Pharmacodynamic Changes Research Articles

Abstract 5125: Depletion of CCR8+ tumor Treg cells with SRF114 or anti-CCR8 therapy promotes robust antitumor activity and reshapes the tumor microenvironment toward a more pro-inflammatory milieu

Abstract FOXP3+ regulatory T (Treg) cells play a crucial role in orchestrating immune responses across several tissues, including the tumor microenvironment (TME). The dominant immune regulatory activity of Treg cells is evidenced, both clinically and preclinically, by the profound inflammatory dysregulation that arises in their absence. Leveraging controlled depletion of Treg cells in tumor tissue while sparing Treg cells in healthy tissue may be achieved through antibody-mediated targeting of the C-C chemokine receptor 8 (CCR8). CCR8 is a seven transmembrane G-coupled chemokine receptor protein whose expression is predominantly upregulated on Treg cells in several types of tumors compared with peripheral blood. Importantly, depletion of CCR8-expressing Treg cells in tumors provides a novel pathway to immunotherapy that is mechanistically independent of checkpoint inhibition (CPI). Using single-cell transcriptome and flow cytometry analyses, we evaluated the pharmacodynamic changes after treatment with anti-CCR8 antibodies to elucidate the effect of tumor Treg cell-targeting therapies on the downstream mechanisms of antitumor immunity within the TME. SRF114, a highly selective human anti-CCR8 afucosylated antibody, and an anti-mouse CCR8 antibody were utilized to preferentially deplete CCR8+ Treg cells in human CCR8 knock-in (hCCR8KI) or wild-type mice, respectively. Treatment with SRF114 or anti-mouse CCR8 antibody resulted in robust monotherapy activity in models susceptible to CPI. Moreover, pronounced monotherapy activity was also seen in checkpoint-resistant model(s), highlighting a mechanistically CPI-independent role for intratumoral Treg cell depletion to elicit potent antitumor activity. Treatment of tumor-bearing mice with anti-CCR8 antibodies resulted in a significant reduction of tumor-associated Treg cells, while peripheral Treg cells remained unchanged. Analysis of bulk tumor lysates showed that anti-CCR8 therapy elevated levels of pro-inflammatory cytokines and pro-angiogenic and chemoattracting factors. Evaluation of effector T cells demonstrated that anti-CCR8 therapy drives proliferation of CD8+ T cells and an increase in intracellular cytokine production of IFNγ, TNFα, and granzyme A. Additionally, the tumor myeloid compartment was strongly affected by anti-CCR8 therapy. Multiple myeloid cell subsets had increased levels of co-stimulatory molecules and expression of PD-L1. Altogether, selective depletion of intratumoral CCR8+ Treg cells results in robust antitumor activity by reshaping the TME toward a more pro-inflammatory milieu, providing an orthogonal approach to CPI for eliciting antitumor immunity and a strong rationale for evaluating SRF114 as a therapeutic agent for the treatment of cancer. SRF114 is currently in Phase 1 clinical studies. Citation Format: Marisella Panduro, Yue Ren, Ricard Masia, Yu Yang, Andrew C. Lake, Vito J. Palombella, Jonathan A. Hill, James F. Mohan. Depletion of CCR8+ tumor Treg cells with SRF114 or anti-CCR8 therapy promotes robust antitumor activity and reshapes the tumor microenvironment toward a more pro-inflammatory milieu. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5125.

Developing a Warning Model of Potentially Inappropriate Medications in Older Chinese Outpatients in Tertiary Hospitals: A Machine-Learning Study.

