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.

Background and aimTo develop and validate a prognostic model for risk-stratified monitoring of 5-aminosalicylate (5-ASA) toxicity. MethodsThis nationwide retrospective cohort study used data from the Clinical Practice Research Datalink (CPRD) Aurum and Gold for model development and validation respectively. It included adults newly diagnosed with inflammatory bowel disease (IBD) and established on 5-ASAs between 01/01/2007 and 31/12/2019. 5-ASA discontinuation with abnormal monitoring blood test result was the outcome of interest. Patients prescribed 5-ASAs for [≥]6 months i.e., established on treatment, were followed-up for up to five years. Penalised Cox-regression was used to develop the risk equation. Model performance was assessed in terms of calibration and discrimination. Statistical analysis was performed using STATA (StataCorp LLC). Results14,109 and 7,523 participants formed the development and validation cohorts with 401 and 243 events respectively. 185, 172, and 64 discontinuations were due to cytopenia, elevated creatinine and elevated liver enzymes respectively in the derivation cohort. Hazardous alcohol intake, chronic kidney disease, thiopurine use, and blood test abnormalities before follow-up were strong prognostic factors. The optimism adjusted R2D in development data was 0.08. The calibration slope and Royston D statistic (95% Confidence Interval) in validation cohort were 0.90 (0.61-1.19) and 0.57 (0.37-0.77) respectively. ConclusionThis prognostic model utilises information available during routine clinical care and can be used to inform decisions on the interval between monitoring blood-tests. The results of this study ought to be considered by guideline writing groups to risk-stratify blood test monitoring during established 5-ASA treatment. What is already known?O_LIRenal, hepatic and blood toxicity are uncommon during long-term 5-aminosalicylate (5-ASA) treatment. C_LIO_LIThere are no mechanisms to predict the risk of these toxicities during established treatment that may be used to risk stratify blood-test monitoring. C_LI What this study adds?O_LIUsing a large national dataset originated during routine care, this study developed a prognostic model that discriminated patients at varying risk of 5-ASA toxicity during established treatment with good performance characteristics validated. C_LIO_LIMost patients were at low-risk of toxicity due to 5-ASAs and could continue with annual monitoring blood-tests while others at high risk may require more frequent monitoring. C_LIO_LIThis prognostic model can be used to make an informed decision on the interval between monitoring blood tests and the findings ought to be considered by guideline writing groups to bring about equitable and sustainable change in clinical practice. C_LI

BackgroundThe trends in sedative use have varied in recent years. Benzodiazepines and z-drugs are indicated for anxiety and sleep disorders, but should be limited to short term use. The aim of this study is to examine trends and patterns in sedative prescribing in Ireland between 2014 and 2022, as well as comparing trends between Ireland and England within the same period. MethodsMonthly data on medicines prescribed and dispensed in primary care on the means-tested General Medical Services (GMS) scheme in Ireland was used. Volumes of prescribed benzodiazepine and z-drug use and patterns of prescribing, including initiations, discontinuations, chronic use, and high-risk prescribing were summarised per year. Other sedating agents (sedating antihistamines, antidepressants, and antipsychotics) were also analysed. Volume of use outcomes were compared with NHS data from England for the same period. ResultsThe rate of benzodiazepine and z-drug dispensings per 1,000 GMS population decreased by 4%, from 1,531 in 2014 to 1,474 in 2022. T By comparison in England, there was a steeper decrease of 27% in the dispensing rate and the level of use was substantially lower, falling from 288 dispensings per 1,000 population in 2014 to 210 in 2022. In Ireland, dispensing rates were highest amongst women and older age groups. High-risk dispensings of benzodiazepines and z-drugs decreased over the study period DiscussionDespite decreases in benzodiazepine and z-drug dispensings, rates remain high in Ireland and may suggest a need for enhanced availability of non-pharmacological interventions, and improved education and deprescribing support for healthcare professionals. Statement of SignificanceThe use of benzodiazepines and z-drugs has decreased in many populations in recent years, while prescribing of other sedatives has increased. In Ireland, comparatively higher levels of prescribing have been previously identified. Describing and quantifying medication use is important to monitor medication safety at the population level, however this can be complex and therefore a range of indicators are needed to capture differences. The findings of this study suggest that benzodiazepine and z-drug dispensing is decreasing in Ireland, including high-risk dispensings and dispensings to older age groups. However, in comparison to England, dispensing rates remain high and suggest a need for enhanced availability of non-pharmacological services and interventions, as well as improved education and deprescribing support for healthcare professionals.

