British Journal of Clinical Pharmacology

BackgroundPrescription opioids account for more than 40% of opioid induced mortalities. With the trend towards increased opioid prescribing set to continue rising, opioid-based adverse drug reactions, (ADRs) and their associated human and financial cost present a major global public health concern. The review examined the relationship between CYP2D6 phenotypes and opioid metabolising. The aim was to establish whether screening for CYP2D6 phenotypes would improve existing opioid dosing strategies and reduce ADRs. MethodA systematic review was conducted using the online Web of Science database. Selected key words and Boolean operator combinations were used to search the relevant literature. Identified studies were screened against pre-defined inclusion/exclusion criteria. Eligible studies were subject to full review and quality assessment. A narrative analysis was performed to synthesise data from the studies included in the final review. ResultsThe review yielded five studies that met the eligibility criteria and were subject to full review. Four of the five studies reported significant effects of CYP2D6 phenotypes on opioid metabolising or opioid based ADRs. Three studies focused exclusively on pharmacokinetics, two studies focused exclusively on ADRs, and one study considered pharmacokinetics and ADRs. All pharmacokinetic studies reported a significant association between CYP2D6 phenotypes and opioid metabolising. Only one of the studies reported a significant association between CYP2D6 phenotypes and ADRs. ConclusionThe majority of evidence considered in the review supports the role of CYP2D6 in the metabolising of opioids and opioid based ADRs. Consequently, CYP2D6 screening should be considered as a potential mechanism for improving existing opioid dosing strategies and reducing ADRs. There is a need for further higher quality primary data studies focusing specifically on CYP2D6 phenotyping in the context of dosage strategies and exploring impact in longitudinal designs. Future studies should also seek to develop cost effective CYP2D6 screening methods to help support the clinical significance of CYP2D6 phenotyping.

ImportanceThe usage of social media is associated with worsening perceptions of body image and increasing access to, and use of, toxic weight loss supplements. Little is known about the effect of nonlethal doses of one mechanistically unique supplement, 2,4-dinitrophenol (DNP). DNP has been banned by the FDA making human studies difficult, but the public still consumes DNP leading to a gap in our knowledge on the effects of DNP. Here we use social media to investigate the use of DNP, providing the largest characterization of its usage to date. ObjectiveDetermine the doses of DNP generally consumed, adverse effects at those doses, and coingestants. DesignCross-sectional analysis of Internet posts. SettingOur study collected publicly available data from 2017-2018 from Internet discussion forums (also called bulletin boards) dedicated to the discussion of weight loss and body building. ParticipantsParticipants are anonymous posters on these Internet forums. Main MeasuresOur main measure was the distribution of reported doses of DNP consumed. Our secondary measure was the frequency of adverse effects reported at those doses. ResultsWe collected 661 posts across 5 online forums. The most commonly ingested dose reported was 150 mg (1-2 pills, depending on formulation), followed by 300 mg (2-3 pills). The most commonly reported adverse effects were sweating and a sensation of warmth, followed by yellow discoloration of secretions. The most common coingestants were antihistamines, cetirizine and loratadine. Conclusions and Relevance2,4-dinitrophenol is a mechanistically unique weight loss agent reported to be associated with sweating and a sensation of warmth at the most commonly reported ingested doses. Common co-ingestants are antihistamines, although itching was not directly reported as a side effect. Coingestion of an antihistamine, which can lessen the bodys ability to dissipate heat, could worsen the side effects of DNP. This is the first formal description derived from social media of DNP usage at nonlethal doses. Further investigation is needed to determine the therapeutic index of DNP. Less toxic derivatives may provide a starting point for pharmacological adjuncts to weight-loss.

IntroductionAcute Liver Failure (ALF) has no effective treatment other than liver transplantation, and is commonly caused by paracetamol overdose. New treatments are needed to treat and prevent ALF. Alternatively activated macrophages (AAMs) can promote resolution of liver necrosis and stimulate hepatocyte proliferation. Using AAMs in unscheduled care requires the use of an allogeneic product. A clinical trial is needed to determine the safety and tolerability of allogeneic AAMs. Methods and analysisA single centre, open-label, dose-escalation, phase 1 randomised trial to determine whether there is dose-limiting toxicity of AAMs in patients with paracetamol-induced acute liver injury. Randomisation will occur at higher doses. Ethics and disseminationThe trial will be conducted according to the ethical principles of the Declaration of Helsinki 2013 and has been approved by North East - York Research Ethics Committee (reference 23/NE/0019), NHS Lothian Research and Development department, and the UK Medicines and Healthcare products Regulatory Agency. When the trial concludes, results will be shared by presentation and publication. Trial registration number: ISRCTN 12637839.

