Dose Of Drug Research Articles

Independent risk factors predicting eradication failure of standard bismuth quadruple therapy for the first‐line treatment of Helicobacter pylori infection in Taiwan

AbstractBismuth quadruple therapy is recommended as the choice treatment for Helicobacter pylori (H. pylori) infection in areas of either low or high clarithromycin resistance in the Maastricht VI/Florence Consensus Report. However, the optimal treatment duration and drug dosages of bismuth quadruple therapy remain unclear. The study aimed to search the independent risk factors predicting eradication failure of standard bismuth quadruple therapy in the first‐line treatment of H. pylori infection. From July 2014 to June 2022, 274 H. pylori‐infected patients who received 10‐day or 14‐day bismuth quadruple therapy containing a proton pump inhibitor, bismuth, tetracycline and metronidazole were included for the study. Post‐treatment H. pylori status was assessed at least 4 weeks after completion of treatment. The relationships between eradication rate and 13 clinical parameters were analyzed by univariate and multivariate analyses. The eradication rates of standard bismuth quadruple therapy were 93.8% and 94.2% by intention‐to‐treat and per‐protocol analyses, respectively. Univariate analysis revealed that patients harboring metronidazole‐resistant strains had a lower eradication rate than those harboring metronidazole‐susceptible strains (88.7% [55/62] vs. 96.7% [148/153]). The other factors including smoking, treatment duration and drug adherence were not significantly associated with cure rate. Multivariate analysis revealed that metronidazole resistance of H. pylori was the only independent risk factors related to eradication failure of standard bismuth quadruple therapy with an odds ratio of 3.8 (95% CI: 1.2–12.4). In conclusion, metronidazole resistance is an independent risk factor predicting eradication failure of standard bismuth quadruple therapy in the first‐line treatment of H. pylori infection. There is no difference in eradication efficacy between 10‐day and 14‐day bismuth quadruple therapies in Taiwan.

Absorption of cinnarizine from type II lipid-based formulations: Impact of lipid chain length, supersaturation, digestion, and precipitation inhibition

Lipid-based formulations (LBFs) are an enabling-formulation approach for lipophilic poorly water-soluble compounds. In LBFs, drugs are commonly pre-dissolved in lipids, and/or surfactants/cosolvents, hereby avoiding the rate-limiting dissolution step. According to the Lipid formulation classification system, proposed by Pouton in 2006, in type II LBFs a surfactant with an HLB-value lower than 12 is added to the lipids. If high drug doses are required, e.g. for preclinical toxicity studies, supersaturated LBFs prepared at elevated temperatures may be a possibility to increase drug exposure. In the present study, the impact of digestion on drug absorption in rats was studied by pre-dosing of the lipase inhibitor orlistat. The lipid chain length of the type II LBFs was varied by administration of a medium-chain- (MC) and a long-chain (LC)-based formulation. Different drug doses, both non-supersaturated and supersaturated, were applied. Due to an inherent precipitation tendency of cinnarizine in supersaturated LBFs, the effect of the addition of the precipitation inhibitor Soluplus® was also investigated. The pharmacokinetic results were also evaluated by multiple linear regression. In most cases LC-based LBFs did not perform better in vivo, in terms of a higher area under the curve (AUC0–24 h) and maximal plasma concentration (Cmax), than MC-based LBFs. The administration of supersaturated LBFs resulted in increased AUC0–24 h (1.5 – 3.2-fold) and Cmax (1.1 – 2.6-fold)-values when compared to the non-supersaturated equivalents. Lipase inhibition led to a decreased drug exposure in most cases, especially for LC formulations (AUC0–24 h reduced to 47 – 67%, Cmax to 46 – 62%). The addition of Soluplus® showed a benefit to drug absorption from supersaturated type II LBFs (1.2 – 1.7-fold AUC0–24 h), due to an increased solubility of cinnarizine in the formulation. Upon dose-normalization of the pharmacokinetic parameters, no beneficial effect of Soluplus® could be demonstrated.

