Dosing Schedule Research Articles

Matching-adjusted indirect comparison of talquetamab vs selinexor-dexamethasone and vs belantamab mafodotin in patients with relapsed/refractory multiple myeloma

Objective Talquetamab is the first GPRC5D-targeting bispecific antibody approved for the treatment of triple-class exposed (TCE) relapsed/refractory multiple myeloma (RRMM). This matching-adjusted indirect comparison (MAIC) study was conducted to compare the effectiveness of talquetamab vs selinexor-dexamethasone (sel-dex) and vs belantamab mafodotin (belamaf) in patients with TCE RRMM. Methods An unanchored MAIC was performed using individual patient-level data from patients treated with subcutaneous talquetamab 0.4 mg/kg weekly (QW) and 0.8 mg/kg every other week (Q2W) from MonumenTAL-1 (NCT03399799/NCT04636552) and published summary data for sel-dex from STORM (NCT02336815) and belamaf from DREAMM-2 (NCT0325678). Patients from MonumenTAL-1 who met key eligibility criteria for STORM and DREAMM-2 were included. Outcomes of interest were overall response rate (ORR), complete response or better (≥CR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Results After adjustment for cross-trial differences, patients treated with both dosing schedules of talquetamab showed significantly better ORR, ≥CR, and DOR vs sel-dex and significantly higher ORR and ≥ CR vs belamaf; DOR was relatively similar to belamaf. PFS was significantly improved with talquetamab Q2W and numerically in favor of talquetamab QW vs sel-dex and significantly improved with both dosing schedules of talquetamab vs belamaf. OS was significantly improved with both dosing schedules of talquetamab vs sel-dex and was numerically in favor of both dosing schedules of talquetamab vs belamaf. Conclusion These analyses show superior effectiveness of both talquetamab dosing schedules vs sel-dex and vs belamaf for most outcomes and highlight talquetamab as an effective treatment option for patients with TCE RRMM.

Novel engineered IL-2 Nemvaleukin alfa combined with PD1 checkpoint blockade enhances the systemic anti-tumor responses of radiation therapy

BackgroundCombining interleukin-2 (IL-2) with radiotherapy (RT) and immune checkpoint blockade (ICB) has emerged as a promising approach to address ICB resistance. However, conventional IL-2 cytokine therapy faces constraints owing to its brief half-life and adverse effects. RDB 1462, the mouse ortholog of Nemvaleukin alfa, is an engineered IL-2 with an intermediate affinity that selectively stimulates antitumor CD8 T and NK cells while limiting regulatory T cell expansion. This study aimed to evaluate the antitumor activity and mechanism of action of the combination of RDB 1462, RT, and anti-PD1 in mouse tumor models.MethodsTwo bilateral lung adenocarcinoma murine models were established using 344SQ-Parental and 344SQ anti-PD1-resistant cell lines. Primary tumors were treated with RT, and secondary tumors were observed for evidence of abscopal effects. We performed immune phenotyping by flow cytometry, analyzed 770 immune-related genes using NanoString, and performed T cell receptor (TCR) repertoire analysis. Serum pro-inflammatory cytokine markers were analyzed by 23-plex kit.ResultsCompared to native IL-2 (RDB 1475), RDB 1462 demonstrated superior systemic antitumoral responses, attributable, at least in part, to augmented levels of CD4 and CD8 T cells with the latter. Our findings reveal substantial reductions in primary and secondary tumor volumes compared to monotherapy controls, with some variability observed among different dosing schedules of RDB 1462 combined with RT. Blood and tumor tissue-based flow cytometric phenotyping reveals an increase in effector memory CD8 and CD4 T cells and a decrease in immunosuppressive cells accompanied by a significant increase in IL-2, IFN-γ, and GM-CSF levels in the combination group. Transcriptomic profiling and TCR sequencing reveal favorable gene expression and T cell repertoire patterns with the dual combination. Furthermore, integrating anti-PD1 therapy with RT and RDB 1462 further reduced primary and secondary tumor volumes, prolonged survival, and decreased lung metastasis. Observations of immune cell profiles indicated that RT with escalating doses of RDB 1462 significantly reduced tumor growth and increased tumor-specific immune cell populations.ConclusionThe addition of Nemvaleukin therapy may enhance responses to RT alone and in combination with anti-PD1.Graphical

Evaluating Dual Process Decision-Making Along the PrEP Consumer Journey: New Insights for Supporting PrEP Use.

