No association between metformin initiation and incident dementia in older adults newly diagnosed with diabetes.

BACKGROUND: Metformin has been suggested to reduce dementia risk; however, most epidemiologic studies have been limited by immortal time bias or confounding due to disease severity. OBJECTIVES: To investigate the association of metformin initiation with incident dementia using strategies that mitigate these important sources of bias. METHODS: Residents of Ontario, Canada ≥66 years newly diagnosed with diabetes from January 1, 2008 to December 31, 2017 entered this retrospective population-based cohort. To consider the indication for metformin monotherapy initiation, people with hemoglobin A1c of 6.5%-8.0% and estimated glomerular filtration rate ≥45 mL/min/1.73 m2 were selected. Using the landmark method to address immortal time bias, exposure was grouped into "metformin monotherapy initiation within 180 days after new diabetes diagnosis" or "no glucose-lowering medications within 180 days." To address disease latency, 1-year lag time was applied to the end of the 180-day landmark period. Incident dementia was defined using a validated algorithm for Alzheimer's disease and related dementias. Adjusted hazard ratios (aHR) and confidence intervals (CIs) were estimated from propensity-score weighted Cox proportional hazard models. RESULTS: Over mean follow-up of 6.77 years from cohort entry, metformin initiation within 180 days after new diabetes diagnosis (N = 12,331; 978 events; 65,762 person-years) showed no association with dementia risk (aHR [95% CI] = 1.05 [0.96-1.15]), compared to delayed or no glucose-lowering medication initiation (N = 22,369; 1768 events; 117,415 person-years). CONCLUSION: Early metformin initiation was not associated with incident dementia in older adults newly diagnosed with diabetes. The utility of metformin to prevent dementia was not supported.

An account on the history of pharmacology in Spain.

Here we present an account on the history of pharmacology in Spain. Pharmacology as an independent science in Europe began with the creation of university chairs. Of particular relevance was the appointment in 1872 of Osswald Shmiedeberg as chairman of an Institute of Pharmacology at the University of Strassbourg, Germany. Teófilo Hernando pioneered in Spain the new emerging pharmacology at the beginning of the XX Century. He made a posdoctoral stay in the laboratory of Schmiedeberg, working on digitalis. In 1912 he won the chair of "Materia Médica y Arte de Recetar" at "Universidad Central of Madrid" (today, "Universidad Complutense de Madrid", UCM). He soon decided to transform such subject to the emerging modern pharmacology, with the teaching of experimental pharmacology in the third course of medical studies and clinical therapeutics (today clinical pharmacology) in the sixth course. This was the status of pharmacology in 1920, supporting the view that Hernando was a pioneer of clinical pharmacology. However, the Spanish Civil War and the II Word War interropted this division of preclinical and clinical pharmacology; only in the 1980's was clinical pharmacolgy partially developed in Spain. From a scientific point of view, Hernando directly trained various young pharmacologists that extended the new science to various Spanish universities. Some of his direct disciples were Benigno Lorenzo Velázquez, Francisco García Valdecasas, Rafael Méndez, Tomás Alday, Gabriel Sánchez de la Cuesta, Dámaso Gutiérrez or Ramón P é rez-Cirera. One of the central research subject was the analysis of the effects of digitalis on the cat and frog heart. In the initiation of the 1970 s pharmacologists trained by those Hernando's students grew throughout various universities and the "Consejo Superior de Investigaciones Científicas" (CSIC). And hence, in 1972 the "Sociedad Española de Farmacología" (SEF) emerged. Later on, in the 1990's the "Sociedad Española de Farmacología Clínica (SEFC) also emerged. The relationship between the two societies is still weak. Out of the vast scope of the pharmacological sciences, Spanish pharmacologists have made relevant contributions in two areas namely, neuropsychopharmacology and cardiovacular pharmacology. Nonetheless, in other areas such as smooth muscle, gastroenterology, pharmacogenetics and hepatic toxicity, Spanish pharmacologists have also made relevant contributions. A succint description of such contributions is made. Finally, some hints on perspectives for the further development of preclinical and clinical pharmacology in Spain, are offered.