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 [≥]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.

ABSTRACT Background: Self medication with analgesics and non steroidal anti inflammatory drugs (NSAIDs) is common in low- and middle income countries and may expose users to preventable adverse outcomes. Evidence from Guinea remains scarce. This study aimed to estimate the prevalence of self medication with analgesics and NSAIDs among pharmacy clients in urban Conakry, identify associated factors, and describe clinical risk situations. Methods: We conducted a pharmacy based analytical cross sectional study in 30 private pharmacies across Conakry, Guinea. A total of 1,032 participants seeking analgesics or NSAIDs were enrolled between November 3, 2012, and April 5, 2013. Self-medication was defined as acquisition or use without a valid medical prescription. Factors associated with self-medication were analysed using multivariable logistic regression. Results: Among 1,032 participants, 603 reported self medication (prevalence 58.4%). Previous unsupervised use was reported by 78.7%. The most frequently used medicines were paracetamol (56.9%, n=587), diclofenac (21.3%, n=220), ibuprofen (17.9%, n=185), and aspirin (3.9%, n=40). Overall, 68.0% (n=702) reported no knowledge of potential adverse effects. Clinical risk situations were frequent: gastrointestinal disorders (41.3%, n=426), hypertension (9.2%, n=95), and pregnancy exposure among reproductive age women (26.0%). In multivariable analysis, self medication was independently associated with previous analgesic/NSAID use (aOR = 2.8, 95% CI: 2.1 to 3.6), lack of knowledge of adverse effects (aOR = 1.9, 95% CI: 1.4 to 2.5), informal occupation (aOR = 1.6, 95% CI: 1.2 to 2.2), and age 18 to 59 years (aOR = 1.5, 95% CI: 1.1 to 2.1). Conclusions: In this pharmacy based study conducted in urban Conakry, self medication with analgesics and NSAIDs was common and frequently associated with limited awareness of potential adverse effects. These findings support the need for strengthened pharmaceutical regulation, pharmacist-led counselling, health literacy interventions, and improved access to primary care. Keywords: self medication; analgesics; NSAIDs; paracetamol; diclofenac; ibuprofen; pharmacy; Guinea; Conakry; drug safety; public health.

Background: Dihydropyridine calcium channel blockers (DHP-CCB) are widely prescribed antihypertensives whose adverse effects may trigger unnecessary prescribing of additional medications, termed prescribing cascades (PC). We aimed to identify potential DHP-CCB-induced PCs using high-throughput sequence symmetry analysis (HTSSA). Methods: Using Medicare claims data (2011-2020), we identified new users aged [≥]66 years with continuous enrollment [≥]360 days before and [≥]180 days after DHP-CCB initiation. We screened for initiation of 446 "marker" drug classes within {+/-}90 days of DHP-CCB initiation. Sequence ratios compared marker drug initiation after versus before DHP-CCB initiation. Adjusted sequence ratios (aSR), accounting for prescribing trends over time, were calculated with 95% CIs >1 considered statistically significant. Clinical experts classified statistically significant signals as potential PCs through consensus. Results: Among 388,862 DHP-CCB initiators (mean age 76.6 {+/-} 7.5 years; 62.5% women, 92.3% with hypertension), 82 of 446 marker drug classes had significantly elevated aSRs, of which 24 were classified as potential PCs. Strongest signals ranked by highest aSR included other systemic hemostatics (aSR 2.99; 95% CI, 1.10-8.16), other nasal preparations (aSR 1.99; 95% CI, 1.47-2.70), and drugs used in erectile dysfunction (aSR 1.85; 95% CI, 1.27-2.70). Other clinically relevant signals, ranked by number needed to harm (lowest to highest), included sulfonamides (NNTH 104; 95% CI, 98-111), electrolyte solutions (NNTH 216; 95% CI, 196-241), and osmotically acting laxatives (NNTH 710; 95% CI, 540-1056). Conclusion: Potential PCs identified in this Medicare cohort reflected known and underrecognized adverse effects of DHP-CCBs. Further studies are needed to evaluate the clinical consequences of these PCs.