BackgroundWhile levothyroxine is one of the most extensively prescribed drugs during pregnancy, the possible effects of levothyroxine on the metabolome are not well known. Our aim was to determine levothyroxine treatment-associated changes in the metabolite profile of umbilical cord serum after birth, as well as in maternal serum samples collected at different stages of pregnancy, and link these to the health of the newborn. MethodsThe study cohort, 118 levothyroxine-treated and 118 healthy control pregnancies, was collected from Kuopio University Hospital, Finland, during the years 2013-2017. Serum metabolite profiles were determined with nuclear magnetic resonance-based metabolomics from 1) umbilical cord blood samples, 2) samples collected during the 1st trimester and 3) during delivery from the pregnant women. There was no difference in demographic characteristics between study groups including gestational age. ResultsThere was a negative correlation between cord blood thyroid stimulating hormone (CBTSH) concentrations and Apgar scores at the 1-minute and 5-minute time-points in levothyroxine-treated pregnancies. Furthermore, the concentrations of cord serum metabolites linked with anaerobic glycolysis, e.g., lactate, citrate and glycerol, as well as all measured amino acids were negatively associated with Apgar scores. Furthermore, cord serum concentrations of lactate ({beta} = 0.50, p < 0.0001), glycerol ({beta} = 0.41, p < 0.0001) and alanine ({beta} = 0.34, p = 0.0005) were positively correlated with CBTSH concentrations in the levothyroxine-treated pregnancies. No differences in the 1st trimester samples were observed between the groups. In the during delivery samples, there was small but significant decrease in cholesteryl esters, cholesterol and phospholipids in small very low-density lipoprotein in the levothyroxine-treated pregnancies. ConclusionsIn the levothyroxine-treated pregnancies, the alterations detected in the cord serum concentrations of metabolites linked to fetal hypoxia and muscle degradation could explain the association between CBTSH and the health of the newborn measured via Apgar scores.

Modafinil, a prescription-only drug, it is mainly used to treat narcolepsy and sleep disorders, but it is also used, without a prescription, as a cognitive enhancer by [~]10% of UK University students. Previous research has focused on the prevalence of, and motivations for, these behaviours. Here we focused specifically on determining whether students view this behaviour as cheating. We used a scenario-based approach to quantify, and qualitatively understand, student views on this topic. Most students did not view this behaviour as cheating, in part due to similarities with freely available stimulants such as caffeine, and a view that cognitive enhancement does not confer new knowledge or understanding. Although a minority of students did view it as cheating, they also expressed strong views, based in part on basic questions of fairness and access. Few students did not have a view either way. These views remained largely unchanged even when presented with considerations of other moderators of the ethics of cognitive enhancement with modafinil.