Population pharmacokinetic modelling and simulation of tranexamic acid in adult trauma patients.

AIMS: The aim of this study is to describe the disposition of tranexamic acid (TXA) in adult trauma patients and derive a dosing regimen that optimizes exposure based on a predefined exposure target. METHODS: We performed a population pharmacokinetic (popPK) analysis of participants enrolled in the Tranexamic Acid Mechanisms and Pharmacokinetics in Traumatic Injury (TAMPITI) trial (≥18 years with traumatic injury, given ≥1 blood product and/or requiring immediate transfer to the operating room) who were randomized to a single dose of either 2 or 4 g of TXA ≤2 h from time of injury. PopPK analysis was conducted using nonlinear mixed-effects modelling (NONMEM). Simulations were then performed using the final model to generate estimated plasma TXA concentrations in 1000 simulated participants. Dosing schemes were evaluated to determine maintenance of TXA plasma concentrations >10 mg/L for ≥8 h after administration of the initial dose. RESULTS: TXA PK was best described by a two-compartment model with proportional residual error and allometric scaling on all parameters. Platelet count, skeletal muscle oxygen saturation measured by near-infrared spectroscopy and interleukin-8 concentration were significant covariates on TXA clearance. Based on simulations, a 2 g IV bolus dose, repeated 3 h later, best achieved the target exposure. CONCLUSIONS: According to simulations from a popPK model of TXA, a 2 g IV bolus with a repeated dose 3 h later would be most likely to maintain concentrations >10 mg/L for 8 h in >95% of adult trauma patients and should be considered for patients with ongoing haemorrhage.

Saliva monitoring of prednisolone in children with first onset steroid-sensitive nephrotic syndrome: Is it possible?

AIMS: Prednisolone is the cornerstone of treatment for idiopathic nephrotic syndrome in children, but is associated with marked side-effects. Therapeutic drug monitoring using saliva would be a patient-friendly option to monitor prednisolone treatment. To assess the feasibility of saliva monitoring, we described the pharmacokinetics (PK) of unbound prednisolone in plasma and saliva of children with first onset steroid-sensitive nephrotic syndrome (SSNS). METHODS: Children (age 2-16 years) with SSNS participating in a randomized, placebo-controlled trial with levamisole were treated with an 18-week tapering schedule of prednisolone. Five serial samples were collected at 4 (saliva) and 8 weeks (saliva and plasma) after first onset. A nonlinear mixed-effects model was used to estimate the PK parameters of unbound prednisolone and the saliva-to-plasma ratio. Monte Carlo simulations were performed to assess the predictive performance of saliva monitoring. RESULTS: From 39 children, 109 plasma and 275 saliva samples were available. Estimates (relative squared error) of unbound plasma clearance and volume of distribution were 93 (5%) L h-1 70 kg-1 and 158 (7%) L 70 kg-1, respectively. Typical saliva-to-plasma ratio was 1.30 (8%). Monte Carlo simulations demonstrated that on basis of 4 saliva samples and a single plasma sample unbound plasma area-under-the-concentration-time curve can be predicted within 20% imprecision in 79% of the patients compared to 87% based on 4 plasma samples. CONCLUSION: Saliva proved to be a reliable and patient-friendly option to determine prednisolone plasma exposure in children with SSNS. This opens opportunities for further PK and pharmacodynamics studies of prednisolone in a variety of paediatric conditions.

Quality indicators for appropriate in-hospital pharmacotherapeutic stewardship: An international modified Delphi study.

