The European Medicines Agency (EMA) started operating under its new legal mandate on 1 April 2022. The mandate brings new responsibilities to the Agency in three different areas: • Reinforcement of the role and activities of the EMA pandemic Task Force(which is now known as the Emergency Task Force (ETF)). • A stronger role of EMA in the monitoring of shortages of critical medicines, medical devices and in-vitro diagnostics, both in anticipation of and during a crisis. • A more coordinated mechanism of European Union (EU) experts advice on medical devices classified as high-risk (class IIa and III or class D (1)) and in-vitro diagnostic medical devices. Here we consider the impact of the COVID-19 pandemic on the operations of EMA and the European medicines regulatory network, and how EMA’s new mandate will strengthen the Agency’s and the Network’s ability to face crises. EMA’s extended mandate brings clear benefits in terms of response to public health emergencies at EU level, which ranges from improvements in crisis management to avoiding medicine shortages and improving access to diagnostics and medical devices that are safe and conform to their expected function.
Title:Tranexamic acid-associated fatal status epilepticus in a paediatric patientAuthor:Dr Santosh Patel MD, FRCA, PG Dip (Med Edu)Consultant AnaesthetistDepartment of anaesthesiaTawam hospitalAl AinUnited Arab EmiratesCorrespondence address: as above.Email: firstname.lastname@example.orgFunding: No source of funding to declareConflicts of interest: Nothing to declareDear Editor,I have read with interest a case report and literature review published in the British journal of pharmacology on tranexamic acid (TXA) associated SE in a 4-year child who underwent tonsillectomy.1 I would like to congratulate the authors for reporting the case despite the fatal outcome. Considering that the use of TXA is expanding to minimise blood loss in a wide range of surgeries, an evidence-based therapeutic approach for its associated seizures is of paramount importance.The authors described in their report (also mentioned in Table 2) and concluded that general anaesthetics, propofol and halogenated inhaled anaesthetics are considered the first line of management of TXA-associated seizures due to their direct activity at glycine receptors. In support of their statement, they have quoted three references (references 35,45,46 in their report). However, in their articles, the authors did not recommend the use of general anaesthetics (propofol and halogenated inhalational anaesthetics) as the first line of treatment for TXA-related seizures. It is valuable to point out to the readers that their conclusion is not valid and needs clarification and correction.TXA-associated hyperexcitability of neural networks is because it is a competitive antagonist of glycine and GABAA receptors.2 Following IV TXA administration, not all seizures progress to status epilepticus. Although TXA-related seizures commonly manifest as generalised tonic-clonic activity, focal seizures have been reported; which are not an indication for the use of general anaesthetics. Refractory status epileptics (RSE) and super RSE are uncommon following IV TXA although this is a common feature following intrathecal TXA.3Propofol’s anticonvulsant, hypnotic, sedative and anaesthetic effects are mediated via multiple complex molecular mechanisms, including modulation of GABAA and glycine receptors. GABAA receptor modulation by propofol has distinct dose-dependent effects likely involving multiple sites of action; clinical concentrations of propofol potentiate GABA-activated currents, increase open channel frequency, and reduce the rate of desensitization, while intermediate concentrations directly activate GABAA channels, and even higher concentrations inhibit receptor function.4Propofol can cause neuroexcitatory effects, including tonic-clonic seizures, particularly during the start or weaning from propofol infusion.5 Among the various mechanisms that have been proposed for these neuroexcitatory symptoms are antagonism of glycine and dopamine receptors, hyposensitization of GABAergic pathways and dysregulated inhibition of NMDA glutamate receptors.6Its use is associated with side effects, including hypotension (and the associated use of vasopressors) and respiratory depression. With prolonged infusion, propofol infusion syndrome (PIS) may occur, which may contribute to morbidity and mortality of RSE. Children are more susceptible to developing this complication. Propofol infusion therapy is not recommended as the first line of treatment for TXA-associated seizures, and its use is reserved for severe cases in children.Inhalational anaesthetics are beneficial for the control of seizure activity via inhibition of NMDA excitotoxicity and potentiation of inhibitory functions of GABAA and glycine receptors. However, it is essential to highlight that there are several limitations to the use of inhalational anaesthetic agents. First, the only clinical evidence of their use is from the minimal number of case reports. Second, TXA-related seizures often manifest in the postoperative period in the recovery room or in ICU, where delivery and scavenging of inhalational agents via ventilator may not be feasible. Third effective end-tidal concentration and optimal therapeutic duration are not known. Finally, in higher concentrations, they cause cardiac depression and cerebral vasodilation. Therefore, their use is limited as salvage therapy for the management of TXA-associated RSE and super RSE.In summary, the authors’ conclusion is incorrect, and clinicians should follow currently available evidence-based professional guidelines to manage TXA-associated status epilepticus.8,9References:1. Aboul-Fotouh S, Habib MZ, Magdy SM, Hassan BEE. Tranexamic acid-associated fatal status epilepticus in a paediatric non-cardiac surgery: A case report and literature review. Bri J Clin Pharmacol 2022;1-6. doi:10.1111/bcp.152962. Lecker I, Wang D, Whissell P, et al. Tranexamic acid-associated seizures: causes and treatment. Ann of Neurol 2015;79(1):18-26. doi:10.1002/ana.245583. Patel S, Robertson B, McConachie I. (2019). Catastrophic drug errors involving tranexamic acid administered during spinal anaesthesia.Anaesthesia ,74(7),904-14 https://doi.org/10.1111/anae.146624. Platholi J, Hemmings H. (2022). Effects of general anesthetica on synaptic transmission and spasticity. Currt Neuropharmacol2022;20(1):27-54. doi: 10.2174/1570159X19666210803105232.5. Walder B, Tramèr MR, Seeck M. (2002). Seizure-like phenomena and propofol: a systematic review. Neurology 2002; 58(9):1327-32. 10.1212/wnl.58.9.13276. Pantelakis L, Alvarez V, Gex G, Godio M. Severe neuroexcitatory reaction: A rare and underrecognized life-threatening complication of propofol-induced anesthesia. The Neurohospitalist2021;11(1):49-53. doi: 10.1177/1941874420929536.7. Godec S, Gradisek MJ, Mirkovic T etal. Ventriculolumbar perfusion and inhalational anesthesia with sevoflurane in an accidental intrathecal injection of tranexamic acid: unreported treatment options. Reg Anesthe Pain Med 2022;47(1):65-68 10.1136/rapm-2021-1024988. Nelson SE, Varelas PN. Status epilepticus, refractory status epilepticus, and super-refractory status epilepticus. Continuum (Minneap Minn). 2018;24(6):1683-1707.9. Vossler DG, Bainbridge JL, Boggs JG etal.. Treatment of refractory convulsive status epilepticus: a comprehensive review by the American Epilepsy Society Treatments Committee. Epilepsy Curr.2020;20(5):245-64.