ObjectivesTo map specialty-specific industry payments to Australian healthcare professionals over a nine year period (2015-24), quantify distribution and concentration of payments, and compare patterns with those reported internationally. DesignRepeated cross-sectional and cohort analysis SettingAll public disclosures of payments by pharmaceutical companies to Australian healthcare professionals, 1 October 2015 to 31 October 2024. Participants23,528 named healthcare professionals who received at least one payment from a Medicines Australia member company. Main outcome measuresPrimary outcomes were: (1) payment volume (number and value of payments, distribution by purpose of payment); (2) profession and specialty reach (proportion of registered practitioners with [&ge;] 1 payment; and (3) concentration of payments (the share of the total value received by top 1%, 5%, and 10% of recipients). Secondary outcomes were persistence of payments across reporting periods, breadth of company relationships, and company-specialty payment patterns. Results104,663 payments with a total value of A$164,445,101 ({pound}79.0m) were reported. Payments ranged from A$1 to A$114,400, with a median of A$1,000 (IQR A$582 to A$1,600). Over 80% of paid clinicians received at least one payment for attending an educational meeting and over 90% of the total value of funding covered travel or fees for service. Medical practitioners accounted for A$148.7m (90.4% of total spending); nurses received A$11.7m (7.1%), and pharmacists A$1.8m (1.1%). In total, 12.2% of doctors, 2.1% of pharmacists, and 1% of nurses in Australia received at least one payment between 2015 and 2024. Specialist reach was highest in clinical haematology and oncology (86%) and rheumatology (82%). Payments were highly concentrated: the top 1% of clinicians received 25% of all dollars, the top 5% 55.3%, and the top 10% 70.5%. Persistence of payments was common, with 30.3% of clinicians appearing in more than two reporting periods. Annual totals peaked in 2016/17 (A$30.8m), contracted between 2018/19 to 2021/22 and rebounded by 2023/24 (A$21.6m). ConclusionPharmaceutical company payments to Australian healthcare professionals were common and highly concentrated, particularly in specialties with current on-patent medicines, mirroring patterns reported in the United States. Competing interests management should prioritise independence in clinician education, avoid company sponsored drug promotion, and maintain robust disclosure and governance. What is already knownIndustry payments to clinicians are common internationally and can influence prescribing. Australian evidence to date has been fragmented by period, profession, or specialty. What this study addsUsing all named disclosures from 2015-24, payments in Australia were widespread, with over 1 in 10 doctors in Australia receiving at least one payment. Payments were also highly concentrated, with the top 1% of recipients receiving 25% of the total payment amount. Haematology and oncology and rheumatology had the highest specialty reach. Findings support stronger competing interests management in medical education and continuing professional development.

This study employed physiologically based pharmacokinetic (PBPK) modelling to compare the extent of fetal exposure between oral and long-acting injectable (LAI) aripiprazole and olanzapine. Adult and pregnancy PBPK models were developed and validated with relevant clinical data. Relevant indices of fetal exposure during pregnancy were predicted from concentration-time data at steady-state dosing for both oral and LAI formulations. Fetal Cmax for aripiprazole was 59-78% higher with LAI than oral, and 68-181% higher with LAI olanzapine than the oral formulation. Predicted C:M ratios (range) was 0.59-0.69 for oral aripiprazole and 0.61-0.66 for LAI aripiprazole, 0.34-0.64 for oral olanzapine and 0.89-0.96 for LAI olanzapine. Also, cumulative fetal exposure over 28 days from oral formulations were generally predicted to be lower compared with their therapeutic-equivalent LAI. As in utero fetal exposure to maternal drugs does not necessarily translate to risk, these data should be interpreted in a broader context that includes benefit-risk assessments.

ImportanceClinical evidence suggests that the time of day of treatment can affect outcomes in many different diseases, but this information is dispersed, imprecise, and heterogeneous. Consequently, practice guidelines and clinical care recommendations seldom specify intervention time. ObjectiveTo understand the sources of variability and summarize clinical findings on the time of day effects of medicine. Data SourcesA systematic search of Pubmed, Google Scholar, and ClinicalTrials.gov for "chronotherapy" OR "time of administration". Study SelectionAny clinical study since 2000, randomized or observational, that compared the effects of treatment at different times of day. We included pharmacologic or surgical interventions having at least one continuous outcome. Data Extraction and SynthesisFor selected studies, we extracted the mean and variance of each time-of-day treatment group. From these, we computed the standardized mean difference (SMD) as the measure of timing effect. Where a study reported multiple outcomes, we selected a single outcome based on a defined order of priority. Main Outcomes and MeasuresWe estimated overall pooled effect size and heterogeneity by a random effects model, followed by outlier detection and subgroup analyses to evaluate how study factors, including drug, design, outcome, and source, associate with timing effect. Results78 studies met the inclusion criteria, comprising 48 distinct interventions over many therapeutic areas. We found an overall effect of time on clinical outcomes but with substantial heterogeneity between studies. Predicted effects range from none to large depending on the study context. Study size, registration status, and source are associated with the magnitude of effect. Larger trials and those that were pre-registered have markedly smaller effects, suggesting that the published record overstates the effects of the timing of medicine on clinical outcomes. In particular, the notion that antihypertensives are more effective if taken at bedtime draws disproportionately from one source in the field, which consistently detects larger effects than the community average. Lastly, among the most highly studied drug timing relationships, aspirins anti-clotting effect stands out, consistently favoring evening over morning dosing. Conclusions and RelevanceWhile accounts of drug timing effects have focused on yes/no, appreciating the range of probable effects may help clarify where circadian medicine meets the threshold for clinical benefit.