Due to multiple comorbid illnesses, polypharmacy, and age-related changes in pharmacokinetics and pharmacodynamics in older adults, the prevalence of potentially inappropriate medications (PIMs) is high, which affects the quality of life of older adults. Building an effective warning model is necessary for the early identification of PIMs to prevent harm caused by medication in geriatric patients. The purpose of this study was to develop a machine learning-based model for the warning of PIMs in older Chinese outpatients. This retrospective study was conducted among geriatric outpatients in nine tertiary hospitals in Chengdu from January 2018 to December 2018. The Beers criteria 2019 were used to assess PIMs in geriatric outpatients. Three problem transformation methods were used to tackle the multilabel classification problem in prescriptions. After the division of patient prescriptions into the training and test sets (8:2), we adopted six widely used classification algorithms to conduct the classification task and assessed the discriminative performance by the accuracy, precision, recall, F1 scores, subset accuracy (ss Acc), and Hamming loss (hm) of each model. The results showed that among 11,741 older patient prescriptions, 5816 PIMs were identified in 4038 (34.39%) patient prescriptions. A total of 41 types of PIMs were identified in these prescriptions. The three-problem transformation methods included label power set (LP), classifier chains (CC), and binary relevance (BR). Six classification algorithms were used to establish the warning models, including Random Forest (RF), Light Gradient Boosting Machine (LightGBM), eXtreme Gradient Boosting (XGBoost), CatBoost, Deep Forest (DF), and TabNet. The CC + CatBoost model had the highest accuracy value (97.83%), recall value (89.34%), F1 value (90.69%), and ss Acc value (97.79%) with a good precision value (92.18%) and the lowest hm value (0.0006). Therefore, the CC + CatBoost model was selected to predict the occurrence of PIM in geriatric Chinese patients. This study's novelty establishes a warning model for PIMs in geriatric patients by using machine learning. With the popularity of electronic patient record systems, sophisticated computer algorithms can be implemented at the bedside to improve medication use safety in geriatric patients in the future.

Safety and Tolerability of Antimicrobial Agents in the Older Patient.

Older patients are at high risk of infections, which often present atypically and are associated with high morbidity and mortality. Antimicrobial treatment in older individuals with infectious diseases represents a clinical challenge, causing an increasing burden on worldwide healthcare systems; immunosenescence and the coexistence of multiple comorbidities determine complex polypharmacy regimens with an increase in drug-drug interactions and spread of multidrug-resistance infections. Aging-induced pharmacokinetic and pharmacodynamic changes can additionally increase the risk of inappropriate drug dosing, with underexposure that is associated with antimicrobial resistance and overexposure that may lead to adverse effects and poor adherence because of low tolerability. These issues need to be considered when starting antimicrobial prescriptions. National and international efforts have been made towards the implementation of antimicrobial stewardship (AMS) interventions to help clinicians improve the appropriateness and safety of antimicrobial prescriptions in both acute and long-term care settings. AMS programs were shown to decrease consumption of antimicrobials and to improve safety in hospitalized patients and older nursing home residents. With the abundance of antimicrobial prescriptions and the recent emergence of multidrug resistant pathogens, an in-depth review of antimicrobial prescriptions in geriatric clinical practice is needed. This review will discuss the special considerations for older individuals needing antimicrobials, including risk factors that shape risk profiles in geriatric populations as well as an evidence-based description of antimicrobial-induced adverse events in this patient population. It will highlight agents of concern for this age group and discuss interventions to mitigate the effects of inappropriate antimicrobial prescribing.

Phase 1 study to determine the safety and dosing of autologous PBMCs modified to present HPV16 antigens (SQZ-PBMC-HPV) in HLA-A*02+ patients with HPV16+ solid tumors

SummaryWe conducted a dose escalation Phase 1 study of autologous PBMCs loaded by microfluidic squeezing (Cell Squeeze® technology) with HPV16 E6 and E7 antigens (SQZ-PBMC-HPV), in HLA-A*02+ patients with advanced/metastatic HPV16+ cancers. Preclinical studies in murine models had shown such cells resulted in stimulation and proliferation of antigen specific CD8+ cells, and demonstrated antitumor activity. Administration of SQZ-PBMC-HPV was every 3 weeks. Enrollment followed a modified 3+3 design with primary objectives to define safety, tolerability, and the recommended Phase 2 dose. Secondary and exploratory objectives were antitumor activity, manufacturing feasibility, and pharmacodynamic evaluation of immune responses. Eighteen patients were enrolled at doses ranging from 0.5 × 106 to 5.0 × 106 live cells/kg. Manufacture proved feasible and required < 24 h within the overall vein-to-vein time of 1 – 2 weeks; at the highest dose, a median of 4 doses were administered. No DLTs were observed. Most related TEAEs were Grade 1 – 2, and one Grade 2 cytokine release syndrome SAE was reported. Tumor biopsies in three patients showed 2 to 8-fold increases in CD8+ tissue infiltrating lymphocytes, including a case that exhibited increased MHC-I+ and PD-L1+ cell densities and reduced numbers of HPV+ cells. Clinical benefit was documented for the latter case. SQZ-PBMC-HPV was well tolerated; 5.0 × 106 live cells/kg with double priming was chosen as the recommended Phase 2 dose. Multiple participants exhibited pharmacodynamic changes consistent with immune responses supporting the proposed mechanism of action for SQZ-PBMC-HPV, including patients previously refractory to checkpoint inhibitors.