Safety evaluation of 8 drug degradants present in over-the-counter cough and cold medications

Although the United States Food & Drug Administration (FDA) has provided guidance on the control of drug degradants for prescription drugs, there is less guidance on how to set degradant specifications for FDA OTC monograph drugs. Given that extensive impurity testing was not part of the safety paradigm in original OTC monographs, a weight of evidence (WOE) approach to qualify OTC degradants is proposed. This approach relies on in silico tools and read-across approaches alongside standard toxicity testing to determine safety. Using several drugs marketed under 21 CFR 341 as case studies, this research demonstrates the utility of a WOE approach across data-rich and data-poor degradants. Based on degradant levels ranging from 1 to 4% of the maximum daily doses of each case study drug and 10th percentile body weight data for each patient group, children were recognized as having the highest potential exposure relative to adults per body mass. Depending on data availability and relationship to the parent API, margins of safety (MOS) or exposure margins were calculated for each degradant. The findings supported safe use, and indicated that this contemporary WOE approach could be utilized to assess OTC degradants. This approach is valuable to establish specifications for degradants in OTCs.

Antiangiogenic-immune-checkpoint inhibitor combinations: lessons from phase III clinical trials.

Antiangiogenic agents, generally antibodies or tyrosine-kinase inhibitors that target the VEGF-VEGFR pathway, are currently among the few combination partners clinically proven to improve the efficacy of immune-checkpoint inhibitors (ICIs). This benefit has been demonstrated in pivotal phase III trials across different cancer types, some with practice-changing results; however, numerous phase III trials have also had negative results. The rationale for using antiangiogenic drugs as partners for ICIs relies primarily on blocking the multiple immunosuppressive effects of VEGF and inducing several different vascular-modulating effects that can stimulate immunity, such as vascular normalization leading to increased intratumoural blood perfusion and flow, and inhibition of pro-apoptotic effects of endothelial cells on T cells, among others. Conversely, VEGF blockade can also cause changes that suppress antitumour immunity, such as increased tumour hypoxia, and reduced intratumoural ingress of co-administered ICIs. As a result, the net clinical benefits from antiangiogenic-ICI combinations will be determined by the balance between the opposing effects of VEGF signalling and its inhibition on the antitumour immune response. In this Perspective, we summarize the results from the currently completed phase III trials evaluating antiangiogenic agent-ICI combinations. We also discuss strategies to improve the efficacy of these combinations, focusing on aspects that include the deleterious functions of VEGF-VEGFR inhibition on antitumour immunity, vessel co-option as a driver of non-angiogenic tumour growth, clinical trial design, or the rationale for drug selection, dosing and scheduling.

Changes Over Time in the Lémann Index and the Inflammatory Bowel Disease Disability Index in a Prospective Cohort of Patients With Crohn's Disease.

Crohn's disease (CD) is a progressive, destructive, and disabling disorder. Our study aimed to assess changes over time in the Lémann index (LI) and the Inflammatory Bowel Disease Disability Index (IBD-DI) in a cohort of CD patients. This was a single-center prospective cohort study of 130 consecutive CD patients with a follow-up of at least 4 years. The LI 1 and the IBD-DI 1 questionnaires were assessed in 2016 and again between September 2020 and October 2021 (LI 2 and IBD-DI 2). Of the 130 patients with assessment of both LI 1 and IBD-DI 1, 61 had calculation of the LI 2 and 98 patients answered the IBD-DI 2 questionnaire, with a median time between the 2 evaluations of 4.2 years. The LI increased for 16 (26%), decreased for 26 (43%), and remained unchanged for 19 (31%) patients. The median LI did not change over time (9.6 vs 9.3; P = .14). Clinical disease activity was significantly associated with bowel damage progression. A high initial LI (>7.9) was not associated with CD progression (surgery, drug dose escalation, or change of biologic). The IBD-DI decreased for 59 (60.2%), increased for 37 (37.8%), and remained unchanged for 2 (2%) patients. The median IBD-DI decreased significantly over time (23.2 vs 21.4; P = .006). There was no correlation between the 2 indexes. This is the first prospective cohort study assessing changes over time in both the LI and the IBD-DI in CD patients. After 4 years, the LI appeared to be stable and the IBD-DI decreased, with no correlation between the 2 indexes.

Risk of cardiovascular disease with high-dose versus low-dose use of non-steroidal anti-inflammatory drugs in ankylosing spondylitis

ObjectiveTo investigate the risk of cardiovascular disease (CVD) associated with increasing dose of a non-steroidal anti-inflammatory drug (NSAID) in patients with ankylosing spondylitis (AS).MethodsUsing the Korean National Health Insurance database,...