OBJECTIVETo describe the patient burden and benefit, and the dynamics of trial success in the development of ixabepilone--a drug that was approved in the US but not in Europe. DATA SOURCESTrials were captured by searching Embase and MEDLINE on July 27, 2015. STUDY SELECTIONInclusion: 1) primary trial reports, 2) interventional trials, 3) human subjects, 4) phase 1 to phase 3, 5) trials of ixabepilone in monotherapy or combination therapy of 6) pre-licensure cancer indications. Exclusion: 1) secondary reports, 2) interim results, 3) meta-analyses, 4) retrospective/observational studies, 5) laboratory analyses (ex vivo tissues), 6) reviews, 7) letters, editorials, guidelines, interviews, abstract-only and poster presentations. DATA EXTRACTION AND SYNTHESISData were independently double-extracted and differences between coders were reconciled by discussion. MAIN OUTCOMES AND MEASURESWe measured risk using the number of drug-related adverse events that were grade 3 or higher, benefit by objective response rate and trial outcomes by whether studies met their primary endpoint with acceptable safety. RESULTSWe identified 39 publications of ixabepilone monotherapy and 23 primary publications of combination therapy, representing 5615 patients and 1598 patient-years of involvement over 11 years and involving 17 different malignancies. In total, 830 patients receiving ixabepilone experienced objective tumour response (16%, 95% CI 12.5%-20.1%), and 74 died from drug-related toxicites (2.2%, 95% CI 1.6%-2.9%). Responding indications and combinations were identified very quickly; thereafter, the search for additional responding indications or combinations did not lead to labelling additions. A total of 11 "uninformative" trials were found, representing 27% of studies testing efficacy, 208 grade 3-4 events and 226 patient-years of involvement (21% and 26% of the portfolio total, respectively). After the European Medicines Agency rejected ixabepilone for licensing, all further trial activity involving ixabepilone was pursued outside of Europe. DISCUSSIONRisk/benefit for patients who enrolled in trials of non-approved indications of ixabepilone did not improve over the course of the drugs development. Clinical value was discovered very quickly; however, a large fraction of trials were uninformative.

BackgroundThe unprecedented context of the COVID-19 pandemic poses the opportunity to study several questions in circumstances that would probably not otherwise occur. We sought to determine the dynamics of pharmaceutical company drug sales revenue, market capitalization and payments to physicians during the pandemic, focusing on payments to so-called key opinion leaders (KOLs). MethodsWe analyzed the CMS Open Payments data of 15 top pharmaceutical company general payments to US physicians. We calculated total payments per year for all physicians, KOLs and 2018 KOLs in subsequent years. Drug-related fold changes in payments, drug revenues and company market capitation were calculated using Q1-2018 as reference. Yearly differences in payments, drug sales revenue and market capitalization were tested using generalized estimation equations (GEE). A double-sided p<0.05 was considered significant. ResultsThe analyzed dataset comprised 8,563,872 payments to 382,779 physicians. In 2020, we observed a reduction in payments to physicians and KOLs compared to prior years. The total amount per KOL physician per company also decreased for each year for KOLs and the 2018 KOLs in the subsequent years. Payments per drug, but neither drug revenues nor pharmaceutical company market capitalization, followed a downward trend in 2020 compared to prior years. GEE analysis confirmed that, compared to 2018, the decrease in payments to KOLs overall and for the top drugs of each company was statistically significant. Yet, no significant differences in drug sales revenue and market capitalization was observed. ConclusionsA substantial and significant reduction in payments to KOLs during the first fiscal year of the COVID-19 pandemic was not associated with a reduction in drug sales revenue of blockbuster drug products and the market capitalization of 15 top pharmaceutical companies. Overall, these findings suggest that a substantial part of pharmaceutical payments to KOLs do not appear to impact top drug sales revenues.

IntroductionSodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor (GLP-1R) agonists reduce the risk of major adverse cardiovascular and kidney events in individuals with various cardiometabolic conditions. The long-term efficacy and safety of these therapies, especially in low- and moderate-risk populations, remain uncertain. MethodsWe conducted a biobank-scale analysis using genetic instruments derived from naturally occurring genetic variations in the genes encoding the targets of SGLT2 inhibitors (SLC5A2) and GLP-1R agonists (GLP1R) that associated with HbA1c levels. This Mendelian randomization study utilized data from the All of Us Research Program, which includes whole genome sequencing and electronic health records of 633,547 participants. ResultsHigher SGLT2 inhibitor genetic instrument scores were associated with a lower risk of heart failure (OR: 0.97, 95% CI: 0.96 to 0.99) and chronic kidney disease (OR: 0.98, 95% CI: 0.96 to 0.99). Higher GLP-1R agonist genetic instrument scores were linked to reduced risks of heart failure (OR: 0.97, 95% CI: 0.95 to 0.99), chronic kidney disease (OR: 0.96, 95% CI: 0.94 to 0.98), and coronary artery disease (OR: 0.98, 95% CI: 0.96 to 0.99). We did not detect associations between the GLP1-R agonist instrument and multiple endocrine neoplasia or medullary thyroid carcinoma. PheWAS identified associations between the SGLT2 inhibitor and GLP-1R agonist genetic instruments and a lower risk of diabetes, but no other phenotypes. ConclusionsThis study demonstrates the utility of biobank-scale health data for pharmacology research and suggests that, if feasible to implement in routine practice, long-term, combined primary prevention with an SGLT2 inhibitor or GLP-1R agonist would safely lower the risk of major adverse cardiovascular and kidney events in low- to moderate-risk adults.

BackgroundLevetiracetam is widely used in post stroke epilepsy. However, it is suspected to possess P-glycoprotein induction properties and therefore a potential significant interaction with DOACs. Our aim was to search for ischemic stroke signals with levetiracetam and the DOACs. MethodsIn this retrospective, pharmacovigilance study, we used the Food and Drug Administration adverse event reporting system to identify ischemic stroke events associated with DOACs and concomitant use of levetiracetam. We evaluated disproportionate reporting by the reporting odds ratio adjusted to age and sex (adj.ROR) and the lower bound of the shrinkage 95% confidence interval ({Omega}025 > 0 is deemed significant for an interaction). ResultsWe identified 1,841 (1.5%), 3,731 (5.3%), 338 (4.9%), and 1,723 (1.3%), ischemic stroke reports with apixaban, dabigatran, edoxaban, and rivaroxaban respectively. When heparin/enoxaparin was used as the comparator the adjusted ROR of the interaction effect was 3.57 (95%CI, 2.81-4.58) between DOACs and levetiracetam. The shrinkage analysis detected an interaction between each of the DOACs and levetiracetam resulting in higher reports of ischemic stroke with the combination compared to each drug alone. The logistic model and shrinkage analysis failed to detect an interaction when queried for hemorrhagic stroke. ConclusionsWe show a strong signal for the levetiracetam interaction with apixaban, dabigatran, edoxaban, and rivaroxaban leading to a 3-5 folds increased reporting risk of ischemic stroke. Our findings suggest the need for pharmacodynamic monitoring, while concomitantly prescribing levetiracetam with the DOACs.

