Aim. To describe the trends in anti-infective use during pregnancy between 2010 and 2019 and determine whether they were prescribed according to drug fetal safety international classification systems. Methods. We conducted a population-based, nationwide study using the French national health data system including all pregnancies ended between 2010 and 2019. Anti-infective were considered according to their pharmacological group and potential harmful risk using the Australian and Swedish classification systems. Prevalence rate was estimated annually and by trimester. Average annual percent change (AAPC) and 95% confidence intervals (CI) were calculated using Joinpoint regression. Results. Among 7,571,035 pregnancies, 3,027,031 (40.0%) received ≥ 1 antibacterial. This proportion decreased significantly from 41.5% in 2010 to 36.1% in 2019 (AAPC=-1.7%, [95%CI, -2.5% to -1.0%]). Conversely, use of antiviral agents increased during the 10 years’ study period for anti-HSV agents (AAPC=4.4%, [3.7%-5.2%]), influenza agents (AAPC=25.4%, [6.2%-48.1%]), and for HIV-antiretroviral agents (HIV-ART) (AAPC=1.3%, [0.6%-2.0%]). Use of influenza vaccine increased from 0.2% in 2010 to 4.2% in 2019 (AAPC=49.7%, [95%CI, 39.3% to 60.9%]). Among all pregnancies, 0.9% had been exposed to a potentially harmful anti-infective agent increasing from 0.7% in 2010 to 1.2% in 2019 (AAPC=6.4%, [4.4%-8.5 %]). Conclusion. Based on more than 7 million pregnancies identified from French nationwide data, this study showed that antibacterials are frequently prescribed during pregnancy although their use has decreased over the past ten years. Our results suggest that anti-infective are generally prescribed in accordance with recommendations, with however a potential for improvement in influenza vaccination.

Background: Multiple myeloma accounts for over 15% of hematological malignancies. In attempt to tackle this malady, the FDA approved four drugs in 2015 which has propagated further development of new anti-multiple myeloma since. However, the health safety of these new agents is still ill-defined. The aim of this study is to delineate the cardiovascular adverse events of these drugs. Methods: We searched the cardiac adverse events of the newly approved FDA drugs since 2015 using the U.S. Food and Drug Administration Adverse Events Reporting System database (FAERS). We calculated the reporting odds ratio (ROR) with 95% confidence for four drugs that have the highest incidence of cardiovascular adverse events. Results: Among the medications that have approved for MM Between 2015-2020, four novel drugs showed the highest incidence of cardiotoxicity. ROR (95% CI) for atrial fibrillation due to elotuzumab, Ixazomib, daratumumab, and panobinostat compared to other FAERS drugs was 5.8 (4.4-7.7), 1.9 (1.5-2.3), 4.8 (4.2-5.6), and 5.7 (4.1-8.1), respectively. The ROR (95% CI) for cardiac failure was 8.2 (6.4-10.5), 4.7 (4.1-5.4), 5.8 (4.9-6.7), and 5.6 (3.8-8.1) and ROR (95% CI) for coronary disease was 2.7 (1.9-3.9), 2.7 (2.3-3.2), 2.3 (1.9-2.8), and 4.6 (3.2-6.6) due to elotuzumab, Ixazomib, daratumumab, and panobinostat versus all other drugs in FAERS. Conclusions: Our results demonstrated that the newly approved antimyeloma therapy (elotuzumab, Ixazomib, daratumumab, panobinostat) are significantly associated previously unknow cardiotoxicity. These results warrant further studies and highlight the importance of considering the cardiac history of patients with multiple myeloma when utilizing these novel agents.