Assessment of soluble skin surface protein levels for monitoring psoriasis vulgaris in adult psoriasis patients using non-invasive transdermal analysis patch: A pilot study.

To improve the care of patients with chronic inflammatory skin conditions, such as psoriasis, there is a need for diagnostic methods that can facilitate personalized medicine. This exploratory pilot study aimed to determine whether non-invasive measurements of inflammation-related proteins from psoriatic skin can be sampled using the FibroTx Transdermal Analysis Patch (TAP) to assess disease severity and monitor pharmacodynamic changes. Ten healthy volunteers and 44 psoriasis vulgaris patients were enrolled in the exploratory pilot study. Skin surface protein measurements for healthy and lesional skin were performed using TAP. Patients' scores of psoriasis activity and severity (PASI) were documented, and differences in the thickness of skin layers were determined using sonography. The study assessed the skin surface protein levels of psoriasis patients undergoing whole-body treatment with narrow-band UVB to evaluate whether the levels of the skin surface proteins IL-1α, IL-1RA CXCL-1/2, and hBD-1 were associated with the disease activity and severity measurements. Using TAP technology, it was observed that there were clear differences in levels of IL-1α, IL-1RA, CXCL-1/2, and hBD-1 between psoriasis lesional and non-lesional skin. In addition, a positive correlation between CXCL-1/2 and desquamation, and between CXCL-1/2 and SLEB thickness was observed. During UVB treatment, the TAP measurements revealed a clear reduction of IL-1RA, CXCL 1/2, and hBD-1 on lesional skin. Further, skin surface measurements of IL-1RA and CXCL-1/2 displayed a different profile than those achieved by visual scoring of local inflammation, thus indicating that measuring the 'molecular root' of inflammation appears to have value as an objective, non-invasive biomarker measurement for scoring disease severity.

Abstract PD2-04: Preclinical development of CodaLytic™, a codon-modified influenza virus, as a novel virotherapeutic agent for breast cancer immunotherapy

Abstract Multiple species of oncolytic viruses (OVs) have been shown to modulate the tumor microenvironment (TME) by increasing immune cell infiltration and activating stimulatory immune responses, leading to the induction of a tumor-specific immune response. Many engineered OVs achieve tumor specificity by either gene deletion or mutations and are then armed with immunomodulatory transgenes to promote anti-tumor immune responses. In an alternative approach, OVs derived from Codagenix’s codon/codon pair modification platform aim to leverage the natural immunostimulatory capacity of selected viral species for efficacy and take advantage of defects in innate immune sensing and apoptosis mechanisms in cancer cells as well as receptor overexpression for tumor selectivity. CodaLytic is a novel virotherapeutic derived from influenza virus strain A/California/07/2009, that is synthetically engineered to contain over 600 silent mutations in hemagglutinin and neuraminidase genes and is being developed as a novel immunotherapeutic for breast cancer. In the orthotopic EMT6 triple-negative breast cancer model, known for its moderate sensitivity to immunotherapies, intratumoral injection of 108 PFU three times a week for up to 4 weeks as a monotherapy led to significant tumor growth inhibition by 76% (p &amp;lt; 0.001 vs vehicle control), translating into a significant survival benefit with a 66% cure rate. Intravenous rechallenge of EMT6 long-term survivors led to a 27-fold reduction in lung nodule formation and a tumor-specific interferon-γ memory response was observed ex vivo in their splenocytes. Anti-tumor efficacy after CodaLytic treatment was accompanied by a change in the composition of the tumor immune infiltrate with significant increases in T, B and NK cells and increased gene expression of pathways and genes related to T cell effector function, dendritic cell activation, antigen presentation and chemoattraction. In immunotherapy-resistant orthotopic 4T1 tumors, combination of CodaLytic with a CTLA-4 inhibitory antibody, but not anti-PD-1 blockade – a combination that had demonstrated combination benefit in several other preclinical models – led to reduction in tumor growth by 75% (p &amp;lt; 0.0001 vs vehicle control and PD-1 combination group). Median overall survival improved from 22 to 30 days with addition of CTLA-4 blockade. Triple combination including PD-1 inhibition led to improved long-term survival beyond 50 days with 30% complete regressions. In summary, these preclinical data demonstrate CodaLytic’s ability to induce broad innate and adaptive changes in the breast cancer TME, resulting in anti-tumor efficacy and prolonged survival. Characterization of the tumor immune infiltrate after CTLA-4 combination and pharmacodynamic changes achieved after CodaLytic/checkpoint combination treatment in human breast cancer tumoroids will further support identification of correlates of efficacy with translational implications. Together with preclinical toxicology data and demonstrated clinical safety of this attenuated influenza virus after intranasal administration in healthy individuals, CodaLytic emerges as a promising novel viroimmunotherapeutic agent and is planned to enter a phase 1 clinical trial in early 2023. Citation Format: Marcin Stawowczyk, Yiwen Zhao, Katie Pfeffer, Juliana Tafrova, James Rodriguez, Chen Yang, Nusrat Jahan, Sybil A. Tasker, Steffen Mueller, J. Robert Coleman, Johanna K. Kaufmann. Preclinical development of CodaLytic™, a codon-modified influenza virus, as a novel virotherapeutic agent for breast cancer immunotherapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD2-04.