AIMS: In-hospital prescribing errors may result in patient harm, such as prolonged hospitalisation and hospital (re)admission, and may be an emotional burden for the prescribers and healthcare professionals involved. Despite efforts, in-hospital prescribing errors and related harm still occur, necessitating an innovative approach. We therefore propose a novel approach, in-hospital pharmacotherapeutic stewardship (IPS). The aim of this study was to reach consensus on a set of quality indicators (QIs) as a basis for IPS. METHODS: A three-round modified Delphi procedure was performed. Potential QIs were retrieved from two systematic searches of the literature, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. In two written questionnaires and a focus meeting (held between the written questionnaire rounds), potential QIs were appraised by an international, multidisciplinary expert panel composed of members of the European Association for Clinical Pharmacology and Therapeutics (EACPT). RESULTS: The expert panel rated 59 QIs and four general statements, of which 35 QIs were accepted with consensus rates ranging between 79% and 97%. These QIs describe the activities of an IPS programme, the team delivering IPS, the patients eligible for the programme and the outcome measures that should be used to evaluate the care delivered. CONCLUSIONS: A framework of 35 QIs for an IPS programme was systematically developed. These QIs can guide hospitals in setting up a pharmacotherapeutic stewardship programme to reduce in-hospital prescribing errors and improve in-hospital medication safety.

Time-varying brentuximab vedotin pharmacokinetics and weight-based dosing in paediatric patients despite lower exposure in those aged 2 to <6 and 6-11 years.

AIMS: We studied the pharmacokinetics and exposure-response relationships of the brentuximab vedotin (BV) antibody-drug conjugate (ADC) and unconjugated monomethyl auristatin E in haematologic malignancies. METHODS: This population pharmacokinetic analysis included data from five adult and three paediatric studies. Exposures in virtual adult and paediatric populations following BV 1.8 mg/kg (maximum 180 mg) intravenously every 3 weeks were simulated. Clinical endpoints included overall response rate, grade ≥2 peripheral neuropathy (PN) and grade ≥3 neutropenia. RESULTS: BV ADC exhibited linear pharmacokinetics, well-described by a three-compartment model, with body weight being the only significant covariate for exposure. Monomethyl auristatin E exhibited time-varying formation rate. Simulated steady-state BV ADC exposures in patients aged 12 to <18 years were similar to those of adult patients, but 23%-38% lower in patients aged 2 to <12 years. Despite lower exposure, clinical activity was observed with BV 1.8 mg/kg every 3 weeks in those aged 2 to <12 years (overall response rate: 2 to <12 years, 60%; 12 to <18 years, 43%). In adult, but not paediatric patients, increased BV ADC exposures were associated with grade ≥2 PN and grade ≥3 neutropenia occurrence. CONCLUSIONS: BV pharmacokinetics in adult and paediatric patients were consistent. BV ADC exposures were lower in patients aged 2 to <12 years vs. ≥12 years, but no apparent clinically relevant differences in efficacy, grade ≥2 PN or grade ≥3 neutropenia were observed. These data support body weight-based dosing of BV in patients irrespective of age; thus, dose adjustment in those 2 to <12 years does not appear warranted.

Establishment of a children's Drugs and Therapeutics Committee to ensure evidence-based and cost-effective medical treatment for children.

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. Following the guidelines outlined by the World Health Organization, we established a cDTC, and recommendations for paediatric 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. In 2019, the capital region established the first cDTC supported by expert councils and an editorial board. A total of 2429 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 paediatric- and six neonatal product ranges throughout capital region. In conclusion, recommendation lists for children governed by a cDTC provide a rational auxiliary tool that can be immediately implemented in the clinic.

Population pharmacokinetic analysis of doravirine in real-world people with HIV.

AIMS: The pharmacokinetics of doravirine has been studied in clinical trials but not in real-world settings. Our study aims to characterize and identify factors influencing doravirine (a CYP3A4 substrate) pharmacokinetics 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. Demographic data, clinical information and comedications were recorded during the routine SHCS visits (every 3-6 months). 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 inhibitors reduced CL by 50%, and a 30% decrease in CL was observed in an 80-year-old compared with 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. CONCLUSIONS: 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 nonadherence or pregnancy.