Cabozantinib monotherapy for advanced adrenocortical carcinoma: a single-arm, phase 2 trial

Adrenocortical carcinoma is a rare malignancy with poor response to systemic chemotherapy. Mitotane is the only approved therapy for adrenocortical carcinoma. Cabozantinib is a multikinase inhibitor approved in multiple malignancies. This is the first prospective trial to explore the anti-tumour activity, safety, and pharmacokinetic profile of cabozantinib in patients with advanced adrenocortical carcinoma. This investigator-initiated, single-arm, phase 2 trial in adult patients (aged ≥18 years) with advanced adrenocortical carcinoma was done at the University of Texas MD Anderson Cancer Center (Houston, TX, USA). Eligible patients had histologically confirmed adrenocortical carcinoma, were not candidates for surgery with curative intent, had measurable disease, had an estimated life expectancy of at least 3 months, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 with adequate organ function. Patients who had used mitotane within 6 months of study participation were required to have a serum mitotane level of less than 2 mg/L. Patients were given oral cabozantinib 60 mg daily with the option of dose reduction to manage adverse events. The primary endpoint was progression-free survival at 4 months, assessed in all patients who received at least one dose of study drug per protocol. This study is registered with ClinicalTrials.gov, NCT03370718, and is now complete. Between March 1, 2018, and May 31, 2021, we enrolled 18 patients (ten males and eight females), all of whom received at least one dose of study treatment. Of the 18 patients, eight (44%) had an ECOG performance status of 0, nine (50%) patients had a performance status of 1, and one (6%) patient had a performance status of 2. Median follow-up was 36·8 months (IQR 30·2-50·3). At 4 months, 13 (72·2%; 95% CI 46·5-90·3) of 18 patients had progression-free survival and median progression-free survival was 6 months (95% CI 4·3 to not reached). One patient remains on treatment. Treatment-related adverse events of grade 3 or worse occurred in 11 (61%) of 18 patients. The most common grade 3 adverse events were lipase elevation (three [17%] of 18 patients), elevated γ-glutamyl transferase concentrations (two [11%] patients), elevated alanine aminotransferase concentrations (two [11%] patients), hypophosphatemia (two [11%] patients), and hypertension (two [11%] patients). One (6%) of 18 patients had grade 4 hypertension. No treatment related deaths occurred on study. Cabozantinib in advanced adrenocortical carcinoma showed promising efficacy with a manageable and anticipated safety profile. Further prospective studies with cabozantinib alone and in combination with immune checkpoint therapy are ongoing. Exelixis.

Motor Complications in Parkinson's Disease: Results from 3343 Patients Followed for up to 12 Years.

Motor complications are well recognized in Parkinson's disease (PD), but their reported prevalence varies and functional impact has not been well studied. To quantify the presence, severity, impact and associated factors for motor complications in PD. Analysis of three large prospective cohort studies of recent-onset PD patients followed for up to 12 years. The MDS-UPDRS part 4 assessed motor complications and multivariable logistic regression tested for associations. Genetic risk score (GRS) for Parkinson's was calculated from 79 single nucleotide polymorphisms. 3343 cases were included (64.7% male). Off periods affected 35.0% (95% CI 33.0, 37.0) at 4-6 years and 59.0% (55.6, 62.3) at 8-10 years. Dyskinesia affected 18.5% (95% CI 16.9, 20.2) at 4-6 years and 42.1% (38.7, 45.5) at 8-10 years. Dystonia affected 13.4% (12.1, 14.9) at 4-6 years and 22.8% (20.1, 25.9) at 8-10 years. Off periods consistently caused greater functional impact than dyskinesia. Motor complications were more common among those with higher drug doses, younger age at diagnosis, female gender, and greater dopaminergic responsiveness (in challenge tests), with associations emerging 2-4 years post-diagnosis. Higher Parkinson's GRS was associated with early dyskinesia (0.026 ≤ P ≤ 0.050 from 2 to 6 years). Off periods are more common and cause greater functional impairment than dyskinesia. We confirm previously reported associations between motor complications with several demographic and medication factors. Greater dopaminergic responsiveness and a higher genetic risk score are two novel and significant independent risk factors for the development of motor complications.

Pharmacometric in silico studies used to facilitate a national dose standardisation process in neonatology - application to amikacin.