With the rise of new and emerging Pre-Exposure Prophylaxis (PrEP) modalities, greater attention is needed to better understand how people who could benefit from PrEP make decisions to initiate, stop, pause, or switch PrEP regimens. In this study we borrow from the field of consumer research to create a consumer-derived PrEP Consumer Journey Model that describes key decision-making touchpoints a PrEP consumer moves through within and outside of a clinical context. Using in-depth interviews (n = 29) with gay and bisexual men who have sex with men, we evaluate which system 1 (emotional) and system 2 (cognitive) attributes are used for decision-making at different touchpoints along the PrEP Consumer Journey. Our results suggest system 1 attributes, such as feeling protected, reducing anxiety, enhancing pleasure, social norms, and taking ownership over health were more salient when consumers moved from pre-contemplation to information gathering, as well as evaluating post-uptake experience. System 2 attributes, including cost, side effects, dosing schedule, and sexual frequency, were present throughout the PrEP Consumer Journey, but particularly influential in the information gathering stage and when pausing, switching, or opting out of PrEP. We contend the PrEP Consumer Journey, and our findings related to decision-making, can help orient medical providers to anticipated patient concerns around PrEP use and ultimately provide more supportive and engaging PrEP counseling and services.

Pediatric Pneumococcal Conjugate Vaccine and Dosing Schedule Perceptions Among Health Care Providers and Caregivers in Germany, France, Spain, and Greece.

Most European infant national immunization programs (NIPs) recommend pneumococcal conjugate vaccines (PCVs), which currently cover 10-15 serotypes administered in a three-dose schedule (two primary plus one booster). Recently, a PCV covering 20 serotypes that is administered in a four-dose schedule (three primary plus one booster) was licensed. An online survey was administered to collect data from health care providers (HCPs) and caregivers of children aged 0-5 (including expectant mothers) in four European countries (Germany, France, Spain, and Greece). All caregiver respondents had a shared or full responsibility to make health decisions for their child. Data on opinions, perceptions, and openness to a change in childhood vaccination dosing schedules were collected, along with demographic information for HCPs as well as caregivers. A total of 601 HCPs and 1954 caregivers were recruited across the four countries. Nearly all HCPs (93%) agreed that broader serotype coverage against pneumococcal disease for children is a significant unmet need, and 92% had a "sense of urgency" to vaccinate children. Both HCPs and caregivers were supportive of an additional PCV dose and doctor visit, assuming it provided at least 20% more serotype coverage than what is currently available. Caregivers strongly agreed on the importance of full vaccination for pneumococcal disease, even if an extra dose and visit to the doctor was required. HCPs and caregivers were virtually unanimous in their support for a PCV with broader serotype coverage and showed a subsequent willingness to include an extra infant dose/visit. These results can help guide broader discussions regarding public health policy and vaccine administration in the context of important efforts to reduce the global disease burden associated with pneumococcal disease.

Influenza Epidemiology and Vaccine Effectiveness Following Funded Influenza Vaccine in Queensland, Australia, 2022.

In 2022, publicly funded influenza vaccine was made available to all residents of Queensland, Australia. This study compared influenza epidemiology in 2022 with previous years (2017-2021) and estimated influenza vaccine effectiveness (VE) during 2022. The study involved a descriptive analysis of influenza notifications and a case-control study to estimate VE. Cases were notifications of laboratory-confirmed influenza, and controls were individuals who were test negative for COVID-19. Cases and controls were matched on age, postcode and specimen collection date. VE against hospitalisation was investigated by matching hospitalised cases to controls. Conditional logistic regression models were adjusted for sex. In 2022, Queensland experienced an early influenza season onset (April-May) and high case numbers (n = 45,311), compared to the previous 5 years (annual average: 29,364) and 2020-2021 (2020:6047; 2021:301) during the COVID-19 pandemic. Adjusted VE (VEadj) against laboratory-confirmed influenza was 39% (95% confidence interval [CI]: 37-41), highest for children aged 30 months to < 5 years (61%, 95% CI: 49-70) and lowest for adults aged ≥ 65 years (24%, 95% CI: 17-30). VEadj against influenza-associated hospitalisation was 54% (95% CI: 48-59). Among children < 9 years of age, VEadj against laboratory-confirmed influenza (55%, 95% CI: 49-61) and hospitalisation (67%, 95% CI: 39-82) was higher in those who received a complete dose schedule. In Queensland, the 2022 influenza season started earlier than the previous 5 years. VE against influenza notifications varied across age groups. VE estimates against influenza-associated hospitalisation were higher than those against laboratory-confirmed influenza.

Transforming the Discovery of Targeted Protein Degraders: The Translational Power of Predictive PK/PD Modeling.