Fluvoxamine for COVID-19 outpatients: for the time being, we might prefer to curb our optimismVladimir TrkuljaRunning head : Fluvoxamin and COVID-19 outpatientsKey words : fluvoxamine, COVID-19, outpatients, hospitalizationsVladimir Trkulja, MD, PhDDepartment of PharmacologyZagreb University School of MedicineŠalata 1110000 Zagreb, Croatiae-mail: [email protected] of words: 613Number of figures/tables: 1To the Editor,A rather elaborate pharmacodynmics rationale 1 and sound pharmacokinetic reasoning 2 support the use of fluvoxamin in early phases of the COVID-19 disease. Two recent meta-analyses, 3, 4 both based on the same three randomized placebo-controlled trials, emphasized the benefit of early fluvoxamine treatment in non-vaccinated adult symptomatic mild COVID-19 outpatients in terms of a reduced risk of disease deterioration over subsequent days. In the first of the meta-analyzed trials, Stop COVID 15, primary outcome was hospitalization or incident hypoxemia needing oxygen treatment within 15 days. The trial was rather small, particularly for a binary outcome (fluvoxamine 2x100 to 3x100 mg/day over 15 days, n=80; placebo n=72) and recorded only 6 events (all with placebo) 5. Stop COVID 2 6followed the same design/outcome, and was stopped at an advanced stage for operational reasons but did not indicate any benefit [incidence 11/272 (4.0%) fluvoxamin vs. 12/275 (4.4%) placebo)]. The meta-analytical pooled estimates 3, 4 were dominated by the results of the TOGETHER trial 7 (fluvoxamine 2x100 mg/day, 10 days) that reported a marked relative reduction in the risk of the primary outcome (emergency room stay of at least 6 hours or hospitalization; over 28 days): 79/741 (11.0%) vs. 119/756 (16.0%), RR=0.69 (95% CrI 0.53-0.90) 7. By far the most events were hospitalizations, but no clear-cut benefit was obvious in this respect [75/741 (10.0%) vs. 97/756 (13.0%), OR=0.77 (0.55-1.05)7]. The meta-analysis by Lee et al.3 focused on hospitalizations and reported a 25% relative risk reduction by a frequentist method (RR=0.75, 95%CI 0.58-0.97), while the Bayesian analysis (weakly informative neutral prior) indicated somewhat more uncertainty (RR=0.78, 95%CrI 0.58-1.08; 81.6% probability of RR ≤0.90) 3. Guo et al.4 employed only frequentist pooling to indicate a marked benefit regarding “study-defined outcomes” (RR=0.69 95%CI 0.54-0.88) and somewhat more uncertainty regarding “hospitalizations” (RR=0.79, 95%CI 0.60-1.03) 4. In the meantime, a report was pubslihed of a randomized placebo-controlled trial conducted in 2020 in Korean outpatients (∼10 days of fluvoxamine 2x100 mg/day)8. It was stopped early for operational reasons8, and the primary outcome (as in Stop COVID trials) was observed in 2/26 treated and 2/26 placebo patients8. Figure 1 depicts meta-analysis of “study-defined primary outcomes” and of “hospitalizations” that uses the same frequentist and Bayesian methodology as used by Lee et al.3 except that (i) it includes the Korean data8 and (ii) employs Hartung-Knapp-Sidik-Jonkman correction shown to yield the least biased confidence interval coverage with small number of trials considerably varying in size9: (a) uncertainty about the benefit regarding “study-defined outcomes” (Figure 1A) is indicated by both the frequentist and Bayesian intervals extending to >1.0 and prediction intervals extending well >1.0. Probability of at least 10% relative risk reduction is 90.0%; (b) uncertainty about the benefit regarding “hospitalizations” (Figure 1B) is even more obvious, with estimate intervals exceding >1.10 (and further extended predictions intervals), with only 73.8% probability of at least 10% relative risk reduction. If one were to disregard two small trials with a few events (and, hence, fragile estimates that could have been by chance, at least in part) 5, 8, for the time being one would be looking at Stop COVID 2 and TOGETHER trial. This means 86/1013 hospitalization events with fluvoxamine vs. 109/1031 events with placebo, and a considerable uncertainty about any practically relevant effect: (i) frequentist RR=0.803 (95%CI 0.422-1.530); (ii) Bayesian RR=0.840 (95%CrI 0.613-1.170) and only 67.4% probablity of at least 10% relative risk reduction. Hopefully, the on-going trials (depicted in ref. 3) will resolve this uncertainty, but presently we might prefer to be cautios rather than overtly optimistic about the actual extent of benefit conveyed by early fluvoxamine treatment in COVID-19 outpatients.

Background: Clinical trial simulations and pharmacometric modeling of biomarker profiles for under-represented groups are challenging because the underlying studies frequently do not have sufficient participants from these groups. Objectives: To investigate generative adversarial networks (GANs), an artificial intelligence (AI) technology that enables realistic simulations of complex patterns, for modeling clinical biomarker profiles of under-represented groups. Methods: GANs consist of generator and discriminator neural networks that operate in tandem. GAN architectures were developed for modeling univariate and joint distributions of a panel of 16 diabetes-relevant biomarkers from the National Health and Nutrition Examination Survey (NHANES), which contains laboratory and clinical biomarker data from a population-based sample of individuals of all ages, racial groups, and ethnicities. Conditional GANs were used to model biomarker profiles for race/ethnicity categories. GAN performance was assessed by comparing GAN outputs to test data. Results: The biomarkers exhibited non-normal distributions and varied in their bivariate correlation patterns. Univariate distributions were modeled with generator and discriminator neural networks consisting of two dense layers with rectified linear unit-activation. The distributions of GAN-generated biomarkers were similar to the test data distributions. The joint distributions of the biomarker panel in the GAN-generated data were dispersed and overlapped with the joint distribution of the test data as assessed by three multi-dimensional projection methods. Conditional GANs satisfactorily modeled the joint distribution of the biomarker panel in the Black, Hispanic, White, and “Other” race/ethnicity categories. Conclusions: GAN are a promising AI approach for generating virtual patient data with realistic biomarker distributions for under-represented race/ethnicity groups.