Pharmacometricin silicoapproaches are frequently applied to guide decisions concerning dosage regimes during the development of new medicines. We aimed to demonstrate how such pharmacometric modelling and simulation can provide a scientific rationale for optimising drug doses in the context of the Swiss national dose standardisation project in paediatrics using amikacin as a case study. Amikacin neonatal dosage is stratified by post-menstrual age (PMA) and post-natal age (PNA) in Switzerland and many other countries. Clinical concerns have been raised for the subpopulation of neonates with a post-menstrual age of 30-35 weeks and a post-natal age of 0-14 days ("subpopulation of clinical concern"), as potentially oto-/nephrotoxic trough concentrations (Ctrough>5 mg/l) were observed with a once-daily dose of 15 mg/kg. We applied a two-compartmental population pharmacokinetic model (amikacin clearance depending on birth weight and post-natal age) to real-world demographic data from 1563 neonates receiving anti-infectives (median birth weight 2.3 kg, median post-natal age six days) and performed pharmacometric dose-exposure simulations to identify extended dosing intervals that would ensure non-toxic Ctrough(Ctrough<5 mg/l) dosages in most neonates. In the subpopulation of clinical concern, Ctrough<5 mg/l was predicted in 59% versus 79-99% of cases in all other subpopulations following the current recommendations. Elevated Ctroughvalues were associated with a post-natal age of less than seven days. Simulations showed that extending the dosing interval to ≥36 h in the subpopulation of clinical concern increased the frequency of a desirable Ctroughbelow 5 mg/l to >80%. Pharmacometricin silicostudies using high-quality real-world demographic data can provide a scientific rationale for national paediatric dose optimisation. This may increase clinical acceptance of fine-tuned standardised dosing recommendations and support their implementation, including in vulnerable subpopulations.

Abstract LB278: Application of phase 1 and pre-clinical data to assist in determining the optimal dosage regimen for cancer drugs using the principles of Project Optimus

Abstract Background: In 2022 and 2023 FDA introduced the Project Optimus initiative and the Draft Guidance “Optimizing the Dosage of Human Prescription Drugs and Biological Products for the Treatment of Oncologic Diseases.” The FDA’s desire is to move away from the maximum tolerated dose (MTD) approach in the development of all oncology drugs and to determine and justify the optimal dosage regimen (ODR), requiring one to evaluate the exposure-response relationship for both the safety and efficacy of oncology drugs. This approach has made the oncology drug developer re-examine their previous beliefs and reconsider the design of the clinical and pre-clinical studies. Processa has begun to implement the ODR evaluation in Phase 1 and pre-clinical studies and will be providing examples as well as how the findings may potentially affect the design of Phase 2/3 trials. Methods/Results: For Next Generation Irinotecan (NGC-Iri), the toxicity and tumor growth inhibition after NGC-Iri administration (as well as tissue distribution of NGC-Iri) were compared to irinotecan in xenograft transplanted mice. Tumor growth inhibition remained constant at 100% for an NGC-Iri dose at the MTD and at 50% of the MTD. However, tumor growth inhibition after irinotecan administration decreased from 100% at the MTD to approximately 64% at 50% of the MTD. The differences seen in the tumor inhibition when NGC-Iri and irinotecan were administered illustrate that the exposure-efficacy profile of NGC-Iri follows a different pattern than the exposure-safety profile and is different from the irinotecan exposure-efficacy profile even though the active molecule is the same. The dose of NGC-Iri can be decreased to improve safety while not significantly sacrificing efficacy, different than what was seen with irinotecan. In a second example, we are evaluating the PK-safety relationship of a different Next Generation drug in our ongoing Phase 1 trial. We have recently found that the exposure-safety relationship is different for our NGC drug than for the approved drug with the same cancer-killing metabolite(s). Based on the difference in exposure-response in the Phase 1 study, we are designing the Phase 2 trial to determine the potential ODR. Conclusion: Both preclinical and Phase 1 oncology trials can be designed to better understand the exposure-response relationships for safety and efficacy which will then help the drug developer in designing the Phase 2 and 3 trials for eventual FDA approval of the ODR. Citation Format: David Young, Sian Bigora, Peter Franks, Mary Nyberg, Yvonne Madden. Application of phase 1 and pre-clinical data to assist in determining the optimal dosage regimen for cancer drugs using the principles of Project Optimus [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB278.

Antimicrobial Potential of Polyphenols: An Update on Alternative for Combating Antimicrobial Resistance.

