Predicting potassium trajectories for risk monitoring in outpatients with heart failure, diabetes mellitus or chronic kidney disease.

Aim: To develop a dynamic prediction model for potassium concentration in the outpatient sector for patients with heart failure (HF), chronic kidney disease (CKD) and/or diabetes mellitus (DM).

Methods: We used administrative claims data from Scotland collected at the Tayside Health Informatics Centre and selected patients between 1 January and 30 June 2020 with underlying conditions of HF, CKD and/or DM. The follow-up time of each patient was divided into assessment periods to predict a patient's maximum potassium value within the next 4 weeks (prediction periods).

Quantification of Arginine-Rich Cyclic Cell-Penetrating Peptide-Lipid Conjugates Using a Surrogate Peptide Extracted by Phospholipase D Digestion and Trifluoroacetic Acid-Based UPLC-MS/MS Analysis.

For the toxicokinetic evaluation of a lipid conjugate of the cell-penetrating peptide cyclic nonaarginine, we aimed to develop a highly sensitive plasma quantification. Due to the amphiphilic properties and high number of basic amino acids, plasma bioanalysis with LC-MS/MS instruments is difficult. Challenges in particular include chromatographic characteristics, minimal extraction recovery, and resistance against collision-induced dissociation.

Transporting trial results to synthetic real-world populations in order to estimate real-world effectiveness of newly marketed medicines.

Introduction: Real-world effectiveness of a new treatment is relevant information for patients, healthcare professionals and payers, especially when patients encountered in routine clinical care differ significantly from those recruited in the randomised controlled trials (RCTs) that led to approval. However, obtaining effect estimates can be challenging when a new drug has only recently been marketed and real-world data (RWD) are not yet available. For new breast cancer (BC) therapies, we illustrate how RCT inferences can be transported to a target population and how a synthetic population can be generated to mimic a target population for which no RWD is yet available.

Towards a prescribing monitoring system for medication safety evaluation within electronic health records: a scoping review.

Background: Medical care can fail for various reasons: diseases can remain undetected and their severity misjudged, therapies can be incorrectly dosed or ineffective, and therapies can trigger new conditions or adverse drug reactions (ADR). To manage the complexity of changing patient circumstances, data-driven techniques play an increasingly important role in monitoring patient safety and treatment success. Therefore, clinical prediction models need to consider longitudinal factors ("Prescribing Monitoring") to ensure clinically meaningful results and avoid misclassification in the dynamic health situation of the individual patient.

Testing Higher Doses of Sildenafil to Repair Brain Injury Secondary to Birth Asphyxia: An Open-Label Dose-Finding Phase 1b Clinical Trial-Sildenafil Administration to Treat Neonatal Encephalopathy-Study 02.

Objective: To evaluate the safety and tolerability of higher doses of sildenafil in neonates with hypoxic-ischemic encephalopathy (HIE) and brain injury.

Study Design: A phase 1b open-label dose-finding clinical trial in neonates with moderate-severe HIE and confirmed brain injury on a day-2 magnetic resonance imaging during therapeutic hypothermia (TH). Enteral sildenafil was administered every 12 hours (q12 h) for 7 days.

Effect of the frequently used antiepileptic drugs carbamazepine, gabapentin, and pregabalin on the pharmacokinetics of edoxaban and other oral factor xa inhibitors in healthy volunteers.

Purpose: Pregabalin, gabapentin, and carbamazepine, a potent inducer of cytochrome P450 (CYP) 3A4 and P-glycoprotein, are frequently used antiepileptic drugs that are often administered together with factor Xa inhibitors (FXaI). We aimed to investigate whether potentially clinically relevant drug-drug interactions occur with these combinations.

Methods: In an open-label fixed-sequence trial in 36 healthy volunteers, we evaluated the pharmacokinetics of 60 mg edoxaban and of a microdosed FXaI cocktail (25 µg apixaban, 50 µg edoxaban, and 25 µg rivaroxaban) before and during treatment with carbamazepine (12 evaluable volunteers, individually dosed to therapeutic concentrations), gabapentin (11 volunteers, titrated to 3 × 400 mg/d), and pregabalin (12 volunteers, titrated to 2 × 300 mg/d).