Targeted protein degraders (TPDs), an emerging therapeutic modality, are attracting considerable interest with the promise to address disease-related proteins that are not druggable with conventional small molecule inhibitors. Despite their novel mechanism of action, the PK/PD relationship of degraders is still approached with a mindset deeply rooted in inhibitor drugs. Here, we establish how predictive mechanistic modeling specifically tailored to TPDs can significantly enhance the value of the available information during lead generation and optimization. By integrating the results from in vitro assays with routinely collected PK data, modeling accurately predicts degradation in vivo. These predictions transform the prioritization of compounds for in vivo studies as well as the selection of optimal dose schedules and most informative measurement time points with the least number of animals. Moreover, the comprehensive modeling framework (1) identifies the PK/PD driver of targeted protein degradation and subsequent downstream pharmacodynamic effects, and (2) uncovers the fundamental difference between degrader and inhibitor PK/PD relationships. The practical utility of our predictive modeling is demonstrated with relevant use cases. This framework will allow researchers to transition from current, mostly serendipity-based approaches to more sound model-informed decision making. Going forward, the presented predictive PK/PD modeling framework lays out a rational path to incorporate inter-species differences in the pharmacology and thus promises to help with getting the dose right in clinical trials.

Prescribing Patterns of Intravenous Artesunate for Severe Malaria and Compliance with National Malaria Treatment Protocol, Gezira State, Sudan

Background: Malaria is a major public health problem in Sudan. Severe malaria, due in majority of cases to P. falciparum, poses a real burden on hospitals. This study aims to describe the prescribing pattern of intravenous artesunate (IV-AS) for severe malaria and compliance with national malaria treatment protocol in Gezira State, Sudan. Methods: The study enrolled severe malaria patients who were admitted to the Wad Madani Teaching Hospital during June – August 2022. Patients were verbally consented and followed at hospital level till discharge. Data was recorded on data collection sheet and analyzed using SPSS version 20. Results: Over three months period, 500 patients were diagnosed as having severe malaria based on clinical criteria and the results of thick blood film. The majority were from rural areas and most of them were male. IV-AS was administered for all patients and 71% of patients discharged after administering three doses of artesunate with no serious adverse effects. In 96.4% of patients, the prescription followed the right dosage schedule. The source of the drug was health insurance fund and private sector in 78.4% and 21.6% respectively. The study investigates the prescribing patterns of intravenous artesunate (IV-AS) for severe malaria and compliance with the national malaria treatment protocol in Gezira State, Sudan. A Chi-Square Test of Independence was used to explore associations between gender and the number of IV-AS doses received, as well as between residence (rural vs. urban) and compliance with the dosage schedule. The results showed no significant association between gender and the number of IV-AS doses received (p = 0.915), and no significant association between residence and compliance with the dosage schedule (p = 0.925). These findings suggest that the prescribing patterns and compliance with the treatment protocol are consistent across different genders and between rural and urban patients. Conclusion: Severe malaria patients were treated with IV-AS according to national malaria treatment guidelines with few exceptions. Most patients discharged after administering three doses of artesunate with no serious adverse side effects. Efforts to establish quality assured microscopy and to maintain the current prescription pattern is highly needed.

Palliative Thoracic Radiotherapy in the Era of Modern Cancer Care for NSCLC.

Palliative thoracic radiotherapy provides rapid and effective symptom relief in approximately two-thirds of NSCLC patients treated. In patients with poor performance status, the degree of palliation appears unrelated to the radiation dose or fractionation schedule. Conversely, in patients with good performance status, higher radiation doses administered over longer periods have shown modest survival benefits. These findings stem from studies conducted before the advent of immunotherapy and targeted therapy in clinical practice. Currently, there are no large prospective studies specifically dedicated to palliative radiotherapy conducted in this new treatment era. Modern radiotherapy technologies are now widely available and are increasingly used for palliative purposes in selected patients, reflecting the expanded array of therapeutic options for disseminated NSCLC and improved prognosis. Some traditional tenets of palliative thoracic radiotherapy, such as the improvement of overall survival with a protracted radiation schedule and the use of simple, cost-effective radiation techniques for palliative purposes, may no longer hold true for patients receiving immunotherapy or targeted therapy. The application of IMRT or SBRT in the context of palliative radiotherapy for NSCLC is not yet sufficiently explored, and this is addressed in this review. Moreover, new risks associated with combining palliative radiotherapy with these systemic treatments are being explored and are discussed within the context of palliative care. The optimal timing, doses, fractionation schedules, and treatment volumes for radiotherapy combined with immunotherapy or targeted therapy are currently subjects of investigation. In emergencies, radiotherapy should be used as a life-saving measure without delay. However, for other indications of palliative thoracic radiotherapy, decisions regarding doses, timing relative to systemic treatments, and treatment volumes should be made in a multidisciplinary context, considering the patient's prognosis, anticipated outcomes, and access to potentially effective treatments. We still lack robust data from prospective studies on this matter. This review examines and discusses available evidence on the use of palliative thoracic radiotherapy within the framework of modern treatment strategies for NSCLC.