The last decade has encountered an increasing demand for plant-based natural antibiotics. This demand has led to more research-based investigations for natural sources of antimicrobial agents and published reports demonstrating that plant extracts are widely applied in modern medicine, reporting potential activity that may be due to polyphenol compounds. Interestingly, the effects of polyphenols on the sensitivity of bacteria to antibiotics have not been well-studied. Hence, the current review encompasses the prospective application of plant-based phenolic extracts from plants of Indian origin. The emergence of resistance to antimicrobial agents has increased the inefficacy of many antimicrobial drugs. Several strategies have been developed in recent times to overcome this issue. A combination of antimicrobial agents is employed for the failing antibiotics, which restores the desirable effect but may have toxicity-related issues. Phytochemicals such as some polyphenols have demonstrated their potent activity as antimicrobial agents of natural origin to work against resistance issues. These agents alone or in combination with certain antibiotics have been shown to enhance the antimicrobial activity against a spectrum of microbes. However, the information regarding the mechanisms and structure-activity relationships remains elusive. The present review also focuses on the possible mechanisms of natural compounds based on their structure- activity relationships for incorporating polyphenolic compounds in the drug-development processes. Besides this work, polyphenols could reduce drug dosage and may diminish the unhidden or hidden side effects of antibiotics. Pre-clinical findings have provided strong evidence that polyphenolic compounds, individually and in combination with already approved antibiotics, work well against the development of resistance. However, more studies must focus on in vivo results, and clinical research needs to specify the importance of polyphenol-based antibacterials in clinical trials.

Decreasing the ability of HCT116 cells to escape from therapy induced senescence by increasing the duration of doxorubicin treatment

Contacts: Maria Anatolievna Zamkova zamkovam@gmail.com Introduction. Due to the toxicity of high doses of chemotherapy, low concentrations used in cancer treatment leads to the development of senescence phenotype in tumor cells, characterized by a block in the cell cycle progression and the absence of division; changes in the transcriptional and metabolic profile of cells. A negative consequence of this stage is acquisition of individual cells the ability to escape from senescence and return to re-proliferation.Aim. To estimate the effect of the duration of drug treatment of HCT116 tumor cells on their ability to escape from therapy induced senescence.Materials and methods. The senescence phenotype was confirmed by the analysis of β-galactosidase activity; cell cycle analysis; estimation of protein levels by western blotting. Colonies were stained with crystal violet dye.Results. In our study, we showed that the duration of HCT116 cells incubation with low-dose doxorubicin affects their ability to return to re-proliferation – increasing the treatment time using same drug dose reduces the process of colony formation. The duration of doxorubicin treatment does not affect the formation of the senescence phenotype, which was confirmed by analyzing different markers of this stage (changes in β-galactosidase activity, cell cycle analysis, assessment of p21 and γH2AX protein levels). However, there is a delay in the development of cellular response to DNA damage caused by doxorubicin in cells exposed to prolong treatment protocol (increase in β-galactosidase activity, formation of polyploid cells).Conclusion. The duration of doxorubicin treatment of HCT116 cancer cells affects long-term consequences, reducing the ability of senescent cells to escape this stage when the incubation time with the drug is extended.

Abstract CT030: Randomized placebo-controlled, biomarker-stratified phase 1b microbiome modulation trial for metastatic melanoma demonstrates impact of antibiotic pre-conditioning regimen on the microbiome and immunity