Phenotypes of Patients with Direct Oral Anticoagulant (DOAC) Underdosing in Atrial Fibrillation: Results from the ARENA Registry.

Background And Objectives: Oral anticoagulation in patients with atrial fibrillation is crucial to prevent thrombus formation in the heart, a major cause of ischemic stroke. The appropriate dose of direct oral anticoagulants (DOAC) - either standard or reduced dose - must be chosen individually in accordance with defined patient characteristics. However, a significant proportion of patients receive inappropriately low DOAC doses (underdosing).

Real-World Application of a Quantitative Systems Pharmacology (QSP) Model to Predict Potassium Concentrations from Electronic Health Records: A Pilot Case towards Prescribing Monitoring of Spironolactone.

Quantitative systems pharmacology (QSP) models are rarely applied prospectively for decision-making in clinical practice. We therefore aimed to operationalize a QSP model for potas-sium homeostasis to predict potassium trajectories based on spironolactone administrations. For this purpose, we proposed a general workflow that was applied to electronic health records (EHR) from patients treated in a German tertiary care hospital.

Identifying Predictors of Heart Failure Readmission in Patients From a Statutory Health Insurance Database: Retrospective Machine Learning Study.

Background: Patients with heart failure (HF) are the most commonly readmitted group of adult patients in Germany. Most patients with HF are readmitted for noncardiovascular reasons. Understanding the relevance of HF management outside the hospital setting is critical to understanding HF and factors that lead to readmission.

[Quality of medication documentation in patientś discharge summaries after implementing new legal requirements].

Introduction: Discharge from hospital is a risk to drug continuity and medication safety. In Germany, new legal requirements concerning the management of patient discharge from the hospital came into force in 2017. They set minimum requirements for the documentation of medications in patient discharge summaries, which are the primary means of communication at transitions of care.

Event Analysis for Automated Estimation of Absent and Persistent Medication Alerts: Novel Methodology.

Background: Event analysis is a promising approach to estimate the acceptance of medication alerts issued by computerized physician order entry (CPOE) systems with an integrated clinical decision support system (CDSS), particularly when alerts cannot be interactively confirmed in the CPOE-CDSS due to its system architecture. Medication documentation is then reviewed for documented evidence of alert acceptance, which can be a time-consuming process, especially when performed manually.

Objective: We present a new automated event analysis approach, which was applied to a large data set generated in a CPOE-CDSS with passive, noninterruptive alerts.

Coadministration of fluconazole to boost subtherapeutic sirolimus concentrations: A case report.

Individual sirolimus whole blood concentrations are highly variable, critically influenced by the concomitant use of cytochrome P450 (CYP) 3A inducers or inhibitors, and also modulated by food. Therapeutic drug monitoring is therefore recommended, especially at treatment start or in circumstances that can influence sirolimus exposure. In this case report, we highlight the challenge of achieving therapeutic sirolimus concentrations and present pragmatic solutions with regimen adaptions, pharmacokinetic enhancement (use of a drug–drug interaction), concentration monitoring, and subsequent modeling of population pharmacokinetics to support treatment decisions.

Effect of Tacrolimus Formulation (Prolonged-Release vs Immediate-Release) on Its Susceptibility to Drug-Drug Interactions with St. John's Wort.

Tacrolimus is metabolized by cytochrome P450 3A (CYP3A) and is susceptible to interactions with the CYP3A and P-glycoprotein inducer St. John's Wort (SJW). CYP3A isozymes are predominantly expressed in the small intestine and liver.

Influence of a Short Course of Ritonavir Used as Booster in Antiviral Therapies Against SARS-CoV-2 on the Exposure of Atorvastatin and Rosuvastatin.

Purpose: Early antiviral treatment with nirmatrelvir/ritonavir is recommended for SARS-CoV-2-infected patients at high risk for severe courses. Such patients are usually chronically ill and susceptible to adverse drug interactions caused by ritonavir. We investigated the interactions of short-term low-dose ritonavir therapy with atorvastatin and rosuvastatin, two statins commonly used in this population.

CYP3A and CYP2C19 Activity Determined by Microdosed Probe Drugs Accurately Predict Voriconazole Clearance in Healthy Adults.