Introduction: Conventional substance-level disproportionality analysis may miss safety patterns specific to a dose form, route, or intended site. More granular analyses are hindered by incomplete, inconsistent reporting of product information. The Pharmaceutical Product Identifier (PhPID), representing products by substance, strength, and dose form, may support more granular analyses. Objective: To explore the use of PhPID-like dose form information for site-specific disproportionality analysis in dexamethasone. Methods: We evaluated VigiBase reports (January 1, 2001 - December 31, 2024) for completeness of dose form and route data. We standardized dexamethasone entries to PhPID Level 3 standards, representing substance and administrable dose form. Through disproportionality analysis (Information Component, IC) we compared substance-level and site-specific results. Results: Among 56.4 million suspected/interacting drugs, dose form was reported in 47.7%, route in 69.4%. Among 109,248 dexamethasone entries, 703 dose form and 80 route variations were mapped to 53 and 44 standard codes respectively; about half could be mapped unambiguously. Site-specific analyses revealed biologically plausible patterns not apparent in substance-level analyses. Ocular use showed higher ICs for glaucoma and cataract, while systemic use showed higher IC for psychiatric and endocrine events (e.g., depression, agitation, Cushing's syndrome). IC time-trends suggested that some signals (e.g., cataract with Ocular use) could emerge earlier in site-specific analyses. Conclusion: More granular product information, aligned with PhPID, may improve signal detection and characterization of site-specific safety issues. These findings support granular identifiers in pharmacovigilance while highlighting the need for better capture and standardization of dose form and route of administration data.

Purpose In deprescribing studies, a prescription-free gap is typically used to determine if patients discontinued their treatment. An appropriate gap depends on the typical time between prescriptions during continued use. This work aims to characterise the interval between prescriptions of chronic drugs using different methods for a cohort of older people in primary care in Ireland. Methods The empirical prescription interval was analysed for 38,154 patients for the twenty most common drug classes and the association between covariates and the interval was analysed using a multi-level model. Estimates were also compared to those obtained from the parametric waiting time distribution (pWTD) approach. Results Available covariates had consistent relationships with prescription intervals across drug classes. For example, each additional prescription issue was associated with an increase in the interval by 5.0 (NSAIDs) to 19.7 days ("Other antidepressants"). Full public health cover was associated with a -29.0 day (inhaled adrenergics) to -11.0 day (opioids) change relative to partial cover, while other/private cover had a -17.9 day (benzodiazepines and associated drugs) to -7.1 day (SSRI and SNRIs) change relative to partial cover. The pWTD also produced consistent estimates of the population interval for most drugs. Conclusions The interval varied substantially within drug classes, due to a mixture of patient, practice and unmodelled factors. Variation between practices was effectively explained, with residual variation between patients and within patients. The pWTD approach is useful for describing complex distributions of intervals, and may be more appropriate for inferring a gap than summarising truncated data.

The safety, tolerability, pharmacokinetics, age-related effects of single (SD) and repeat (RD) doses of CMS121, a novel small molecule fisetin derivative, were evaluated in healthy adult volunteers. The effects of food were also evaluated in healthy young adult subjects. SD of up to 1800 mg or RD up to 900 mg/day for 7 days was generally well tolerated, with the majority of TEAEs mild in severity. Generally, the pharmacokinetics of CMS121 and its metabolites were well characterized and increased in a dose-proportional or slightly greater than dose-proportional manner across the range of doses assessed. CMS121-C2 metabolite appears to contribute the most to the presence of the molar-equivalent CMS121 in plasma than the parent compound or the other metabolites (i.e. CMS121-C1 and CMS121-C3). Urinary excretion of CMS121 metabolites was minimal, implying urinary excretion may not be a major clearance route by which CMS121 is eliminated after oral dosing. There is a significant effect of age on the pharmacokinetics of CMS121 and its metabolites, with higher systemic exposures to CMS121 and its metabolites and longer terminal elimination half-lives in elderly subjects. Systemic exposures to CMS121 were higher in the fed state by approximately 50%.