Abstract Background: Gut microbiota modulation shows promise in improving immune checkpoint blockade (ICB) response; however, precision biomarker-driven trials using rationally-designed consortia are lacking. To address this, we performed a multi-center, randomized placebo-controlled, biomarker-stratified phase 1 trial in patients with ICB-naïve unresectable or metastatic melanoma using SER-401, a bacterial consortia enriched for Firmicutes spores and Ruminococcaceae. Methods: MCGRAW was a multi-center, randomized, blinded, and placebo-controlled phase 1b study in patients with advanced melanoma. Patients were randomized 2:1 to the SER-401 active or placebo arm, respectively, and stratified by baseline stool Ruminococcaceae abundance. Patients received an oral vancomycin (vanco) preparative regimen+SER-401 (vanco+SER-401 arm), versus placebo antibiotic+placebo (Placebo arm), followed by nivolumab. Stool, blood and tumor samples were collected at baseline and on treatment. The primary endpoint was safety, with additional secondary endpoints (SER-401 microbiome engraftment, overall response rate (ORR), disease control rate (DCR), and other translational endpoints). The study was not powered for comparison between arms. Results: 14 patients were randomized (n=8 vanco+SER-401, n=6 placebo). In the vanco+SER-401 arm, ORR was 25.0% and DCR was 37.5%, with no Grade 3-4 treatment-related adverse events (TRAE); in the placebo arm, ORR was 66.7% and DCR was 83.3%, with 1 (17%) TRAE. Notably, pre-conditioning with vanco was associated with significant shift in the microbiome taxonomic composition, with depletion of target families such as Ruminococcaceae (p=0.008, Wilcoxon signed-rank test), and other spore-formers, followed by their recovery post dosing with SER-401. There was a significant increase in multiple ICB-resistance associated pathways (e.g. butyrate synthesis, p&amp;lt;0.0001), and a decrease in response-associated pathways after vanco preconditioning; these changes did normalize by nivolumab initiation. There was corresponding increase in systemic proteomic markers of inflammation after vanco, which also normalized by first dose of immunotherapy. Conclusions: This first-of-its-kind, placebo-controlled, randomized biomarker-driven microbiome modulation trial demonstrated that SER-401 and anti-PD1 are a safe combination in melanoma patients. The study was limited by poor accrual during the COVID-19 pandemic. Nonetheless, important insights were gained via translational analyses, suggesting that antibiotic preconditioning and interventional drug dosing regimens should be carefully considered when designing such trials. Additional placebo-controlled biomarker-driven microbiome trials are needed in this age of precision medicine. Trial registration: ClinicalTrials.gov (NCT03817125) Citation Format: Isabella C. Glitza Oliva, Yongwoo David Seo, Christine N. Spencer, Jennifer R. Wortman, Elizabeth M. Burton, Farah A. Alayli, Christopher Loo, Shikha Gautam, Ashish V. Damania, Julie Densmore, Justin Fairchild, Christopher Cabanski, Matthew C. Wong, Christine B. Peterson, Brian Weiner, Nathan Hicks, John Aunins, Christopher McChalicher, Michael T. Tetzlaff, Omid Hamid, Patrick A. Ott, Genevieve M. Boland, Ryan J. Sullivan, Kenneth F. Grossmann, Nadim J. Ajami, Theresa M. LaVallee, Matthew R. Henn, Hussein A. Tawbi, Jennifer A. Wargo. Randomized placebo-controlled, biomarker-stratified phase 1b microbiome modulation trial for metastatic melanoma demonstrates impact of antibiotic pre-conditioning regimen on the microbiome and immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT030.

Abstract CT064: Impact of food and high gastric pH on the bioavailability of the WEE1 inhibitor Debio 0123 assessed in a phase 1 dose escalation study

Abstract Debio 0123 (D0123), an oral, brain-penetrant, highly selective WEE1 inhibitor, is currently in clinical development, both in combination and as monotherapy, for the treatment of patients with solid tumors. Food and gastric acid-reducing agents e.g. proton pump inhibitors (PPIs) may modify the solubility, bioavailability, safety and efficacy of oral cancer drugs. Polymedication in cancer patients is common and food restrictions can impact patient compliance and wellbeing. In order to adequately inform drug dosing in clinical trials, effects of food and high gastric pH on D0123 bioavailability were studied over three cycles in patients treated in the dose escalation of a Phase 1 study of D0123 in combination with Carboplatin (CTID NCT03968653).D0123 was given on Days 1-3 and 8-10 of each 21-day cycle in combination with carboplatin on Day 1. Current standard administration of D0123 is in fasted conditions and PPIs are prohibited. Dose-limiting toxicities were evaluated in cycle 1. The effect of food and high-gastric pH were assessed in cycles 2 and 3, respectively. In cycle 2 on Day 10, patients were receiving a high-fat meal and in cycle 3, the PPI lanzoprazole 30 mg BID was administered from Day 7 to 11. PK parameters (area under the curve (AUC), maximum concentration (Cmax)) were determined post-Day 10 dose and compared between cycle 1 (fasted) and cycle 2 (fed) or 3 (high gastric pH). Preliminary data from 3 cohorts, 3 dose levels (n=10) resulted in about 5 pairwise comparisons for food and for high gastric pH effects. Absence of D0123 accumulation between cycles was confirmed, allowing for inter-cycle comparison. Oral bioavailability of D0123 appears pH-dependent, suggesting that co-medication with PPIs should be avoided. In contrast, food intake has a limited impact on drug absorption, at all doses tested. Furthermore, D0123 administration with food may increase treatment convenience and tolerability, leading to its implementation in other D0123 trials. TABLE 1. NAND Mean change [ min ; max ] Effect of food (cycle 2 versus cycle 1) Effect of high gastric pH (cycle 3 versus cycle 1) AUC24 -3% [ -17% ; +8% ] -31% [ -39%; -23% ] Cmax -10% [ -26% ; 0% ] -33% [ -41% ; -20% ] Citation Format: Anne Bellon, Omar Saavedra, Ingrid M. Desar, Mathilde Jalving, Jourik A. Gietema, Carla van Herpen, Stefan van Ravensteijn, Esteban Rodrigo Imedio, Sylvia van Haren, Melanie Wirth, Sandrine Micallef, Vito Dozio, Rikke Frederiksen Franzen, Marie-Claude Roubaudi-Fraschini, Valerie Nicolas-Metral, Hans Gelderblom. Impact of food and high gastric pH on the bioavailability of the WEE1 inhibitor Debio 0123 assessed in a phase 1 dose escalation study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT064.