Background and ObjectivesClopidogrel is an antiplatelet used in both primary and secondary prevention of cardiovascular diseases. It is a prodrug, requiring CYP2C19 for its metabolism to the active metabolite. The ABCD-GENE score, combining clinical attributes (age, body mass index, chronic kidney disease, diabetes mellitus), with genetic information (presence of 1 or 2 loss of function (LOF) alleles in the CYP2C19 gene) has been shown to identify patients with higher risk of recurrent cardiovascular events in high-risk populations undergoing percutaneous coronary intervention. We aimed to determine if the ABCD-GENE score or LOF alleles were associated with an increased risk of vascular events among clopidogrel users in a general population. MethodsWe conducted a population based cohort study with UK Biobanks primary care prescription records to identify clopidogrel users. ABCD-GENE scores were calculated with closest available data from the first date of clopidogrel prescription. The number of LOF alleles present, and the clinical component ABCD, were separate exposures. The outcome of interest was a composite endpoint of vascular events comprised of myocardial infarction, ischemic stroke, and death due to either of these. We performed Cox proportional hazards models with clopidogrel as a time varying exposure to predict hazards of these outcomes. In order to determine the drug specificity of these exposures, the analyses were repeated in aspirin users, and in non-users of either aspirin or clopidogrel. ResultsAmong 11,248 clopidogrel users, 3,365 (30%) developed a vascular event over a mean follow-up of 5.95{+/-}3.94 years. ABCD-GENE score [&ge;]10 was associated with an increased risk of vascular events (HR 1.13, 95% CI 1.03-1.23). In aspirin users, and in non-users of either aspirin or clopidogrel, the ABCD-GENE score was also associated with increased risk of vascular events. In clopidogrel users, aspirin users, and non-users of either drug, the ABCD score was associated with increased risk of vascular events. The presence of two CYP2C19 LOF alleles was associated with an increased risk of vascular events in aspirin and non-users but not in clopidogrel users. DiscussionIn this population-based cohort study, the ABCD-GENE score was associated with an increased risk of vascular events in clopidogrel users, aspirin users, and in non-users of either drug. The clinical component, ABCD was also associated with an increased risk of vascular events in all three groups. This suggests that the ABCD-GENE score is not specific to clopidogrel users in identifying persons at high risk of vascular events in a general sample with low baseline CYP2C19 LOF allele frequency.

BackgroundPre-treatment DPYD screening is mandated in the UK and EU to reduce the risk of severe and potentially fatal fluoropyrimidine-related toxicity. Four DPYD gene variants which are more prominently found in Europeans are tested. MethodsOur systematic review in patients of non-European ancestry followed PRISMA guidelines to identify relevant articles up to April 2023. Published in silico functional predictions and in vitro functional data were also extracted. We also undertook in silico prediction for all DPYD variants identified. ResultsIn 32 studies, published between 1998 and 2022, 53 DPYD variants were evaluated in patients from 12 countries encompassing 5 ethnic groups: African American, East Asian, Latin American, Middle Eastern, and South Asian. One of the 4 common European DPYD variants, c.1905+1G>A, is also present in South Asian, East Asian and Middle Eastern patients with severe fluoropyrimidine-related toxicity. There seems to be relatively strong evidence for the c.557A>G variant, which is found in individuals of African ancestry, but is not currently included in the UK genotyping panel. ConclusionExtending UK pre-treatment DPYD screening to include variants that are present in some non-European ancestry groups will improve patient safety and reduce race and health inequalities in ethnically diverse societies.

BackgroundAGILE (NCT04746183) is a Phase Ib/IIa platform, evaluating candidates to treat COVID-19. CST-6 evaluated the safety and optimal dose of a novel intravenous (IV) formulation of favipiravir. MethodsCST-6 was a dose-escalating, open-label, randomised, controlled, Bayesian adaptive Phase Ib trial. Hospitalised adults with PCR-confirmed SARS-CoV-2 infection, within 14 days of symptomatic COVID-19 were randomised 2:1 in groups of 6 (n = 4 favipiravir, n = 2 standard of care (SoC)) to ascending doses of IV favipiravir twice daily (b.i.d.) for 7 days or SoC. Clinical data, safety evaluations, virology and pharmacokinetic (PK) samples were collected. The primary outcome was safety. Secondary outcomes included clinical, PK and virological endpoints. Results24 participants enrolled between 10/Sep/2022 and 01/Nov/2023 [10/24 female; median age 74 years (range 52-93)]. Favipiravir was well tolerated despite a high background rate of unrelated adverse events (AEs). No dose limiting toxicities (DLTs) were observed, with a model-predicted DLT risk of 16.8% and probability of unacceptable toxicity of 2.7% at the highest dose level. No SAEs were deemed related to favipiravir but an expected association with asymptomatic, transient hyperuricaemia was observed. PK exposures increased disproportionally to dose with significant accumulation in plasma, but with marked variability between participants within each cohort. ConclusionsA novel formulation of favipiravir was safe at sustained high doses that reached PK targets in a study group with frailty and complex health profiles. Plasma concentrations demonstrated accumulation. Significant variability in PK parameters between individuals was noted. We consider doses up to 2400mg b.i.d. to be safe for further evaluation. https://clinicaltrials.gov/study/NCT04746183 Key pointsO_LIA novel intravenous formulation of favipiravir, was safe and well tolerated in a frail and complex population, up to a dose of 2400mg b.i.d. C_LIO_LISignificant inter-individual variability in pharmacokinetic parameters was observed. C_LIO_LIPharmacokinetic modelling suggests pre-specified target concentrations were met. C_LI