Artificial intelligence and machine learning for clinical pharmacology.

Artificial intelligence (AI) will impact many aspects of clinical pharmacology, including drug discovery and development, clinical trials, personalized medicine, pharmacogenomics, pharmacovigilance and clinical toxicology. The rapid progress of AI in healthcare means clinical pharmacologists should have an understanding of AI and its implementation in clinical practice. As with any new therapy or health technology, it is imperative that AI tools are subject to robust and stringent evaluation to ensure that they enhance clinical practice in a safe and equitable manner. This review serves as an introduction to AI for the clinical pharmacologist, highlighting current applications, aspects of model development and issues surrounding evaluation and deployment. The aim of this article is to empower clinical pharmacologists to embrace and lead on the safe and effective use of AI within healthcare.

A physiological approach to renal clearance: From premature neonates to adults.

AIMS: We propose using glomerular filtration rate (GFR) as the physiological basis for distinguishing components of renal clearance. METHODS: Gentamicin, amikacin and vancomycin are thought to be predominantly excreted by the kidneys. A mixed-effects joint model of the pharmacokinetics of these drugs was developed, with a wide dispersion of weight, age and serum creatinine. A dataset created from 18 sources resulted in 27,338 drug concentrations from 9,901 patients. Body size and composition, maturation and renal function were used to describe differences in drug clearance and volume of distribution. RESULTS: This study demonstrates that GFR is a predictor of two distinct components of renal elimination clearance: (1) GFR clearance associated with normal GFR and (2) non-GFR clearance not associated with normal GFR. All three drugs had GFR clearance estimated as a drug-specific percentage of normal GFR (gentamicin 39%, amikacin 90% and vancomycin 57%). The total clearance (sum of GFR and non-GFR clearance), standardized to 70 kg total body mass, 176 cm, male, renal function 1, was 5.58 L/h (95% confidence interval [CI] 5.50-5.69) (gentamicin), 7.77 L/h (95% CI 7.26-8.19) (amikacin) and 4.70 L/h (95% CI 4.61-4.80) (vancomycin). CONCLUSIONS: GFR provides a physiological basis for renal drug elimination. It has been used to distinguish two elimination components. This physiological approach has been applied to describe clearance and volume of distribution from premature neonates to elderly adults with a wide dispersion of size, body composition and renal function. Dose individualization has been implemented using target concentration intervention.

Population kinetic/pharmacodynamic modelling of the haemodynamic effects of cafedrine/theodrenaline (Akrinor) under general anaesthesia.

AIMS: The 20:1 combination of cafedrine and theodrenaline (C/T) is widely used in Germany for the treatment of arterial hypotension. Since there is little knowledge about the impact of covariates on the effect, the aim was to develop a kinetic/pharmacodynamic covariate model describing mean arterial pressure (MAP), systolic (SBP) and diastolic blood pressure (DBP), and heart rate (HR) for 30 min after the administration of C/T. METHODS: Data of patients receiving C/T from the HYPOTENS study (NCT02893241, DRKS00010740) were analysed using nonlinear mixed-effects modelling techniques. RESULTS: Overall, 16 579 measurements from 315 patients were analysed. The combination of two kinetic compartments and a delayed effect model, coupled with distinct Emax models for HR, SBP and DBP, described the data best. The model included age, sex, body mass index (BMI), antihypertensive medication, American Society of Anaesthesiologists (ASA) physical status classification grade, baseline SBP at the time of hypotension and pre-surgery HR as covariates (all P < .001). A higher baseline SBP led to a lower absolute increase in MAP. Patients with higher age, higher BMI and lower ASA grade showed smaller increases in MAP. The initial increase was similar for male and female patients. The long-term effect was higher in women. Concomitant antihypertensive medication caused a delayed effect and a lower maximum MAP. The HR increased only slightly (median increase 2.6 bpm, P < .001). CONCLUSIONS: Seven covariates with an impact on the effect of C/T could be identified. The results will enable physicians to optimize the dose with respect to individual patients.