A Dynamic Gradient Stiffness Material Platform to Manipulate Cardiac Fibroblasts' Spatio‐Temporal Behavior

AbstractAfter myocardial infarction, there exists a spatiotemporal variation of cardiac tissue stiffness across the infarcted border region outward to remote regions, influencing adverse remodeling and cardiac fibrosis, and this stiffness gradient changes over time. Here, a platform with dynamic, tunable, and reversible gradient stiffness can recapitulate in vitro the time‐dependent stiffness range across the infarction border that occurs as part of the remodeling process is presented. This platform enables the observation of time‐dependent interaction between cardiac fibroblasts and their mechanical microenvironment in a spatiotemporal manner. Specifically, the competition and cooperation of a chemical cue (antifibrotic drug) and mechanical cue (gradient softening) in tandem to attenuate the fibrotic responses of cardiac fibroblasts is examined. Applying a combined intervention showed either additive or antagonistic effects on fibrosis‐related gene regulation compared to separate interventions of drug or softening. This work reveals the spatiotemporal variation of fibrotic response in cardiac fibroblasts as well as the complexity of antifibrotic drug dosing with stiffness changes and their combinatory effect on cardiac fibroblasts. This platform provides a unique in vitro tool to study disease progression mechanisms in a more clinically relevant microenvironment and also serves as a cost‐effective model for potential therapeutic screening.

Abstract CT218: Phase II open label trial of Minnelide™ in patients with chemotherapy refractory metastatic pancreatic cancer

Abstract Background: Triptolide and its water-soluble prodrug, Minnelide™, have shown promising activity against pancreatic ductal adenocarcinoma (PDAC) in both in vitro and in vivo experiments. Triptolide induces apoptosis in pancreatic cancer cells by different pathways, including caspase-dependent apoptotic death and caspase -independent autophagic death. It inhibits the activity of the TFIIH general transcription factor complex and modulates the transcriptional landscape of both the stroma and cancer cell compartments. In the epithelial tumour compartment, triptolide down-regulates key transcription factors such as c-MYC. Preclinical investigations indicate significant activity against super enhancer targets. In the phase I clinical trial of Minnelide™ activity in highly refractory metastatic pancreatic carcinoma was observed. Hence, we undertook this study in patients with chemotherapy refractory metastatic PDAC. Our aims were to determine clinical anticancer effects, and to define effects of the drug on super enhancer expression and downstream effects. Methods: Eligibility criteria included stage IV PDAC progressing on standard chemotherapy, Karnofsky performance status ≥ 70%, and measurable disease by RECIST 1.1. Planned sample size was up to 35 patients with interim analysis after the first 18 evaluable patients, aiming for at least a 20% difference in DCR (10% v 30%). Minnelide™ 0.67 mg/m2 was administered intravenously over 30 minutes on days 1-21, followed by a 7-day rest period in a 28-day cycle. Exploratory objectives included: analyses of paired tumour biopsies for changes in immune cell infiltration, stromal activation, chromatin accessibility, proteomics and metabolism. Results: 17 patients were treated. There were no RECIST responses or stable disease. However, evidence of activity was observed in 4 of 15 evaluable patients. This activity included progression after 117 days treatment in 1 patient and reductions in CT tumour size or FDG-PET uptake and/or significant decreases in circulating CA19.9 levels in 3 others. Minnelide was generally well tolerated. Treatment related toxicities &amp;gt; 3 were: neutropenia 4 patients and cerebellar ataxia 1 patient.Exploratory analyses included ATAC-Seq on paired biopsies where gene ontology analyses showed downregulation of genes negatively regulating cell cycle and upregulation of genes controlling cell cycle checkpoints. Other exploratory analyses will be presented. Conclusions: The study identified a tolerable drug dose and evidence of activity in a highly chemotherapy-refractory population which provides encouraging proof for the principle of targeting TFIIH in human PDAC. Supported by SU2C, Cancer Research UK, Lustgarten Foundation Citation Format: David Propper, Erkut Borazanci, Peter J. O'Dwyer, Daniel Von Hoff, Joseph Hartlebury, Corina E. Antal, Gerard I. Evan, HaiYong Han, Michael Downes, Ronald Evans, Joshua Rabinowitz, Emmanuel Petricoin, Ashok Saluja, Mohana Velagapudi, Hitendra Patel. Phase II open label trial of Minnelide™ in patients with chemotherapy refractory metastatic pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT218.