Clinical and Hemodynamic Outcomes with Enalapril Orodispersible Minitablets in Young Children with Heart Failure Due to Congenital Heart Disease.

Background: The angiotensin-converting enzyme inhibitor (ACEI) enalapril is often administered to infants and young children with heart failure (HF) in various dosing regimens and formulations not adapted for their age. Methods: This prospective, two-center, open-label 8-week study evaluated an age-appropriate formulation of orodispersible minitablets (ODMTs) of enalapril (0.25 mg and 1 mg) in children aged 0 to 6 years with HF due to congenital heart disease. An age/weight-based dosing schedule was followed. Measures of echocardiographic parameters, blood pressure, heart rate, modified Ross score, and biochemistry were obtained over the 8-week period. The following two groups were assessed: ACEI-naïve and ACEI-pretreated patients. Results: In total, 53 children (age range of 0.05 to 4.8 years) were enrolled and 29 were ACEI-naïve. The average enalapril dose was 0.098 mg/kg (0.06-0.17 mg/kg) in the naïve group and 0.15 mg/kg (0.07-0.3 mg/kg) in pretreated patients. After 8 weeks, the modified Ross score and left ventricular diastolic dimension (LVD) z-score showed a significant decrease in both groups (p < 0.005). During 8 weeks follow-up, there were no difference in the z-scores for the systolic blood pressure (p = 0.071) or heart rate (p = 0.146). Conclusions: Pediatric patients treated with ODMTs of enalapril for 8 weeks had favorable improvements in LVD and HF symptoms.

Evaluation of the Effectiveness of Additional Risk Minimization Measures for Ixazomib Citrate for Relapsed/Refractory Multiple Myeloma in Japan: A Web-Based Survey Among Pharmacists.

Ixazomib citrate (IXA) in combination with lenalidomide and dexamethasone (IRD therapy) has been approved for the treatment of relapsed or refractory multiple myeloma. In Japan, as these three drugs have different dosing schedules, dosing instructions for patients have been prepared and distributed to patients via healthcare professionals to promote an understanding of the appropriate dosing regimen, as an additional risk minimization measure (aRMM). This survey aimed to investigate whether the aRMM material is being utilized for the adequate use of IXA. A web-based questionnaire survey was conducted among in-hospital pharmacists in Japan who instructed patients on IXA dosing for IRD therapy. The primary endpoint was the proportion of pharmacists who provided patients with the contents of the aRMM material (i.e., how to take IXA). The secondary endpoints were the proportion of pharmacists who had obtained the aRMM material and the proportion of pharmacists who understood the importance of explaining how to take IXA to patients. Of the 330 pharmacists who completed the questionnaire, 93.0% answered that they had explained how to take IXA to patients. Of those who answered that they had explained how to take IXA, 33.2% responded that they had experience in using the aRMM material. In addition, 37.6% of the pharmacists answered that they had obtained the aRMM material. Moreover, 95.8% stated that they knew how to take IXA, and 90.3, 9.1, 0.3, and 0.3% of pharmacists answered that the importance of explaining how to take IXA was "very important," "probably important," "less important" and "not important," respectively. How to take IXA was explained to patients by pharmacists and the aRMM material was utilized at the time of the explanation, indicating that the aRMM material contributes to the promotion of the appropriate use of IXA.

RESTORE: Once-nightly oxybate dosing preference and nocturnal experience with twice-nightly oxybates