Background And Objective: Voriconazole is an important broad-spectrum anti-fungal drug with nonlinear pharmacokinetics. The aim of this single centre fixed-sequence open-label drug-drug interaction trial in healthy participants (N = 17) was to determine whether microdosed probe drugs for CYP3A and CYP2C19 reliably predict voriconazole clearance (CL).

Methods: At baseline, a single oral microdose of the paradigm substrates midazolam (CYP3A) and omeprazole (CYP2C19) were given to estimate their clearances (CL).

Mortality and Hospitalizations Among Patients Enrolled in an Interprofessional Medication Management Program.

Background: Measures for improving medication safety in outpatient care are often complex and involve medication reviews. Over the period 2016-2022 (with a preceeding one-year pilot phase), an interprofessional medication management program- the Medicines Initiative Saxony-Thuringia (Arzneimittelinitiative Sachsen-Thüringen, ARMIN)-was implemented in two German federal states. More than 5000 patients received a medication review by the end of 2019 by a team composed of physicians and pharmacists and were provided with joint, continuous care thereafter.

Effect of Clarithromycin, a Strong CYP3A and P-glycoprotein Inhibitor, on the Pharmacokinetics of Edoxaban in Healthy Volunteers and the Evaluation of the Drug Interaction with Other Oral Factor Xa Inhibitors by a Microdose Cocktail Approach.

Purpose: We assessed the differential effect of clarithromycin, a strong inhibitor of cytochrome P450 (CYP) 3A4 and P-glycoprotein, on the pharmacokinetics of a regular dose of edoxaban and on a microdose cocktail of factor Xa inhibitors (FXaI). Concurrently, CYP3A activity was determined with a midazolam microdose.

Methods: In an open-label fixed-sequence trial in 12 healthy volunteers, the pharmacokinetics of a microdosed FXaI cocktail (μ-FXaI; 25 μg apixaban, 50 μg edoxaban, and 25 μg rivaroxaban) and of 60 mg edoxaban before and during clarithromycin (2 x 500 mg/d) dosed to steady-state was evaluated.

Anticholinergic burden measures, symptoms, and fall-associated risk in older adults with polypharmacy: Development and validation of a prognostic model.

Background: Anticholinergic burden has been associated with adverse outcomes such as falls. To date, no gold standard measure has been identified to assess anticholinergic burden, and no conclusion has been drawn on which of the different measure algorithms best predicts falls in older patients from general practice. This study compared the ability of five measures of anticholinergic burden to predict falls.

Analysing and improving preoperative medication management in cardiac surgery.

Aims: The objective of this study was to analyse the preoperative medication management within the cardiac surgery patient population and measure the effectiveness of an interprofessional intervention in routine care.

Methods: A jointly developed preoperative medication management was implemented in routine care on multiple levels (inclusion in admission letter to primary care, hotline for inquiries, pocket cards for physicians and correspondence with referring centres). The effectiveness was evaluated by analysing preoperative management before and after implementation.

Quantification of the Time Course of CYP3A Inhibition, Activation, and Induction Using a Population Pharmacokinetic Model of Microdosed Midazolam Continuous Infusion.

Background: Cytochrome P450 (CYP) 3A contributes to the metabolism of many approved drugs. CYP3A perpetrator drugs can profoundly alter the exposure of CYP3A substrates. However, effects of such drug-drug interactions are usually reported as maximum effects rather than studied as time-dependent processes.

A prediction model for nonpersistence or nonadherence to direct oral anticoagulants in hospitalized patients with atrial fibrillation.

Medication adherence and persistence is fundamental for drug effectiveness, which is also true for the prevention of strokes in patients with atrial fibrillation (AF). Adherence to direct oral anticoagulants (DOACs) as first-line agents is often high in the early posthospital period. However, adherence often sharply declines (or eventually leads to nonpersistence) in the post-discharge ambulatory period, rendering stroke prevention ineffective.

HIOPP-6 - a pilot study on the evaluation of an electronic tool to assess and reduce the complexity of drug treatment considering patients' views.

Background: A complex drug treatment might pose a barrier to safe and reliable drug administration for patients. Therefore, a novel tool automatically analyzes structured medication data for factors possibly contributing to complexity and subsequently personalizes the results by evaluating the relevance of each identified factor for the patient by means of key questions. Hence, tailor-made optimization measures can be proposed.