Elemental Characterization of Leaf Extracts of Three Different Species of Mulberry: Morus. alba L., Morus. nigra L. and Morus. indica L., Using Inductively Coupled Plasma -Atomic Emission Spectroscopy (ICP-AES)

The present study aimed to compare the elemental composition of leaf extracts from three different plant species of Mulberry, Morus alba L., Morus nigra L., and Morus indica L. The results showed that ten essential elements of biological importance for human metabolism, such as Copper, Chromium, Iron, Manganese, Sodium, Zinc, Calcium, Nickel, Lead, and Cadmium, were present in varying concentrations, well below the World Health Organization, (WHO's) daily intake limits. Mulberry leaves are an economical and readily available source of essential mineral elements vital for human health, which can be used to fortify functional foods, treat various diseases, and act as nutraceuticals. The information obtained could be used to determine the efficacy and dosage of herbal drugs manufactured from the leaf extracts of the Mulberry plant, making it a new contributor to food supplements and nutraceutical products.

Intelligent supervision of PIVAS drug dispensing based on image recognition technology.

Pharmacy Intravenous Admixture Services (PIVAS) are places dedicated to the centralized dispensing of intravenous drugs, usually managed and operated by professional pharmacists and pharmacy technicians, and are an integral part of modern healthcare. However, the workflow of PIVAS has some problems, such as low efficiency and error-prone. This study aims to improve the efficiency of drug dispensing, reduce the rate of manual misjudgment, and minimize drug errors by conducting an in-depth study of the entire workflow of PIVAS and applying image recognition technology to the drug checking and dispensing process. Firstly, through experimental comparison, a target detection model suitable for drug category recognition is selected in the drug-checking process of PIVAS, and it is improved to improve the recognition accuracy and speed of intravenous drug categories. Secondly, a corner detection model for drug dosage recognition was studied in the drug dispensing stage to further increase drug dispensing accuracy. Then the PIVAS drug category recognition system and PIVAS drug dosage recognition system were designed and implemented.

Randomized Placebo-Controlled, Biomarker-Stratified Phase Ib Microbiome Modulation in Melanoma: Impact of Antibiotic Preconditioning on Microbiome and Immunity.

This first-of-its-kind, placebo-controlled, randomized biomarker-driven microbiome modulation trial demonstrated that vancomycin + SER-401 and anti-PD-1 are safe in melanoma patients. Although limited by poor accrual during the pandemic, important insights were gained via translational analyses, suggesting that antibiotic preconditioning and interventional drug dosing regimens should be carefully considered when designing such trials.

An “On Demand” canakinumab regimen for treating children with Colchicine-Resistant familial Mediterranean fever – A multicentre study

ObjectivesCanakinumab, a human monoclonal antibody targeted at interleukin-1 beta, has demonstrated safety and efficacy in preventing familial Mediterranean fever (FMF) attacks among individuals with colchicine-resistant (crFMF). The manufacturer orders prescribe monthly subcutaneous injections. However, a subset of our patients is treated with an “canakinumab on demand ” (COD) strategy, with wider intervals between drug administrations. Therefore, we aimed to compare disease activity and drug safety between COD and “canakinumab fixed frequency” (CFF) policies. MethodsThis retrospective study collected data from three Israeli paediatric rheumatology centres, of children with crFMF who were treated with canakinumab. Epidemiological and clinical parameters, cumulative drug dosages, and adverse events were compared between children treated by both policies. ResultsTwenty-five (49 %) children were treated according to COD policy and 26 according to CFF policy. Demographic parameters and most of the disease features did not differ significantly between the groups. Both groups showed significant reduction in attacks after canakinumab introduction. The median number (interquartile range) of attacks per month did not differ significantly between the COD and CFF groups (0.33 (0.08, 0.58) and 0.13 (0, 0.5), respectively, p = 0.485 (even though, per definition, COD patients presumably had an attack before receiving the second canakinumab dose). The mean monthly dose was lower for the COD than the CFF group (1.13 ± 1.13 vs. 3.16 ± 1.46 mg/kg, p < 0.001). Adverse events were similar between the groups. ConclusionFor individuals with crFMF, COD compared to CFF policy can achieve similar efficacy and safety, with a lower accumulated canakinumab dose, rendering it less immunosuppressive and less expensive.