CYP2D6 isoenzyme and ABCB1 gene polymorphisms associated with postoperative nausea and vomiting in women undergoing laparoscopic cholecystectomy: a randomized trial

IntroductionPostoperative nausea and vomiting is still a common complication. Serotonin receptor antagonists are commonly used in clinical practice for antiemetic prophylaxis. Interindividual variations in drug response, including single nucleotide polymorphisms, are related to pharmacokinetic and pharmacodynamic changes in these drugs and may lead to a poor therapeutic response. This study aimed to evaluate the influence of CYP2D6 isoenzyme and ABCB1 gene polymorphisms on the frequency of postoperative nausea and vomiting with the use of ondansetron or palonosetron. MethodsA randomized, double-blind clinical trial including 82 women aged 60 years or over undergoing laparoscopic cholecystectomy was conducted. Patients were randomized to receive either ondansetron or palonosetron for postoperative nausea and vomiting prophylaxis. DNA was extracted from saliva. Genetic polymorphisms were analyzed by real-time polymerase chain reaction. The following polymorphisms were analyzed: rs3892097 C/T, rs1128503 A/G, rs16947 A/G, rs1065852 A/G, rs1045642 A/G, rs2032582 C/A, and rs20325821 C/A. ResultsOverall, vomiting, and severe nausea occurred in 22.5% and 57.5% of patients, respectively. In the palonosetron group, patients with the GG genotype (rs16947 A/G) experienced more severe nausea (p = 0.043). In the ondansetron group, patients with the AA genotype (rs16947 A/G) presented mild nausea (p = 0.034), and those with the AA genotype (rs1065852 A/G) experienced more vomiting (p = 0.034). ConclusionA low antiemetic response was observed with ondansetron in the presence of the AA genotype (rs16947 A/G) and the AA genotype (rs1065852 A/G), and a low therapeutic response was found with palonosetron in the presence of the GG genotype (rs16947 A/G) in laparoscopic cholecystectomy. RegisterClinicalTrials.gov.

Prognostic value of integrated liquid biopsies in patients (pts) with metastatic urothelial cancer (mUC).

547 Background: Despite recent therapeutic advancements for patients with mUC, including checkpoint inhibitors (CPIs), anti-FGFR and antibody-drug conjugates (ADCs), biomarker data to predict therapeutic response and identify mechanisms of resistance remain limited. Ongoing randomized clinical trials evaluating the combination of CPIs and ADCs in these pts underscore the need to develop biomarkers to better understand who might best respond to these therapies. Here, we employ a liquid biopsy approach to molecularly characterize circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA), including those isolated with Trop-2, the target of the novel drug Sacituzumab Govitecan and Datopotamab Deruxtecan. Methods: 104 blood samples serially collected from pts being treated for mUC were used for CTC collection using anti-EpCAM and Trop-2 antibodies in parallel. CTCs were isolated and stained for immune markers PD-L1 and HLA I using the VERSA (Versatile Exclusion-based Rare Sample Analysis) platform. Plasma was isolated for paired analysis of CTC and ctDNA content. CTCs were analyzed for enumeration and single-cell protein analysis. Overall survival (OS) was defined from time of sample collection, and survival analyses were performed using the Kaplan-Meier method. Results: We observed significantly shorter OS in pts with higher CTC burden (≥ 20 CTCs/7.5 mL blood) in samples captured with either EpCAM (median 34.1 vs 3.1 mo, P &lt; 0.01) or Trop-2 (median 34.1 vs 6.2 months, P &lt; 0.01). Furthermore, EpCAM and Trop-2 CTC burdens were higher at progression timepoints relative to responding or stable timepoints, when stratified according to treatment modality (table). Inter and intra-patient heterogeneous PD-L1 and HLA I expression and co-expression was observed on CTCs although no significant differences were seen globally between EpCAM and Trop-2 CTCs. In a cohort of pts treated with CPIs, we observed dynamic phenotypic changes in the ratio of HLA:PD-L1 that differed between EpCAM and Trop-2 CTCs. ctDNA analysis identified concordant increases in tumor fraction and acquired genomic mutations. When examined longitudinally across individual pts, these findings in tandem with changes in enumeration, suggest the emergence of different CTC subpopulations that may serve as biomarkers of resistance. Conclusions: We identify the prognostic significance of CTC enumeration with parallel EpCAM and Trop-2 CTC isolation and demonstrate the utility of a liquid biopsy assay that can detect pharmacodynamic changes in CTC burden and immune marker expression throughout the course of treatment. [Table: see text]