Objective/BackgroundPreference for extended-release, once-nightly sodium oxybate (ON-SXB, FT218) vs twice-nightly immediate-release (IR) oxybate was assessed in participants switching from IR oxybate to ON-SXB in an open-label/switch study, RESTORE (NCT04451668). Patients/MethodsParticipants aged ≥16 years with narcolepsy who completed the phase 3 REST-ON trial, were oxybate-naive, or were on a stable IR oxybate dose (≥1 month) were eligible for RESTORE. For participants who switched from twice-nightly dosing to ON-SXB, initial doses were closest or equivalent to their previous nightly IR oxybate dose. These participants completed a questionnaire at baseline about nocturnal adverse events associated with the middle-of-the-night IR oxybate dose in the preceding 3 months, a preference questionnaire after 3 months of stable-dose ON-SXB, and an end-of-study (EOS) questionnaire. ResultsThere were 130 switch participants; 92/98 (93.9 %) who completed the preference questionnaire preferred ON-SXB. At baseline, 69.2 % reported missing their second IR oxybate dose at least once; in these cases, 80 % felt worse the next day. Approximately 39 % reported taking a second nightly IR oxybate dose >4 h after the first dose, 51 % of whom felt somewhat to extremely groggy/unsteady the next morning; 120 participants (92 %) reported getting out of bed after their second oxybate dose. Of those, 9 (8 %) reported falls and 5 (4 %) reported injuries. Of the switch participants who completed the EOS questionnaire, 91.2 % felt better able to follow the recommended ON-SXB dosing schedule. ConclusionsThe second nightly IR oxybate dose presents significant treatment burdens and adherence concerns. Participants overwhelmingly preferred the once-nightly dosing regimen of ON-SXB.

A pentavalent peptide vaccine elicits Aβ and tau antibodies with prophylactic activity in an Alzheimer’s disease mouse model

Amyloid-β (Aβ) and hyperphosphorylated tau protein are targets for Alzheimer’s Disease (AD) immunotherapies, which are generally focused on single epitopes within Aβ or tau. However, due to the complexity of both Aβ and tau in AD pathogenesis, a multipronged approach simultaneously targeting multiple epitopes of both proteins could overcome limitations of monotherapies. Herein, we propose an active AD immunotherapy based on a nanoparticle vaccine comprising two Aβ peptides (1–14 and pyroglutamate pE3-14) and three tau peptides (centered on phosphorylated pT181, pT217 and pS396/404). These correspond to both soluble and aggregated targets and are displayed on the surface of immunogenic liposomes in an orientation that maintains reactivity with epitope-specific monoclonal antibodies. Intramuscular immunization of mice with individual epitopes resulted in minimally cross-reactive antibody induction, while simultaneous co-display of 5 antigens (“5-plex”) induced antibodies against all epitopes without immune interference. Post-immune sera recognized plaques and neurofibrillary tangles from human AD brain tissue. Vaccine administration to 3xTg-AD mice using a prophylactic dosing schedule inhibited tau and amyloid pathologies and resulted in improved cognitive function. Immunization was well tolerated and did not induce antigen-specific cellular responses or persistent inflammatory responses in the peripheral or central nervous system. Antibody levels could be reversed by halting monthly vaccinations. Altogether, these results indicate that active immune therapies based on nanoparticle formulations of multiple Aβ and tau epitopes warrant further study for treating early-stage AD.

A systematic review on the use of phytotherapy in managing clinical depression

Introduction: The use of medicinal plants in the management of depression, also known as phytotherapy or herbal medicine for depression, is an area of growing interest in the field of mental health and complementary medicine. Methods: This study used a systematic assessment of pertinent literature to assess the effectiveness of medicinal herbs in treating mild to severe depression. A comprehensive literature search was conducted to identify randomized controlled trials (RCTs) that reported data on the intervention, control group, adverse events, outcome measurements, and main findings. A summary and analysis were done on the included research data. Results: We included 23 RCTs investigating the efficacy of herbal medicines, including Crocus sativus, Lavandula angustifolia, Melissa officinalis, and Echium amoenum, in treating depression. In general, saffron showed encouraging outcomes when used to treat mild to severe depression. With no discernible variations in the reported adverse effects, it proved to be equally efficacious as well-known antidepressants like imipramine and fluoxetine. However, it is noteworthy that not all trials yielded favorable results. Conclusion: More investigation is required to fully understand the mechanisms of action, ideal dosage schedules, long-term effects, and relative efficacy of medicinal plants in depressive treatment.

Mathematical Modeling of Tumor Immune Interactions: The Role of Anti-FGFR and Anti-PD-1 in the Combination Therapy.

Bladder cancer poses a significant global health burden with high incidence and recurrence rates. This study addresses the therapeutic challenges in advanced bladder cancer, focusing on the competitive mechanisms of ligand or drug binding to receptors. We developed a refined mathematical model that integrates the dynamics of tumor cells and immune responses, particularly targeting fibroblast growth factor receptor 3 (FGFR3) and immune checkpoint inhibitors (ICIs). This study contributes to understanding combination therapies by elucidating the competitive binding dynamics and quantifying the synergistic effects. The findings highlight the importance of personalized immunotherapeutic strategies, considering factors such as drug dosage, dosing schedules, and patient-specific parameters. Our model further reveals that ligand-independent activated-state receptors are the most essential drivers of tumor proliferation. Moreover, we found that PD-L1 expression rate was more important than PD-1 in driving the dynamic evolution of tumor and immune cells. The proposed mathematical model provides a comprehensive framework for unraveling the complexities of combination therapies in advanced bladder cancer. As research progresses, this multidisciplinary approach contributes valuable insights toward optimizing therapeutic strategies and advancing cancer treatment paradigms.