Aim There is still only little knowledge about alterations of blood concentrations of psychotropic drugs during pregnancy, the transfer of psychotropic drugs into breast-milk and the effects on exposed children. Methods We investigated changes in concentrations of psychopharmacological medication during pregnancy and lactation in serum and breast milk at different time points in a naturalistic sample of 60 mothers and observed the development of the exposed children in the first 12 months. Results We found a decrease in serum concentrations from the first to the second trimester of amitriptyline, duloxetine, escitalopram, quetiapine and sertraline. Citalopram stayed rather stable during pregnancy, sertraline levels interestingly increased again from the second to the third trimester. Highest concentration-by-dose-ratios in breast milk were found for venlafaxine as well as lamotrigine, lowest for quetiapine and clomipramine. Similarly, clomipramine and quetiapine showed lowest milk/serum-penetration-ratios. Regarding the birth outcome measures in children we found no significant differences between in utero exposed compared to non-exposed new-borns. There were no significant differences in the development in the first 12 months. Conclusion Psychotropic medication in the peripartum needs a balancing of risks and benefits and a continuous therapeutic drug monitoring (TDM) can be a guidance for clinicians to monitor drug alteration patterns, which are likely to occur due to physiological pregnancy-associated changes in pharmacokinetics. Accordingly, TDM can optimize a medication in pregnancy and lactation with the lowest but effective dose.

Aim To evaluate the number and nature of reported congenital malformations (CMs) after intrauterine exposure to non-tumour necrosis factor inhibitors (non-TNFis) compared to certolizumab pegol (CZP) Material and methods A retrospective comparative study was conducted in the EudraVigilance (EV) database. EV is a pharmacovigilance database, which can be used for detecting safety signals and generating hypotheses on possible relations between drugs and adverse events. A supposedly safe biologic (CZP) was considered as the reference group. Pregnancy-reports of non-TNFis and CZP were extracted. Odds ratios (ORs) for CMs were calculated for each non-TNFi, versus CZP (quantitative assessment). Then, CM patterns were compared to CZP in consultation with a clinical geneticist (qualitative assessment). Results ORs were not statistically significant except for belimumab and vedolizumab (similar in magnitude). Although qualitative analyses did not show any specific patterns for belimumab but three cases of corpus callosum agenesis (CCA) were identified for vedolizumab (versus null in CZP and other investigated non-TNFis). Two of the CCA cases were associated with other neurological CMs (one cerebral ventriculomegaly with microcephaly and one polymicrogyria). This may indicate that these CCAs are related to undiagnosed genetic alterations or are associated with the underlying maternal disease, although a definite relationship with vedolizumab exposure cannot be ruled out. Conclusion No special safety signal was identified regarding the occurrence of CMs after exposure to non-TNFis, except for vedolizumab. Based on available information, no firm conclusions can be made regarding observed CCAs in the vedolizumab group (it warrants further research)

Aim: Although there is a high risk of gastrointestinal (GI) bleeding in the elderly, few studies have quantified the impact of risk factors on GI complications in elderly nonsteroidal anti-inflammatory drug (NSAID) users. This study aimed to develop and validate a risk prediction score to identify high-risk elderly patients using NSAID for severe GI complications. Methods: We used the following two Korean claims datasets: customized data with an enrollment period 2016–2017 for model development, and the sample data in 2019 for external validation. We conducted a nested case-control study for model development and validation. NSAID users were identified as the elderly (≥ 65 years) who received NSAIDs for more than 30 days. Patients who experienced serious GI complications, defined as hospitalizations or emergency department visits, were diagnosed with GI bleeding or perforation. We derived a model using logistic regression and cross-validation. Results: In the external validation cohort, we identified 372 cases from 254,551 patients. We identified 8,176 cases and 81,760 controls with a 1:10 matched follow-up period in the derivation cohort. In the external validation cohort, we identified 372 cases from 254,551 patients. The risk predictors were high-dose NSAIDs, NSAID type, complicated GI ulcer history, male sex, concomitant gastroprotective agents, relevant co-medications, severe renal disease, and cirrhosis. Area under the receiver operating characteristic curves was 0.77 (95% confidence interval, 0.75–0.80) in the external validation dataset. Conclusion: The prediction model may be a useful tool for reducing the risk of serious GI complications by identifying high-risk elderly patients.