RP7214 is a potent and selective inhibitor of human mitochondrial enzyme dihydroorotate dehydrogenase (DHODH). This paper describes the results from a Phase 1 study that evaluated safety and pharmacokinetics of single and multiple ascending doses (SAD and MAD) and the food effect of RP7214 in healthy subjects. Target engagement of DHODH was also evaluated. A randomized, double-blind, placebo-controlled trial of single-dose (100, 200, and 400 mg QD) and multiple doses (200 and 400 mg BID for 7 days) followed by food effect at a single dose of 200 mg was conducted. A total of 18 healthy volunteers (HVs) (6 subjects in each of three cohorts) in the SAD part, 12 (6 subjects each in two cohorts) in the MAD part, and 12 in the food effect study were enrolled. RP7214 was well tolerated at all dose levels. None of the subjects reported any RP7214-related adverse events. RP7214 showed dose-proportional pharmacokinetics after single and multiple dosing. Steady-state concentrations were reached within about 3–6 days. The mean plasma half-life of RP724 at steady-state was approximately 13h. RP7214 showed accumulation on multiple dosing.. Food did not impact the absorption of RP7214. RP7214 showed dose-dependent inhibition of DHODH as measured by analyzing accumulating DHO levels, confirming target engagement. The rapid absorption and high systemic exposure of RP724 with a favorable safety profile shows the potential for the development of RP7214 in SARS-CoV-2 infection and acute myeloid leukemia. (NCT04680429). Keywords: RP7214, dihydroorotate dehydrogenase, SAD, MAD, HV
Guillain- Barre Syndrome (GBS), an autoimmune neurological disease of peripheral nerves has been causally associated with COVID-19 vaccination in adults. However, no such report has been published so far in children. We describe a 13-year old female child who presented to emergency department with complaints of bilateral upper limb, lower limb and truncal weakness over three days following first dose of recombinant protein subunit COVID-19 vaccine (Corbevax). Clinical examination and nerve conduction studies showed pure motor axonal polyneuropathy with absent compound muscle action potential (CMAP) in all sampled nerves of upper and lower limbs which was consistent with the diagnosis of GBS after ruling out possible alternative aetiologies. A temporal association between first dose of protein subunit COVID-19 vaccine administered a day prior and symptom onset was noted. The causality assessment using World Health Organization (WHO) tool for adverse event following immunization (AEFI) assessment indicated vaccine-product related reaction categorized as A1. Patient’s clinical condition improved after seven sessions of plasmapheresis. The purpose of this report is to create awareness among the health care professionals about COVID-19 vaccine induced GBS in children as early diagnosis and management can be critical in avoiding complications and improving patient outcomes.
“Pharmacovigilance is the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other medication-related problem”, according to the WHO. With the increasing volume of legislation, pharmacovigilance systems have shifted from reactive (responding to emerging risks), to planned, active, risk-proportionate approaches operating throughout the lifecycle of medicines. Whilst medicines are beneficial to society, adverse reactions represent a significant cause of concern. They are a major cause of failed regulatory authorizations, and withdrawal from the marketplace post-approval. Evaluation of real-world data plays an increasingly important role in pharmacovigilance. There is great interest on the part of the regulators, MAHs, academia and patients in optimizing the use of safety data. Innovative approaches, including pharmacogenetics and passive measures (sensors), will lead to increased complexity in data collation and evaluation, and inevitably to an increase in the volume of case reports. There is a multiplicity of regulations and guidelines on how to manage these data, with an inherent lack of harmonization. We summarize the current characterization of safety data types, sources, and the classification of these data. Using this benchmark, we discuss the future requirements of an effective pharmacovigilance ecosystem, keeping the principle of parsimony in mind.
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@example.comNumber 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.
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: 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.
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.