Exploring the contribution of genetic variants to high sunitinib exposure in patients with cancer.

Sunitinib exhibits considerable interindividual variability in exposure. While the target total plasma concentration of sunitinib and its active metabolite is 50-87.5ng/mL for the intermittent dosing schedule, ~10-21% of patients experience higher exposures (>87.5ng/mL), correlated with an increased risk for toxicity. Previous research identified single nucleotide variants (SNVs) in genes from the sunitinib pharmacokinetic pathway to be associated with efficacy and toxicity. However, significant interindividual variability in exposure remains unexplained. Our aim was to identify genetic variants associated with supratherapeutic exposure of sunitinib. This was a genome-wide association study. Cases were identified during routine therapeutic drug monitoring and consisted of patients with dose-normalized sunitinib plasma concentrations >87.5 ng/mL (intermittent dosing) or >75 ng/mL (continuous dosing). Controls were sampled from the historical cohort EuroTARGET who tolerated the standard dose of 50 mg in an intermittent schedule. SNVs were tested for an association with sunitinib exposure. A P-value ≤5 × 10-8 was considered significant and a P-value between 5 × 10-8 and 5 × 10-6 was considered suggestive. Sixty-nine cases and 345 controls were included for association analysis. One SNV (rs6923761), located on the gene glucagon-like peptide 1 receptor, was significantly associated with increased sunitinib exposure (P = 7.86 × 10-19). Twelve SNVs were suggestive for an association with sunitinib exposure (P≤ 5 × 10-6). While rs6923671 is associated with high sunitinib exposure, the underlying mechanism is not yet clarified and warrants further investigation. We could not confirm the earlier found associations between SNVs in candidate genes involved in the pharmacokinetic pathway of sunitinib and its efficacy and toxicity.

Antibacterial action of penicillin against Mycobacterium avium complex.

β-lactam antibiotics are promising treatments for Mycobacterium avium complex (MAC) lung disease. We hypothesized that benzylpenicillin has efficacy against MAC. Benzylpenicillin lung concentration-time profiles of seven doses in three dosing schedules were administered for 28 days using the hollow fiber system model of intracellular MAC (HFS-MAC). Data were analyzed using the inhibitory sigmoid maximal effect (Emax) model for each sampling day, while two ordinary differential equations (ODEs) were used for the wild-type and penicillin-resistant mutants. Benzylpenicillin killed >2.1 log10 colony-forming unit (CFU)/mL below Day 0, better than azithromycin, ethambutol, and rifabutin. Efficacy was terminated by acquired resistance. Sigmoid Emax parameter estimates significantly differed between sampling days and were a poor fit. However, ODE model parameter estimates vs. exposure were a better fit. The exposure mediating Emax was 84.6% (95% CI 76.91-82.98) of time concentration exceeded the minimum inhibitory concentration (MIC). In Monte Carlo experiments, 24 million international units of benzylpenicillin continuous infusion achieved the target exposure in lungs of >90% of 10,000 subjects until an MIC of 64 mg/L, designated the susceptibility breakpoint. Benzylpenicillin demonstrated a better bactericidal effect against MAC than guideline-recommended drugs before the development of resistance. Its role in combination therapy with other drugs with better efficacy than guideline-recommended drugs should be explored.

International consensus on methotrexate dosing for patients with atopic dermatitis: An eDelphi study.

Despite the widespread off-label use of methotrexate (MTX) for the treatment of atopic dermatitis (AD), there is limited high-quality evidence on dosing regimens and existing guidelines do not provide clear recommendations regarding dosing strategies. The aim of this study was to achieve international consensus among AD experts to standardize the dosing regimen for MTX treatment in adults and children with AD. An electronic Delphi (eDelphi) study was conducted from October 2021 to September 2022. Recruitment was conducted through dermatology societies and AD interest groups. Participation was open to dermatologists and dermatology residents experienced in treating AD patients with MTX. The study consisted of three online rounds. The first round was informed by a systematic review of relevant literature, and subsequent rounds were adjusted based on the results of the previous round. Participants voted on 19 proposals using a 9-point scale (1-3 disagree, 4-6 neither agree nor disagree, 7-9 agree). Consensus was achieved when at least 70% of participants agreed, and less than 15% disagreed. Proposals that did not reach consensus in the first three rounds were discussed in a consensus meeting, where consensus was defined as less than 30% disagreement. In total, 152 participants completed Round 1, 104 (68%) completed all survey rounds, and 43 (28%) joined the consensus meeting. Consensus was achieved on 7 proposals in Round 1, 4 in Round 2 and 6 in Round 3. The final 2 proposals reached consensus during the consensus meeting. Consensus topics include test dose, start dose, maximum dose, administration route, dosing schedule, management of stopping treatment, treatment duration and folic acid supplementation. This eDelphi study achieved consensus on 19 proposals related to MTX dosing for adults and children with AD. These results aim to guide prescribing decisions and encourage a standardized global approach to MTX use in AD.

