes. Tamoxifen and metabolites were quantitated using LC-MS/MS. The population had high frequencies of the CYP2D6 reduced function alleles, *17 (15%) and *29 (18%). The median endoxifen concentration was 4.78 ng/ml and 55% of the patients, mostly intermediate metabolizers were below the endoxifen therapeutic threshold 5.97 ng/ml. The CYP2D6 phenotypes and activity scores were significantly associated with endoxifen plasma concentrations (p = 0.0151) and with endoxifen to N-desmethyl tamoxifen ratios (p = 0.0006).

Aim: This study was conducted to develop a population pharmacokinetic (PK) model of methotrexate in Korean patients with hematologic malignancy, identify factors affecting methotrexate PK, and propose optimal dosage regimen for the Korean population. Methods: Data were retrospectively collected from 188 patients with acute leukemia or non-Hodgkin’s lymphoma who were admitted to Severance Hospital for the period from 2005 to 2015. Using demographic factors and laboratory results as potential covariates for PK parameters, model development was performed using NONMEM and optimal dosing regimens were developed using the final PK model. Results: A two-compartment model incorporating body weight via allometry best described the data, yielding typical parameter values of 25.99L for central volume of distribution (V_1), 18.76L for peripheral volume of distribution (V_2), 12.9L/h for clearance (CL) and 0.646L/h for inter-compartmental clearance. Covariate analyses showed that, at the weight of 50kg, CL decreased by 0.11 L/h for each one-year increase in age above 14 years old and decreased to 0.8-fold when serum creatinine level doubled, indicating the importance of age-specific dose individualization in methotrexate treatment. Volume of distribution at steady state derived from PK parameters (=V_1+V_2) was 0.90L/kg, which was similar to those in the Western or Chinese population. Optimal doses simulated from the final model successfully produced the PK measures close to the target chosen. Conclusion: The population PK model and optimal dosage regimens developed in this study can be used as a basis to achieve precision dosing in Korean patients with hematologic malignancy.

Purpose Chemodenervation with botulinum neurotoxin type A (BoNTA) is the preferred method for focal spasticity management among various treatment options. While BoNTA injection is considered safe, its widespread use and increasing evidence raise safety concerns. Case In this paper, we present a patient with central pontine myelinolysis, a rare disease, who developed Acute Respiratory Distress Syndrome (ARDS) on the third day after BoNTA application to the spastic gastrocnemius muscle group and required intubation in the intensive care unit due to this complication. Conclusion To our knowledge, this is the first case reported in the literature to develop an acute pulmonary complication after BoNTA injection into spastic lower extremity muscles.

Whole bowel irrigation is a method of gastric decontamination in the poisoned patient involving administration of large volumes of osmotically balanced polyethylene glycol-electrolyte solution to empty the gastrointestinal tract of ingested toxins before absorption, limiting systemic toxicity. While this approach may seem intuitive and it can lead to expulsion of tablets or packets in the rectal effluent, there is a lack of evidence correlating this with improved patient outcomes. Administration of whole bowel irrigation is also challenging to the inexperienced physician and associated with adverse effects, which may be serious. Recommendations for the consideration of whole bowel irrigation are limited to patients who have ingested modified release preparations, those of have ingested pharmaceuticals not adsorbed by activated charcoal, and for the removal of packages in body packers. Until more robust evidence is available from high-quality prospective studies demonstrating efficacy, the use of whole bowel irrigation should not be used routinely in poisoned patients.

Background: Several medicinal treatments for avoiding post-operative ileus (POI) after abdominal surgery have been evaluated in randomised controlled trials. This network meta-analysis aimed to explore the relative effectiveness of these different treatments on ileus outcome measures. Methods: A systematic literature review was performed to identify randomised controlled trials (RCTs) comparing treatments for post-operative ileus following abdominal surgery. A Bayesian network meta-analysis was performed. Direct and indirect comparisons of all regimens were simultaneously compared using random-effects network meta-analysis. Results: A total of 38 randomised controlled trials were included in this network meta-analysis reporting on 6371 patients. Our network meta-analysis shows that prokinetics significantly reduce the duration of first gas (Mean difference (MD) (hours) – 16; credible interval - 30, - 3.1; surface under the cumulative ranking curve (SUCRA) 0.418), duration of first bowel movements (Mean difference (MD) (hours) -25; credible interval - 39, - 11; SUCRA 0.25) and duration of post-operative hospitalisation (Mean difference (MD) (hours) – 1.9; credible interval – 3.8, - 0.040; SUCRA 0.34). Opioid antagonists are the only treatment that significantly improve the duration of food recovery (Mean difference (MD) (hours) - 19; credible interval - 26, - 14; SUCRA 0.163). Conclusion: Based on our meta-analysis, the two most consistent pharmacological treatments able to effectively reduce POI after abdominal surgery are prokinetics and opioid antagonists. The absence of clear superiority of one treatment over another highlights the limits of the pharmacological principles available.