Aim: Older adults are particularly affected by medication-related harm (MRH) during transitions of care. There are no clinical tools predicting those at highest risk of MRH post-hospital discharge. The PRIME study (prospective study to develop a model to stratify the risk of MRH in hospitalized patients) developed and internally validated a risk-prediction tool (RPT) that provides a percentage score of MRH in adults over 65 in the eight-weeks following hospital discharge. This qualitative study aimed to explore the views of hospital pharmacists around enablers and barriers to clinical implementation of the PRIME-RPT. Methods: Ten hospital pharmacists: (band 6 (n=3); band 7 (n=2); band 8 (n=5)) participated in semi-structured interviews at the Royal Sussex County Hospital (Brighton, UK). The pharmacists were presented with five case-vignettes each with a calculated PRIME-RPT score to help guide discussion. Case-vignettes were designed to be representative of common clinical encounters. Data were thematically analysed using a ‘framework’ approach. Results: Seven themes emerged in relation to the PRIME-RPT: 1. providing a medicine-prioritisation aide; 2. acting as a deprescribing alert; 3. facilitating a holistic review of patient’s medication management; 4. simplifying communication of MRH to patients and the multidisciplinary team; 5. streamlining community follow-up and integration of risk discussion into clinical practice; 6. identifying barriers for the RPTs integration in clinical practice and 7. acknowledging its limitations. Conclusion: Hospital pharmacists found the PRIME-RPT beneficial in identifying older patients at high-risk of MRH following hospital discharge, facilitating prioritising interventions to those at highest risk while still acknowledging its limitations.

Aim: Guidelines establish a framework for how therapeutics and vaccines are developed, assessed and approved. They influence which innovations are likely to be approved in the EU, and by that, they have an impact on the pipeline decisions taken by the research-based industry. This study analyses the level of acceptance for changes suggested by stakeholders within the authoring groups at the EMA. Methods: We looked at 87 guidelines from EMA Working Parties (WPs) launched for consultation between 2013-2017. Acceptance of stakeholder proposals and the time between the end of consultation and guideline adoption were studied as well as the openness of different Working Parties to accept changes. Results: Adoption of a guideline after the close of public consultation took at least 4 months, with average 12-16 months. The number of accepted and rejected comments were nearly equal across the stakeholders, with government having slightly higher chance for acceptance. Academia and NGOs had generally higher chances to have their comments accepted for general and indication-level guidelines. Government and individual companies had highest acceptance for molecule-level guidelines and trade associations for indication-level guidelines. The EMA WPs working with emerging technologies were more open to accept proposed changes. Conclusion: This pattern of progress in regulatory science at EMA demonstrates the essential and interrelated role of academia, industry, government and civil society – described as the quadruple helix model - to promote establishment of a strong innovation ecosystem in Europe. Further integration and utilisation of competences of each stakeholder is necessary for guideline development.

This study aimed to examine gabapentin utilization trends among older adults with different cognitive statuses and investigate concurrent medication use of potentially inappropriate medications. Data were extracted from National Alzheimer’s Coordinating Center Uniform Data Set (2006-2019). We estimated the yearly prevalence of gabapentin use, both overall and within subgroups defined by cognitive status [normal, mild cognitive impairment, and dementia] and demographics [age and sex] for participants aged 65+. Additionally, we assessed the prevalence of concurrent use of gabapentin with opioids, combined opioids and benzodiazepine, antidepressant, and antipsychotic. Participants reported gabapentin use increased from 2006 to 2019 in both overall and every participant subgroup. About 10-30% of gabapentin users reported to concurrently use of opioids, and more than 50% gabapentin users with dementia reported to concurrently use gabapentin with antidepressants. Given increasing use among older adults, rigorous studies are needed to examine the safety of gabapentin in this population.

The initial purposes of regulation of medicines in England were principally to raise government revenue, to discourage murder by poisoning, and to regulate the activities of pharmacists. It was only much later that regulators sought to ensure that medicines were of good quality, reasonably safe, and at least somewhat effective, and to regulate misuse of drugs. Here we survey the history of the regulation of medicines and poisons in England from the perspective of clinicians with an interest in therapeutics.