IntroductionFinerenone, a non-steroidal mineralocorticoid receptor antagonist (MRA), has demonstrated greater receptor selectivity and fewer side effects compared to older mineralocorticoid receptor antagonists. Clinical trials support its efficacy in reducing kidney disease progression, cardiovascular events, and heart failure outcomes across various patient populations, however, anecdotally, the drug appears infrequently utilized in clinical practice. MethodsA serial, cross-sectional analysis of IQVIAs National Prescription Audit (NPA), which covers over 70% of U.S. outpatient prescription activity, was conducted from July 2021 to December 2024 to examine finerenone prescribing trends focusing on cardiologists and nephrologists. For added context, prescription rates of finerenone were compared to those of two other medications with related mechanisms or indications commonly used in Cardiovascular-Kidney-Metabolic (CKM) syndrome, spironolactone and empagliflozin. Prescribing trends were correlated with total search activity using Google Trends. ResultsWe found that finerenone was prescribed at a rate of 30,180 prescriptions/month in December 2022, increasing to 45,420 in December 2023, and 60,756 prescriptions/month in December 2024. This modest increase correlated with changes in Google search activity, with mild inflections after the release of major clinical trial data. The ratio of total prescriptions from nephrologists (15.81 prescriptions per nephrologist) to cardiologists (0.70 prescriptions per cardiologist) in 2024 was approximately 23:1. The proportion of finerenone prescriptions to other CKM therapies remained low, with finerenone prescriptions numerically representing 3.0% of empagliflozin prescriptions and 2.6% of spironolactone prescriptions in 2024. ConclusionThe adoption of finerenone has been modest, especially among cardiologists compared to nephrologists, and lags behind other CKM therapies. However, recent trends show an upward shift in its use that correlates with public interest related to clinical trial results.

Low drug adherence is a major obstacle to the benefits of pharmacotherapies and it is therefore important to identify factors associated with discontinuing or being poorly adherent to a prescribed treatment regimen. Using high-quality nationwide health registry data and genome-wide genotyping, we evaluate the impact of socio-demographic and genetic risk factors on adherence and persistence for 5 common medication classes that require long-term, regular therapy (N = 1 814 591 individuals from Finnish nationwide registries, 217 005 with genetic data from Finland and Estonia). Need for social assistance and immigration status showed a notable negative effect on persistence and adherence across the examined medications (odd ratios between 0.48 and 0.82 for persistence and between 1.1% to 4.3% decrease in adherence) while demographic and health factors showed comparably modest or inconsistent effects. A genome-wide scan did not identify genetic variants associated with the two phenotypes, while some pharmacogenes (i.e. CYP2C9 and SLCO1B1) were modestly associated with persistence, but not with adherence. We observed significant genetic correlations between medication adherence and participation in research studies. Overall, our findings suggest that socio-economically disadvantaged groups would benefit from targeted interventions to improve the dispensing and uptake of pharmacological treatments.