Evaluation of artificial intelligence-generated drug therapy communication skill competencies in medical education.

AIMS: This study compared three artificial intelligence (AI) platforms' potential to identify drug therapy communication competencies expected of a graduating medical doctor. METHODS: We presented three AI platforms, namely, Poe Assistant©, ChatGPT© and Google Bard©, with structured queries to generate communication skill competencies and case scenarios appropriate for graduating medical doctors. These case scenarios comprised 15 prototypical medical conditions that required drug prescriptions. Two authors independently evaluated the AI-enhanced clinical encounters, which integrated a diverse range of information to create patient-centred care plans. Through a consensus-based approach using a checklist, the communication components generated for each scenario were assessed. The instructions and warnings provided for each case scenario were evaluated by referencing the British National Formulary. RESULTS: AI platforms demonstrated overlap in competency domains generated, albeit with variations in wording. The domains of knowledge (basic and clinical pharmacology, prescribing, communication and drug safety) were unanimously recognized by all platforms. A broad consensus among Poe Assistant© and ChatGPT© on drug therapy-related communication issues specific to each case scenario was evident. The consensus primarily encompassed salutation, generic drug prescribed, treatment goals and follow-up schedules. Differences were observed in patient instruction clarity, listed side effects, warnings and patient empowerment. Google Bard did not provide guidance on patient communication issues. CONCLUSIONS: AI platforms recognized competencies with variations in how these were stated. Poe Assistant© and ChatGPT© exhibited alignment of communication issues. However, significant discrepancies were observed in specific skill components, indicating the necessity of human intervention to critically evaluate AI-generated outputs.

Artificial intelligence in clinical pharmacology: A case study and scoping review of large language models and bioweapon potential.

This paper aims to explore the possibility of employing large language models (LLMs) - a type of artificial intelligence (AI) - in clinical pharmacology, with a focus on its possible misuse in bioweapon development. Additionally, ethical considerations, legislation and potential risk reduction measures are analysed. The existing literature is reviewed to investigate the potential misuse of AI and LLMs in bioweapon creation. The search includes articles from PubMed, Scopus and Web of Science Core Collection that were identified using a specific protocol. To explore the regulatory landscape, the OECD.ai platform was used. The review highlights the dual-use vulnerability of AI and LLMs, with a focus on bioweapon development. Subsequently, a case study is used to illustrate the potential of AI manipulation resulting in harmful substance synthesis. Existing regulations inadequately address the ethical concerns tied to AI and LLMs. Mitigation measures are proposed, including technical solutions (explainable AI), establishing ethical guidelines through collaborative efforts, and implementing policy changes to create a comprehensive regulatory framework. The integration of AI and LLMs into clinical pharmacology presents invaluable opportunities, while also introducing significant ethical and safety considerations. Addressing the dual-use nature of AI requires robust regulations, as well as adopting a strategic approach grounded in technical solutions and ethical values following the principles of transparency, accountability and safety. Additionally, AI's potential role in developing countermeasures against novel hazardous substances is underscored. By adopting a proactive approach, the potential benefits of AI and LLMs can be fully harnessed while minimizing the associated risks.

A first-in-human study of the novel immunology antibody-drug conjugate, ABBV-3373, in healthy participants.