The incidence of new-onset seizures, which we defined as de novo seizures occurring within four weeks of receiving any of the FDA-approved Covid 19 vaccinations as reported in patient-reported data compiled in the US Centers for Disease Control and Prevention Vaccine Adverse Events Reporting System Data (CDC VAERS) has not been explored. The VAERS database contains de-identified patient-reported adverse events following vaccinations and represents post-marketing surveillance and analysis of vaccine safety. After adjusting for time at risk, this resulted in estimated incidence rates of 3.19 seizures per 100,000 persons per year for either Pfizer, Moderna or Janssen vaccines and 0.090 seizures per 100,000 persons per year for the influenza vaccine. A data-driven, individualized dataset that is comprehensive and coupled with a longitudinal follow-up in larger numbers of vaccinated individuals is needed to expand on our preliminary findings of vaccine-related seizures. The VAERS database helps in the identification of a safety signal detection and is fundamentally a hypothesis-generating system; the data or results cannot be used to analyze cause and effect.

Aim A parent-metabolite population pharmacokinetic (popPK) model of iberdomide was developed and the influence of demographic and disease-related covariates on popPK parameters was assessed based on data from three clinical studies of iberdomide (dose range, 0.1 to 6 mg) in healthy subjects (N=81) and subjects with relapsed and refractory multiple myeloma (N=245). Methods Nonlinear mixed effects modeling was used to develop the popPK model based on data from 326 subjects across 3 clinical studies. Results The pharmacokinetics (PK) of iberdomide were adequately described with a two-compartment model with first-order absorption and elimination. A first order conversion rate was used to link the one-compartment linear elimination metabolite model with the parent model. Subject type (multiple myeloma subjects vs. healthy subject) was a statistically significant covariate on apparent clearance (CL/F) and apparent volume of distribution for the central compartment (V1/F), suggesting different PK between subjects with multiple myeloma and healthy subjects. Aspartate aminotransferase (AST), alkaline phosphatase (ALP) and sex were statistically but not clinically relevant covariates on CL/F. Metabolite (M12) PK tracked the PK of iberdomide. The metabolite to parent ratio was consistent across doses and combinations. Conclusion In conclusion, the parent-metabolite population pharmacokinetic model adequately described the time course PK data of iberdomide and M12. Iberdomide and M12 show robust PK exposure, not complicated by demographic factors, combination, hepatic or (mild and moderate) renal impairments. The model can be used to guide the dosing strategy for special patient population and inform future iberdomide study design.

A document by GianPietro Sechi. Click on the document to view its contents.

Direct-acting oral anticoagulants (DOACs) are licensed for the prevention of thromboembolism in non-valvular atrial fibrillation amongst other indications. Prescribers use information derived from the summary of product characteristics which is based on the key trials supporting the DOAC’s market authorisation. However, prescribers may be aware of the limitations of these trials regarding underrepresentation of patient populations commonly encountered in clinical practice and how this may adversely impact them. This review highlights the gaps in the licensing evidence using 3 clinical vignettes that explore prescribing challenges in the elderly, obese and female patients.

Re letter to British Journal of Clinical Pharmacology

Aim: Residual neuromuscular blockade is a common complication after general anaesthesia. Sugammadex can reverse the action of aminosteroid neuromuscular blockers. Our study aimed to explore sugammadex safety issues in the real world and determine the spectrum of adverse reactions. Methods: All sugammadex-related adverse events reported in VigiBase between 2010 and 2019 were classified by group queries according to the Medical Dictionary for Regulatory Activities. A disproportionality analysis of data was performed using the information component (IC); positive IC values were deemed significant. Results: Overall, 16,219,410 adverse events were reported, and 2032 were associated with sugammadex. The most frequent reactions were recurrence of neuromuscular blockade (n = 54, IC: 6.74, 95% credibility interval [CI]: 6.33–7.10), laryngospasm (n = 53, IC: 6.05, IC025:5.64), bronchospasm (n = 119, IC: 5.63 , IC025:5.36), and bradycardia (n = 169, IC: 5.13, IC025:4.90). Fatal cases were more likely with cardiac disorders, especially in patients over 65 years. In addition, the common adverse drug reactions (ADRs) differed between different age groups (P < 0.01). The ADRs were higher between 0–17 years than in other age groups. The onset time of common ADRs was typically within one day, and 68.9% occurred within half an hour after sugammadex administration. Conclusions: Anaesthesiologists should carefully monitor the anaesthesia recovery period to correct the adverse drug reactions caused by sugammadex and recommend monitoring neuromuscular function throughout the anaesthesia process. Sugammadex should be used carefully in patients with cardiovascular diseases, and ECG and hemodynamic changes monitored after medication.

In this special issue of the British Journal of Clinical Pharmacology, we highlight innovative methodologies in pediatric drug development.