GLP-1 receptor agonists (GLP-1 RAs) are effective in delaying progression of chronic kidney disease in individuals with type 2 diabetes mellitus (T2DM). We evaluated whether GLP-1 RA prescription is associated with reduced nephrotoxicity in adults receiving long-term lithium therapy. We conducted a retrospective, propensity score-matched cohort study using electronic health records from the TriNetX global network, which includes de-identified data from over 127 million patients across 109 healthcare organizations. The study population consisted of adults aged [&ge;]18 years with T2DM, with lithium exposure within the 2 years preceding the index date and at least one prescription for a GLP-1 RA. The primary efficacy outcome was the rate of renal nephrotoxicity in persons with T2DM prescribed lithium and a GLP-1 RA versus those with T2DM prescribed lithium but no GLP-1 RA or other antidiabetic agents. Nephrotoxicity was a composite of ICD-10 and CPT-coded renal disease. Incidence and time-to-event outcomes were assessed using Kaplan-Meier curves and Cox proportional hazards models. In our 24-month analysis, 462 matched patient pairs were included. Initiation of a GLP-1 RA during lithium therapy was associated with a lower incidence of renal events versus lithium alone (6{middle dot}1% vs 10{middle dot}4%), corresponding to a risk difference of -4.3% (95% CI -7{middle dot}86 to -0{middle dot}80), a risk ratio of 0{middle dot}58 (95% CI 0{middle dot}37-0{middle dot}91; p=0{middle dot}017), and higher event-free survival (89{middle dot}0% vs 83{middle dot}2%; log-rank p=0{middle dot}037). GLP-1 receptor agonist therapy was associated with a reduction in reports of lithium-associated nephrotoxicity. Our findings provide impetus to conduct mechanistic renal histopathologic studies combining GLP-1 RAs with lithium.

BackgroundCarriers of the CYP2C19 Loss of Function (LoF) allele may experience decreased efficacy of clopidogrel in secondary prevention after cardiovascular events. Randomized clinical trials of clopidogrel in patients with known CYP2C19 carrier status provided inconsistent results. Our aim was to pool the evidence on the effect of clopidogrel on outcome, according to CYP2C19 LoF status, in a meta-analysis. MethodsA systematic review and meta-analysis of randomized controlled trials (RCTs) on the effect of clopidogrel according to CYP2C19 LoF status in patients with cardiovascular disease and recent TIA or stroke was performed. The primary outcomes were 1) ischemic stroke and 2) major adverse cardiac events (MACE). We used random effects analysis to estimate the effect of clopidogrel as a pooled odds ratio (OR) in carriers and non-carriers of the LoF variant and tested for interaction between clopidogrel and CYP2C19. ResultsWe included six RCTs with a total of 15,141 participants comparing combined clopidogrel and aspirin therapy to aspirin monotherapy. The effect of clopidogrel on MACE was OR=0.70 in CYP2C19 non-variant carriers compared to OR=0.84 in CYP2C19 variant carriers (pinteraction=0.13). In patients with a recent TIA or minor ischemic stroke, the OR for the effect of clopidogrel on MACE was OR=0.52 in CYP2C19 non-variant carriers compared to OR=0.84 in CYP2C19 variant carriers (pinteraction=0.02) while in patients with cardiovascular disease the difference in effect was not evident (non-variant carriers OR=0.76, variant carriers OR= 0.84, pinteraction=0.50). ConclusionOur meta-analysis could not establish that overall, clopidogrel is less effective in patients with a recent MI, minor stroke or TIA and a CYP2C19 LoF genotype. However, the size and direction of the difference in effect warrants further research. Registration - URL: https://www.crd.york.ac.uk/prospero/; Unique identifier: CRD42021242993.

BackgroundDrug suitability is determined by safety, efficacy, and pathological appropriateness. The pharmacogenomics of drug suitability can be assessed by analyzing drug response and drug choice in large population cohorts. MethodsWe investigated drug response and drug choice for dyslipidemia and hypertension using genetic, phenotypic, and prescribing data from the UK Biobank and the All of Us Research Program. Drug response was reassessed with rigorous biomarker scaling, while genome-wide association studies (GWAS) and polygenic scores were used to examine genetic factors influencing drug choice. ResultsConventional analyses showed that variants influencing baseline LDL cholesterol (LDL-C) were inversely associated with absolute LDL-C change but concordant with relative change following statin therapy; these signals disappeared after applying a variance-stabilizing Box-Cox transformation, indicating a methodological artifact in biomarker scaling. GWAS for drug choice identified several significant loci and unique genetic correlation patterns with cardiometabolic traits. Polygenic scores for drug choice yielded statistically significant predictive performance, which was enhanced by incorporating demographic factors, though prediction strength in clinical settings remains modest. ConclusionVariance-stabilizing transformation corrects spurious pharmacogenetic associations introduced by biomarker scaling. Genetic variation informs drug choice for dyslipidemia and hypertension, but current polygenic scores provide only modest benefits in clinical application.