BackgroundPain is a major public health issue, and a common reason people seek medical care. Pharmacological treatments depend on the type of pain and carry different risks and benefits. The aim of this study was to examine trends in analgesic prescribing in Ireland and England between 2014 and 2022. MethodsMonthly data on medicines prescribed and dispensed in primary care were used. For Ireland, data on the means-tested General Medical Services (GMS) scheme were used, covering approximately 32% of the population. For England, data from the NHS Digital platform for all general practices were used. Outcomes were the volume of prescribed analgesic use, including rates of dispensings, costs, and standard doses (including oral morphine equivalents (OMEs) for opioids) per 1,000 population, summarised per year for each drug class/drug. ResultsIn Ireland, the rate of analgesia dispensings increased between 2014 and 2022 for most drugs. Opioid dispensings increased from 979 to 1,220 per 1,000 population, while paracetamol increased from 1,295 to 1,824. Systemic NSAIDs decreased from 781 to 734. In England, most analgesia dispensing rates decreased, with opioids decreasing from 721 to 585 per 1,000 population, paracetamol from 734 to 484, and systemic NSAIDs from 259 to 167. DiscussionSubstantially different dispensing patterns were found in Ireland and England, with higher increasing overall rates in Ireland and lower decreasing rates in England, potentially driven by the older age and lower socioeconomic status of GMS patients in Ireland. Further research to understand drivers for this higher volume of use is required.

Topiramate (TPM) is approved for seizures and migraine prophylaxis and is used off-label for several neuropsychiatric conditions. The available dosage forms, including tablets and sprinkle capsules, are unsuitable for patients who may be unable to take medicine orally. The resulting potential treatment interruptions could have untoward consequences and underscores the importance of developing a parenteral formulation. In this study, we developed a population pharmacokinetic model of a novel, intravenous TPM formulation using data from a study in patients with epilepsy or migraine receiving a single intravenous dose of stable-labeled TPM. In total, 246 TPM concentrations from 20 adult patients were included for model development. A three-compartment pharmacokinetic model with linear elimination fit the concentration-time data best. Simulations for various loading and maintenance regimens for patients with and without enzyme-inducing comedications were performed. The final estimates(95% confidence interval (CI)) for CL (L/h), V1 (L), and the peripheral volumes, V2 and V3 for a 70 kg person were 1.31(1.01 - 1.53), 9.84 (8.49 - 11.0), 39.1 (36.5 - 41.8)L, and 9.01 (6.41 - 44.3) respectively. The use of enzyme-inducing co-medication was the only significant covariate, associated with a 63% increase in clearance .Goodness-of-fit plots and visual predictive checks indicate satisfactory model performance and prediction. The simulation results indicate that adjusting doses for patients receiving IV TPM can mitigate the changes in plasma TPM concentrations resulting from enzyme induction. This population pharmacokinetic model for intravenous topiramate can inform dosing decisions for patients with epilepsy when used as either initiation or bridging therapy.

Background. Polypharmacy is an important source of phenoconversion caused by drug interactions potentially modulated by genetic variability. Aims. To develop a linear phenoconversion model for TDM data and provide quantitative estimates of drug-drug-gene interactions (DDGIs) in the pharmacogenetic phenotype groups of CYP2C19. Methods. Escitalopram TDM data in a large real-world sample (n=2,852) was analysed for phenoconversion of CYP2C19 activity. Co-medication was identified by reprocessing high-resolution mass-spectra (Orbitrap). We developed a statistical model to identify inhibition from co-medication in the CYP2C19 and in alternative elimination pathways. We extended the model to estimate the inhibition ensuing from individual co-medications, using a single model for all data to account for multiple co-medications and confounders simultaneously. A Bayesian approach allowed us to stabilize the fit and provide well-calibrated credibility intervals. Results. Reprocessing of TDM analyses identified 17 co-medications, which were shown to phenoconvert CYP2C19 activity proportionally to the activity in non-medicated phenotypes. Phenoconversion decreased the original CYP2C19 activity by about one third for a co-medication that corresponded to a 100% substrate of CYP2C19. The extent of CYP2C19 phenoconversion correlated strongly with the fractional contribution of CYP2C19 to the metabolism of the specific co-medication reported in the pharmacogenetic literature (R2=0.55) so long as the mechanism was competitive inhibition. Conclusion. We provide the statistical methodology to estimate phenoconversion from co-medication in TDM data and combine TDM and pharmacogenetic datasets in future studies aiming at establishing quantitative models of DDGIs.