Two dose levels of once-weekly fosravuconazole versus daily itraconazole in combination with surgery in patients with eumycetoma in Sudan: a randomised, double-blind, phase 2, proof-of-concept superiority trial

Eumycetoma is an implantation mycosis characterised by a large subcutaneous mass in the extremities commonly caused by the fungus Madurella mycetomatis. Despite the long duration of treatment, commonly a minimum of 12 months, treatment failure is frequent and can lead to amputation. We aimed to compare the efficacy of two doses of fosravuconazole, a synthetic antifungal designed for use in onychomycosis and repurposed for mycetoma, with standard-of-care itraconazole, both in combination with surgery. This phase 2, randomised, double-blind, active-controlled, superiority trial was conducted in a single centre in Sudan. Patients with eumycetoma caused by M mycetomatis, who were aged 15 years or older, with a set lesion diameter (>2 cm and ≤16 cm) requiring surgery were included. There was a limit of 20 female patients in the initial enrolment, owing to preclinical toxicity concerns. Exclusion criteria included previous surgical or medical treatment for eumycetoma; presence of loco-regional lymphatic extension; osteomyelitis, or other bone involvement; pregnancy or lactation; severe concomitant diseases; a BMI under 16 kg/m2; contraindication to use of the study drugs; pre-existing liver disease; lymphatic extension; osteomyelitis; transaminase levels more than two times the laboratory's upper limit of normal, or elevated levels of alkaline phosphatase or bilirubin; or any history of hypersensitivity to any azole antifungal drug. Patients were randomly allocated in a 1:1:1 ratio to 300 mg fosravuconazole weekly for 12 months (group 1); 200 mg fosravuconazole weekly for 12 months (group 2); or 400 mg itraconazole daily for 12 months (group 3) using a random number list with non-disclosed fixed blocks of size 12, with equal allocation to each of the three arms within a block. To ensure masking between groups, placebo pills were used to disguise the difference in dosing schedules. All groups took pills twice daily with meals. In all groups, surgery was performed at 6 months. The primary outcome was complete cure at end of treatment at the month 12 visit, as evidenced by absence of mycetoma mass, sinuses, and discharge; normal ultrasonography or MRI examination of the eumycetoma site; and, if a mass was present, negative fungal culture from the former mycetoma site. The primary outcome was assessed in the modified intention-to-treat (mITT) population (all patients who received one or more treatment dose with one or more primary efficacy assessment). Safety was assessed in all patients who received one or more doses of the study drug. This study is registered with ClinicalTrials.gov (NCT03086226) and is complete. Between May 9, 2017, and June 10, 2021, 104 patients were randomly allocated (34 in group 1 and 2, respectively, and 36 in group 3). 86 (83%) of 104 patients were male and 18 (17%) patients were female. After an unplanned second interim analysis, the study was terminated early for futility. Complete cure at 12 months in the mITT population was 17 (50%) of 34 (95% CI 32-68) for group 1, 22 (65%) of 34 (47-80) for group 2, and 27 (75%) of 36 (58-88) in group 3. Neither dose of fosravuconazole was superior to itraconazole (p=0·35 for 200 mg fosravuconazole vs p=0·030 for 300 mg fosravuconazole). 83 patients had a total of 205 treatment-emergent adverse events, and two patients had serious adverse events that led to discontinuation, neither related to treatment. Treatment with either dose of fosravuconazole was not superior to itraconazole, and the two doses had a numerically lower efficacy. However, fosravuconazole presented no new safety signals, and its lower pill burden and reduced risk of drug-drug interactions compared with the relatively expensive and inaccessible itraconazole suggests further research into effective treatments with a shorter duration and higher cure rate, without the need for surgery are warranted. Drugs for Neglected Diseases initiative.