AIMS: ABBV-3373, an immunology antibody-drug conjugate composed of adalimumab conjugated to a proprietary glucocorticoid receptor modulator (the small-molecule payload), has the potential to treat immune-mediated inflammatory diseases. This first-in-human study investigated the pharmacokinetics (PK), immunogenicity, pharmacodynamics (PD) using a safety PD marker, and safety/tolerability of ABBV-3373 in healthy adults. METHODS: Fifty-five participants were randomly assigned to single-dose subcutaneous (SC; 30, 100 or 300 mg) or intravenous (IV; 30, 300 or 900 mg) ABBV-3373 or placebo. Eight additional participants received a single dose of 10 mg oral prednisone for evaluation of systemic glucocorticoid effects. Blood samples were collected for up to 85 days postdose for PK, anti-drug antibody and serum cortisol (safety PD marker) assessments. RESULTS: ABBV-3373 and total antibody displayed antibody-like SC/IV PK profiles and the unconjugated/free payload in circulation exhibited formation rate-limited kinetics with exposure several fold lower than ABBV-3373 or total antibody. Treatment-emergent anti-drug antibody incidence was 69%, with loss of exposure in 6% (SC) and 5% (IV) of participants, but without any impact on safety. ABBV-3373 up to 300 mg SC/IV had no apparent impact on serum cortisol, and only caused a transient decrease at 900 mg IV. Treatment-emergent adverse events were primarily mild in severity, and no pattern emerged with respect to dose or route of administration. CONCLUSIONS: ABBV-3373 had favourable PK profiles, manageable immunogenicity, and was generally well-tolerated. Except for a transient effect at 900 mg IV, there was no apparent impact on serum cortisol. Study results supported further clinical development of ABBV-3373.

Sugammadex Use Outside of the Postoperative Setting.

BACKGROUND: Sugammadex rapidly reverses the nondepolarizing neuromuscular blocking agents (NMBAs) rocuronium and vecuronium. The role of sugammadex is not well-defined outside of the postoperative setting. OBJECTIVE: This study aims to describe sugammadex use outside the postoperative setting for the reversal of nondepolarizing NMBAs. METHODS: This was a single-center, retrospective cohort study conducted in patients who received sugammadex outside of the postoperative setting at an academic medical center between June 2016 and November 2022. The primary outcome was the effect of sugammadex use for rocuronium reversal, defined as any increase in train-of-four (TOF) after sugammadex administration and/or progress note documentation if TOF was unavailable. Secondary outcomes included adverse events and documentation of contraceptive counseling in patients taking hormonal contraceptives with child-bearing ability. RESULTS: A total of 14 383 patients received sugammadex during the study period. Of those patients, 39 (0.3%) were outside of the postoperative setting for the reversal of rocuronium and included in the study. Twenty-nine (74%) patients had an increase in TOF after sugammadex administration and/or progress note documentation if TOF was unavailable. Ten (26%) patients lacked documentation regarding the effect of sugammadex. No adverse reactions were reported. Three (8%) patients included in the study were of child-bearing ability, and 1 of the 3 patients was counseled on using an alternative method of contraception following sugammadex administration. CONCLUSION AND RELEVANCE: There is a paucity of literature for the use of sugammadex outside of the postoperative setting. This study found that while the use of sugammadex was rare, overall, it was safe and well-tolerated.

Pirtobrutinib: A New and Distinctive Treatment Option for B-Cell Malignancies.

OBJECTIVE: The objective was to evaluate the efficacy/safety of pirtobrutinib in the treatment of B-cell malignancies and distinguish it from other available Bruton's tyrosine kinase (BTK) inhibitors. DATA SOURCES: A literature search of PubMed (January 2021 through November 2023) and Clinicaltrials.gov was conducted using terms pirtobrutinib, Jaypirca, and LOXO 305. Licensing trials of available BTK inhibitors were also reviewed. STUDY SELECTION AND DATA EXTRACTION: Relevant English-language clinical trials were evaluated. DATA SYNTHESIS: Pirtobrutinib was approved by the US Food and Drug Administration for the treatment of relapsed/refractory mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) based largely on a phase 1/2 study in B-cell malignancies. Pirtobrutinib demonstrated a 73% overall response rate (ORR) in the CLL population and 58% in MCL. Pirtobrutinib has activity in patients resistant to earlier-generation, covalent BTK inhibitors. In fact, the ORRs were similar in BTK-pretreated and naïve patients. Adverse effects include fatigue, diarrhea, bleeding, and infection. Atrial fibrillation, a class effect of BTK inhibitors, may be less common with pirtobrutinib. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE IN COMPARISON WITH EXISTING DRUGS: Compared with earlier-generation BTK inhibitors, pirtobrutinib is more selective for BTK and binds noncovalently to the receptor. Ongoing studies are evaluating pirtobrutinib's use in multiple B-cell malignancies and comparing it with other BTK inhibitors. CONCLUSION: The characteristics of pirtobrutinib render it useful in the treatment of B-cell malignancies no longer responding to a previous BTK inhibitor, and results from ongoing clinical trials may support future expanded use.