Background: Mocravimod is an oral sphingosine-1-phosphate (S1P) receptor modulator. This Phase 1 multiple-ascending-dose study evaluated its safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) in healthy volunteers. Methods: In this double-blind, randomized, placebo-controlled, parallel-group trial, 60 healthy male volunteers were enrolled in five cohorts. Mocravimod was administered once daily at 0.3, 0.6, 1.2, or 3.0 mg for 14 days, or at 2.0 mg for 28 days. Safety assessments included adverse events (AEs), laboratory tests, vital signs, electrocardiography, and Holter monitoring. PK of mocravimod and its active metabolite, mocravimod-phosphate, and PD effects on absolute lymphocyte count (ALC) and leukocyte subsets were assessed. Results: Fifty-nine of 60 participants completed the study. One participant in the 3.0 mg cohort discontinued treatment because of asymptomatic transaminase elevation. No deaths or serious AEs occurred. AEs were mostly mild or moderate, transient, and showed no clear dose relationship. Mocravimod produced dose-dependent reductions in ALC from 0.6 mg onward, with maximum geometric mean reductions of 65%, 74%, 83%, and 77% at 0.6, 1.2, 2.0, and 3.0 mg, respectively. ALC values recovered to above the lower limit of normal during follow-up in all cohorts. Holter monitoring showed an initial placebo-corrected reduction in heart rate of approximately 10-15 beats/min at doses of 1.2-3.0 mg, which attenuated with continued dosing. One participant in the 3.0 mg cohort had a recurrent daytime second-degree atrioventricular block (Mobitz I/Wenckebach), reported as a mild non-dose-limiting AE. No QT prolongation was observed. Exposure to mocravimod and mocravimod-phosphate increased approximately dose-proportionally. Steady state was reached by Day 14 (Day 28 in the 2.0 mg cohort), accumulation was approximately five- to sevenfold, terminal half-lives were approximately 100-40 hours for both analytes, and parent-to-metabolite exposure ratios were close to 1. Conclusions: Once-daily mocravimod up to 3.0 mg for 14 days and 2.0 mg for 28 days was generally well tolerated and showed predictable S1P-modulator class effects on lymphocyte counts and heart rate, with PK properties supporting once-daily dosing and further clinical 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.

ObjectiveUsing US claims data and the most up-to-date pharmacoepidemiological study design tools we aimed to investigate two safety signals for (1) macrolides and heart failure; and (2) non-steroidal anti-inflammatory drugs (NSAIDs) and pneumonia generated from a large-scale screening analysis using a self-controlled sequence symmetry design in Danish data. MethodsWe used IBM Marketscan data to conduct two new-user, active-comparator cohort studies. In the macrolides example, the exposure was clarithromycin or azithromycin and the comparator was amoxicillin/clavulanate, in patients with sinusitis. In the NSAIDs example, the exposure was oral NSAIDs and the comparator was topical diclofenac, in patients with osteoarthritis. We used Cox proportional hazards regression to estimate hazard ratios (HR) and 95% confidence intervals (CI) to adjust for approximately 50 investigator-specified confounders in a propensity score (PS) matched analysis. In a secondary analysis, we used high-dimensional PS (hd-PS) to adjust for 200 additional proxy confounders. ResultsWe had 1,012,364 propensity score matched patients exposed to clarithromycin or azithromycin versus amoxicillin/clavulanate. With 162 outcomes among clarithromycin or azithromycin exposed patients and 134 among amoxicillin/clavulanate, the HR for overall heart failure was 1.14 (95% CI 0.90 - 1.43). In the NSAIDs example, we included 94,490 patients after propensity score matching. With 794 pneumonia outcomes among oral NSAID patients and 700 among topical diclofenac, we found HR 0.98 (95% CI 0.89 - 1.09). Some upward bias was suspected as larger HRs were observed in the days immediately following exposure for both the macrolides and NSAIDs examples. We found similar results in the hd-PS matched analyses for both examples. ConclusionOur findings for NSAIDs and pneumonia suggest the original signal may have been due to protopathic or detection bias. Our analyses for macrolides and heart failure with short-term follow-up also suggest bias, although we encourage further research.

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.