Reduction in preventable time-critical dose omissions: impact of electronic medication management systems on in-patients

Background: The omission of time-critical medication doses may result in poor patient outcomes. There are few publications about the influence of electronic medication management (EMM) systems, including automated dispensing cabinets (ADC), on timely medication administration. The study aimed to evaluate the influence of EMM systems, including ADCs, on timely medication administration 6 and 30 months after EMM implementation, focussing on preventable time-critical medication dose omissions and documented reasons for not administering a dose. Methods: Data on doses of regular inpatient medications not administered were obtained from electronic medication records (EMR) over 1 week in March 2019 and 4 weeks in March 2021. An omission was a dose not administered before the next due dose. Time-critical medications were defined using the health service’s guidelines. Reasons for doses not being administered were obtained from nursing documentation in the EMR collated from digital health reports. Reasons for time-critical medication doses not given were defined as ‘valid’ or ‘preventable’. Results: In 2019 and 2021, 620 and 2524 patients with 44,756 and 146,940 scheduled medication doses were reviewed. Of these, 4385 (9.8%) and 19,610 (13.4%) doses were not administered. In 2019 and 2021, there were 593 (1.3%) and 1811 (1.2%), p < 0.0001, time-critical doses not administered. Preventable time-critical dose omissions decreased from 0.20% in 2019 to 0.15% (p = 0.015) in 2021. Wards with ADCs had a significantly lower rate of time-critical dose omissions compared to those without ADCs (1.1% vs 1.3%, p = 0.014). Conclusion: With the introduction of an EMM system, there was a decrease in the rate of time-critical medications not administered, including a reduced rate of preventable omissions over the 24-month period. Regular assessment of time-critical medication administration will help target patient safety improvements.

Population Pharmacokinetics of Capivasertib in Patients with Advanced or Metastatic Solid Tumours.

Overactivation of the PI3K/AKT pathway can occur in many cancers. Capivasertib is a potent, selective pan-AKT inhibitor. The objectives of this analysis were to develop a population pharmacokinetic model for capivasertib and to quantitatively assess the impact of intrinsic and extrinsic factors on the pharmacokinetics of capivasertib. Pharmacokinetic data from four phase I and II studies were combined. Capivasertib was administered orally at a dose range of 80-800mg twice daily over 28-day and 21-day cycles as monotherapy or in combination with paclitaxel or fulvestrant, using continuous dosing or one of two intermittent dosing schedules: either 4 days on, 3 days off (4/3) or 2days on, 5days off (2/5). Several models and approaches were tested for their ability to describe capivasertib disposition. The covariates assessed included dose, schedule, age, body weight, race, sex, creatinine clearance, hepatic function, renal function, smoking status, food effect, formulation, and concomitant use with paclitaxel, fulvestrant, cytochrome P450, family 3, subfamily A (CYP3A)inducers, CYP3A inhibitors and acid-reducing agents. A total of 3963 capivasertib plasma concentrations from 441 patients were included. Capivasertib pharmacokinetics was adequately described by a three-compartment model where the apparent clearance (CL/F) presented a moderate time-dependent and dose-dependent clearance. Following oral administration of multiple doses of capivasertib (400 mg twice daily; [4/3]), the initial CL/F was 62.2 L/h (between-subject variability 39.3%), and after approximately 120 hours, CL/F decreased by 18%. The effective half-life was 8.34 h. Steady state was predicted to be reached on every third and fourth dosing day each week from the second week with exposure levels that produced robust inhibition of AKT but not of other related kinases. The area under the plasma concentration-time curve and maximum plasma concentration of capivasertib were proportional between the dose levels of 80-480mg after multiple doses but more than proportional beyond 480mg. Schedule, age, race, sex, creatinine clearance, hepatic function, renal function, smoking status and concomitant use with fulvestrant, CYP3A inducers, CYP3A inhibitors or acid-reducing agents were not significant covariates for capivasertib pharmacokinetics. Concomitant use of paclitaxel, food effect and formulation statistically significantly affected capivasertib pharmacokinetics, but the effect was low. Body weight was statistically significantly related to capivasertib CL/F, with a 12% reduction in CL/F at steady state and a 14% increase in the area under the curve for 12 hours at steady state and maximum concentration at steady state at a lower body weight (47 kg vs 67 kg reference). Capivasertib pharmacokinetics showed moderate between-subject variability, and most covariates assessed had no significant impact. Body weight, dose, concomitant use of paclitaxel, food effect and formulation showed statistically significant effects. However, these were predicted to impact exposure to capivasertib by <20% and were not expected to be clinically relevant. Based on the population pharmacokinetics, no a priori dose adjustment is needed for intrinsic and extrinsic factors.