Angiotensin Receptor Blocker-Related Sprue-like Enteropathy: Review of Food and Drug Administration Adverse Event Reporting System.

BACKGROUND: Sprue-like enteropathy (SE) related to olmesartan use was first reported in 2012. In 2017, the manufacturer of Benicar paid $300 million for 2300 claims for olmesartan-related SE. OBJECTIVE: A study in 2019 suggested that SE was related to olmesartan and with the possibility of angiotensin receptor blocker (ARB) class effect. To further characterize this condition, our group examined reports of ARB-related SE to Food and Drug Administration Adverse Event Reporting System (FAERS). METHODS: All reports of ARB-related SE from January 2017 to December 2021 were downloaded from the FAERS database. Gastrointestinal adverse events including SE were reviewed. Reporter categories included physicians, pharmacists, other health care professionals, consumers, and attorneys. RESULTS: A total of 106 590 reports of ARB-related adverse effects were analyzed. Sprue-like enteropathy was identified in 4337 cases (4.1% of total reports). Of these, 4240 cases (98.0%) of ARB-related SE were reported in patients using products with olmesartan, and 97 cases of SE were reported for all other ARBs (eprosartan, losartan, telmisartan, irbesartan, valsartan, and candesartan). Reports of olmesartan-related SE increased rapidly in 2017, continued at a high rate in 2018 and 2019, and essentially stopped in 2020 and 2021. CONCLUSIONS AND RELEVANCE: Reports to FAERS for ARB-related SE are mostly related to olmesartan. There was a steep decline in reports of olmesartan-related SE following the lawsuit with potential of lawyer interference. There are reports of SE related to ARBs other than olmesartan, with increased physician awareness and the potential to discover a class effect with future studies.

Activities of clinical pharmacologists across Europe: A survey by the European association of clinical pharmacology and therapeutics.

PURPOSE: In order to explore clinical pharmacology and therapeutics (CPT) teaching and practices across continental Europe, the European Association of Clinical Pharmacology and Therapeutics (EACPT) made a survey in 2022 amongst its 27 affiliated societies. METHODS: The survey was made available online to EACPT representatives, and 47 filled-in questionnaires were received from 25 countries (one to five per country), representing all geographic areas of Europe. RESULTS: Clinical pharmacologists (CPs) spend 25%, 30%, 15%, and 25% of their time in teaching, hospital activities, committees, and research, respectively, with large variations across and within countries. CPT courses are given at Schools of Medicine in all the countries except one, mostly organized and taught by medical doctors (MDs). In Central, Western, and Southern Europe, the teachers may have medicine or pharmacy training. Therapeutic drug monitoring and pharmacovigilance were the hospital activities most frequently reported, and clinical/forensic toxicology, rounds of visits, and pharmacogenetics the least. Two-thirds of the panel think CPs should be MDs. However, the transversal nature of CPT was underlined, with patients/diseases and drugs as gravity centres, thus calling for the complementary skills of MDs and PharmDs. Besides, most respondents reported that clinical pharmacists in their country are involved in rounds of visits, pharmacovigilance, TDM, and/or pharmacogenetic testing and that collaborations with them would be beneficial. CONCLUSION: CPT comes with a plurality of backgrounds and activities, all required to embrace the different pathologies and the whole lifecycle of medicinal products, but all of them being rarely performed in any given country. The willingness to use common CPT teaching material and prescribing exams at the European level is a good sign of increasing harmonisation of our discipline Europewide.