The practice of documenting pharmacists’ interventions (PIs) has been endorsed by many hospital pharmacists’ societies and organizations worldwide. Current systems for recording PIs have been developed to generate data on better patient and healthcare outcomes, but harmonization and transferability are apparently minimal. The present work aims to provide a descriptive and comprehensive overview of the currently utilized PIs documentation and classification (D/C) tools contributing to increased evidence systematization. A systematic literature search was conducted in PUBMED, Scopus, Web of Science and CINAHL. Studies from 2008, after the release of the Basel Statements, were included if interventions were made by the hospital or clinical pharmacists in a global hospital setting. Publications quality assessment was accomplished using the Mixed Methods Appraisal Tool (MMAT). A total of 26 studies were included. Three studies did not refer to the D/C method, 10 used an in-house developed D/C method, seven used externally developed D/C tools and six studies described method validation or translation. Evidence confirmed that most of the D/C systems are designed in-house, but external development and validation of PI systems to be used in hospital practice is gradually increasing. Reports on validated PIs D/C tools that are being used in hospital clinical practice are limited, including countries with advanced hospital pharmacy practice. Unmet needs and gaps in practice were identified. Further research should be conducted to understand why using validated D/C methods is not a disseminated practice, knowing patients’ and organizational advantages.

AIMS The aim of this umbrella review was to identify tools and guidelines available to aid the deprescribing process of potentially inappropriate medications (PIM), evaluate their methods of development and validation, and describe at what level of evidence medications are included in the tools and guidelines. METHODS Searches were conducted on MEDLINE(Ovid), Embase.com, Cochrane CDSR, CINAHL (EBSCO), Web of Science Core Collection, and guideline databases from the date of inception to July 7, 2022. We described and compared the different characteristics and contents of tools and guidelines. RESULTS From 10,606 records screened, 23 systematic reviews and guidelines met the inclusion criteria. We then identified 90 tools (67 explicit, 12 mixed, 11 implicit), and 9 guidelines. The majority were developed for use in older adults (n = 74). Nineteen tools targeted older adults with limited life expectancy (LLE), and 7 targeted children <18 years. The majority (97%) of explicit/mixed tools were validated through Delphi techniques (n = 61). Two tools and eight guidelines provided information on the level of evidence for the included medications, of which less than a quarter were included based on high-quality evidence. CONCLUSION Existing tools are available for a diversity of populations. Discrepancies identified in categorizing medications as appropriate or not can be a result of low quality evidence. Particularly, tools for patients with LLE were developed based on very limited evidence, and research to generate this evidence is highly needed. Our medication lists, along with the level of evidence, could facilitate efforts to strengthen the evidence.

Aim: This study evaluated the effects of SHR0302 on the pharmacokinetics of cytochrome P450 (CYP) probe substrates. Methods: We performed a single-center, open-label, three-period drug-drug interaction (DDI) study in 24 healthy subjects (NCT05392127). Subjects received a single oral dose of 5 mg warfarin (CYP2C9), 20 mg omeprazole (CYP2C19), and 15 mg midazolam (CYP3A4) on day 1, 8, and 22, and received 0.5 mg repaglinide (CYP2C8) on day 7, 14, and 28. Multiple oral doses of 8 mg SHR0302 were administered once daily from day 8 to day 28. Results: The exposure of S-warfarin and repaglinide were comparable before and after SHR0302 administration. AUC of midazolam was not affected by SHR0302, whereas the administration of SHR0302 slightly decreased the Cmax of midazolam by 7.6% (single dose) and 15.7% (once daily for 14 days). The AUC0-t, AUC0-inf, and Cmax of omeprazole were slightly decreased after a single dose of SHR0302 by 19.2%, 21.8%, and 23.5%, respectively. In the presence of SHR0302 for 14 days, the AUC0-t, AUC0-inf, and Cmax of omeprazole were marginally reduced by 3.0%, 16.4%, and 8.3%, respectively. According to the induction mechanism of the CYP enzyme, for the investigation of the induction effect, the results of multiple administration of the perpetrator were more reliable than those of the single dose. Conclusion: The results demonstrated that co-administration of SHR0302 is unlikely to have a clinically meaningful effect on the exposure of drugs metabolized by CYP3A4, CYP2C8, CYP2C9, and CYP2C19 in healthy subjects.

C. Abstract AIM: Sevoflurane is an ether-based inhalational anesthetic that induces and maintains general anesthesia. Our study aimed to detect sevoflurane-induced nephrogenic diabetes insipidus using Data Mining Algorithms (DMAs) and molecular docking. The FAERS database was analyzed using OpenVigil 2.1 for disproportionality analysis. Methods: We analyzed FAERS data from 2004 to 2022 to determine the incidence of nephrogenic diabetes insipidus associated with sevoflurane. Reporting Odds Ratios (RORs) and Proportional Odds Ratios (PRRs) with 95% confidence intervals were calculated. We also used molecular docking with AutoDock Vina to examine sevoflurane’s binding affinity to relevant receptors. Results: A total of 554 nephrogenic diabetes insipidus cases were reported in FAERS, of which 2.5% (14 cases) were associated with sevoflurane. Positive signals were observed for sevoflurane with reporting odds ratios (ROR) of 76.012 (95% CI: 44.67-129.35) and proportional odds ratios (PRR) of 75.72 (Chi-sq: 934.688). Of the 14 cases, 50% required hospitalization, 14% resulted in death, and the remaining cases were categorized as other outcomes. Molecular docking analysis showed that sevoflurane exhibited high binding affinity towards AQP2 (4NEF) and AVRP2 (6U1N) with docking scores of -4.9 and -5.3, respectively. Conclusion: Sevoflurane use is significantly associated with the incidence of nephrogenic diabetes insipidus. Healthcare professionals should be cautious when using this medication and report any adverse events to regulatory agencies. Further research is needed to validate these findings and identify risk factors while performing statistical adjustments to prevent false-positives. Clinical monitoring is crucial to validate potential adverse effects of Sevoflurane.