IntroductionRanitidine is a member of the H2-blocker class of medications, commonly used in the treatment gastroesophageal reflux and peptic ulcer disease. Recent laboratory analyses have demonstrated that ranitidine may yield the probable carcinogen, N-Nitrosodimethylamine (NDMA). Here, we characterized the kinetics of NDMA production from ranitidine under various simulated gastric conditions. Moreover, we conducted a cross-sectional epidemiologic analysis to evaluate potential associations between ranitidine use and various cancer presentations. MethodsThe formation of NDMA in the presence of ranitidine was studied in a series of experiments conducted in simulated gastric fluid (SGF), while varying pH, nitrite concentration, and time of reaction. Chemical analyses of NDMA yield were performed by liquid chromatography-high resolution mass spectrometry per FDA guidelines on the detection of NDMA from ranitidine drug products. To evaluate potential associations between ranitidine use and cancer diagnoses, we conducted a cross-sectional analysis among a population of oncology patients, following institutional review board approval. Analyses were limited to those reporting use of ranitidine or an active comparator (i.e. proton-pump inhibitor [PPI] or other H2-blocker) to partially mitigate potential confounding. Multivariable logistic regression was employed to identify associations between ranitidine and certain cancers, adjusted for age, sex, race, ethnicity, and body-mass index. ResultsIncreasing sodium nitrite concentrations in SGF at pH 1.2 were associated with increasing NDMA yield. At a pH of 2.5, previously identified as the optimal reaction condition, samples collected at incubation times of 1, 2 and 4 hours (approximating typical gastric emptying conditions) showed a continued increase in NDMA over time. Notably, the reaction trajectory suggests NDMA may have continued to form beyond the last observed timepoint of 4 hours. On cross-sectional analysis of an oncology population, use of ranitidine (versus active comparators) was associated with increased odds of presenting with cancers of the breast (OR=1.58; 95%CI: 1.23-2.01) as compared to presentation with another cancer. Similar positive associations were observed for cancers of the thyroid (OR=1.89; 95%CI: 1.18-2.92), bladder (OR=1.58; 95%CI: 1.10-2.21), and prostate (OR=1.80; 95%CI: 1.34-2.39). Conversely, ranitidine was inversely associated with cancers of the colorectum (OR=0.48; 95%CI: 0.30-0.74) and brain (OR=0.56; 95%CI: 0.33-0.89). ConclusionUnder simulated gastric conditions, ranitidine yields increasing amounts of NDMA over time (up to, and likely beyond 4 hours) and with increasing concentrations of sodium nitrite. In addition, among a cohort of cancer patients reporting use of H2-blockers or PPIs at the time of diagnosis, we found an association between ranitidine use and cancers of the breast, thyroid, bladder and prostate. We further observed unexplained inverse associations with cancers of the brain and colorectum. These associations reflect the odds of presenting with different cancers exclusively among an oncology population, and do not directly represent risk in a general population (as there were no cancer-free individuals in this study). Moreover, these exploratory analyses are to be viewed as hypothesis generating and should prompt analyses of larger cohorts with longer follow-up.

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.

ObjectiveTo establish an optimized sotalol dosing strategy for fetal tachycardia by using a pregnancy computational model for dose simulations. MethodsA physiologically-based computational model, including pregnancy-related changes and placental transfer values, was established and verified. Simulations of the current dosing advises and prospective dosing scenarios were performed. To avoid maternal dose-related toxicity (QT-prolongation) we aimed for maternal concentrations <2.5 mg/L. Based on neonatal concentration-effect data, we aimed for a fetal Ctrough concentrations of 0.4 - 1.0 mg/L. ResultsThe pregnancy physiologically-based pharmacokinetic model accurately predicted maternal and fetal exposures. Predictions indicate that almost 16% of maternal plasma concentrations exceed the toxic level of 2.5 mg/L at the maximum oral daily dose of 480 milligram, while 90% of fetuses have a Ctrough concentration within the therapeutic window. When lowering the maximum daily dose to 400 mg, 0.1% of maternal plasma concentrations exceed 2.5 mg/L, while 87% of the fetal plasma concentrations remain in the therapeutic window. Additionally dosing 480 mg in three times daily reduces the risk of high maternal plasma exposure to 0.3%, while maintaining effective fetal Ctrough concentrations in 95% of fetuses. ConclusionPregnancy computational modeling can be used to adequately predict maternal and fetal sotalol exposures. Our simulations suggest that daily doses should not exceed 400 milligram and that dividing the oral daily dose over three doses improves the balance between high maternal plasma exposure and effective fetal concentrations. FundingThis publication is based on research funded by the Bill & Melinda Gates Foundation (INV-023795).