Intraoperative pharmacologic opioid minimisation strategies and patient-centred outcomes after surgery: a scoping review.

BACKGROUND: Postoperative patient-centred outcome measures are essential to capture the patient's experience after surgery. Although a large number of pharmacologic opioid minimisation strategies (i.e. opioid alternatives) are used for patients undergoing surgery, it remains unclear which strategies are most promising in terms of patient-centred outcome improvements. This scoping review had two main objectives: (1) to map and describe evidence from clinical trials assessing the patient-centred effectiveness of pharmacologic intraoperative opioid minimisation strategies in adult surgical patients, and (2) to identify promising pharmacologic opioid minimisation strategies. METHODS: We searched MEDLINE, Embase, CENTRAL, Web of Science, and CINAHL databases from inception to February 2023. We included trials investigating the use of opioid minimisation strategies in adult surgical patients and reporting at least one patient-centred outcome. Study screening and data extraction were conducted independently by at least two reviewers. RESULTS: Of 24,842 citations screened for eligibility, 2803 trials assessed the effectiveness of intraoperative opioid minimisation strategies. Of these, 457 trials (67,060 participants) met eligibility criteria, reporting at least one patient-centred outcome. In the 107 trials that included a patient-centred primary outcome, patient wellbeing was the most frequently used domain (55 trials). Based on aggregate findings, dexmedetomidine, systemic lidocaine, and COX-2 inhibitors were promising strategies, while paracetamol, ketamine, and gabapentinoids were less promising. Almost half of the trials (253 trials) did not report a protocol or registration number. CONCLUSIONS: Researchers should prioritise and include patient-centred outcomes in the assessment of opioid minimisation strategy effectiveness. We identified three potentially promising pharmacologic intraoperative opioid minimisation strategies that should be further assessed through systematic reviews and multicentre trials. Findings from our scoping review may be influenced by selective outcome reporting bias. STUDY REGISTRATION: OSF - https://osf.io/7kea3.

Therapeutic drug monitoring in anticancer agents: perspectives of Australian medical oncologists.

BACKGROUND: In the development of anticancer agents for solid tumours, body surface area continues to be used to personalise dosing despite minimal evidence for its use over other dosing strategies. With the development of tyrosine kinase inhibitors and other oral targeted anticancer agents, dosing using therapeutic drug monitoring (TDM) is now utilised in many health systems but has had limited uptake in Australia. AIM: To determine attitudes and barriers to the implementation of TDM among Australian oncologists. METHODS: A comprehensive questionnaire was developed by the Dutch Pharmacology Oncology Group from semistructured interviews of stakeholders. Seventy-nine questions across seven domains were developed with three free-text responses. This was rationalised to 17 questions with three free-text responses for Australian medical oncologists who identified limited experience with TDM. RESULTS: Fifty-seven responses were received, with 49 clinicians (86%) identifying limited experience of performing TDM in daily practice. Clinicians were positive (62-91% agree/strongly agree across seven questions) about the advantages of TDM. There was a mixed response for cost-effectiveness and scientific evidence being a barrier to implementation, but strong agreement that prospective studies were needed (75% agreed or strongly agreed); that national treatment guidelines would enable practice (80%) and that a 'pharmacology of oncolytics' education programme would be useful (96%) to provide knowledge for dose individualisation. CONCLUSION: Despite the limited experience of TDM in oncology in Australia, medical oncologists appear positive about the potential benefit to their patients. We have identified three barriers to implementation that could be targeted for increased adoption of TDM in oncology in Australia.