The potential and pitfalls of artificial intelligence in clinical pharmacology.

Artificial intelligence (AI) involves using data and algorithms to perform activities normally achieved through human intelligence. AI and its key component machine learning contextualize data and enhance decision making to transform how we operate, discover, and develop drugs. Transforming clinical pharmacology (CP) as AI-augmented CP (AI/CP) requires an ecosystem including digitized data collection, standardized processes, complementary technologies, and an ethical framework. This commentary aims to highlight the future perspectives of AI/CP in drug development.

Pancreatic Cancer Resistance to Treatment: The Role of Microbiota.

Pancreatic cancer (PC) is an aggressive malignancy and the fourth leading cause of cancer death in the United States and Europe. It is estimated that PC will be the second leading cause of cancer death by 2030. In addition to late diagnosis, treatment resistance is a major cause of shortened survival in pancreatic cancer. In this context, there is growing evidence that microbes play a regulatory role, particularly in therapy resistance and in creating a microenvironment in the tumor, that favors cancer progression. The presence of certain bacteria belonging to the gamma-proteobacteria or mycoplasmas appears to be associated with both pharmacokinetic and pharmacodynamic changes. Recent evidence suggests that the microbiota may also play a role in resistance mechanisms to immunotherapy and radiotherapy. However, the interactions between microbiota and therapy are bilateral and modulate therapy tolerance. Future perspectives are increasingly focused on elucidating the role of the microbiota in tumorigenesis and processes of therapy resistance, and a better understanding of these mechanisms may provide important opportunities to improve survival in these patients.

Phase Ib open-label, multicenter study of pixatimod, an activator of TLR9, in combination with nivolumab in subjects with microsatellite-stable metastatic colorectal cancer, metastatic pancreatic ductal adenocarcinoma and other solid tumors

BackgroundPixatimod is a unique activator of the Toll-like Receptor 9 pathway. This phase I trial evaluated safety, efficacy and pharmacodynamics of pixatimod and PD-1 inhibitor nivolumab in immunologically cold cancers.Methods3+3...

Approach to acute psychosis in older adults.

Approach to acute psychosis in older adults.

Which four medication classes have important pharmacogenetic considerations?

Medications often are prescribed without knowledge of a patient's pharmacogenetic profile. Initial therapy may require subsequent modification due to adverse reactions or lack of efficacy. Although many variables, including changes in pharmacokinetics, pharmacodynamics, or patient nonadherence, may account for these outcomes, information about a patient's ability to metabolize or transport drugs across membranes may be used to optimize therapy, resulting in improved medication outcomes.

Changes in Pharmacokinetics and Pharmacodynamics of Losartan in Experimental Diseased Rats Treated with Curcuma longa and Lepidium sativum.

The current study investigated "pharmacodynamics and pharmacokinetics interactions" of losartan with Curcuma longa (CUR) and Lepidium sativum (LS) in hypertensive rats. Hypertension was induced by oral administration of L-NAME (40 mg/kg) for two weeks. Oral administration of CUR or LS shows some substantial antihypertensive activity. The systolic blood pressure (SBP) of hypertensive rats was decreased by 7.04% and 8.78% 12 h after treatment with CUR and LS, respectively, as compared to rats treated with L-NAME alone. LS and CUR display the ability to potentiate the blood pressure-lowering effects of losartan in hypertensive rats. A greater decrease in SBP, by 11.66% and 13.74%, was observed in hypertensive rats treated with CUR + losartan and LS + losartan, respectively. Further, both the investigated herbs, CUR and LS, caused an increase in plasma concentrations of losartan in hypertensive rats. The AUC0-t, AUC0-inf and AUMC0-inf of losartan were increased by 1.25-fold, 1.28-fold and 1.09-fold in hypertensive rats treated with CUR + losartan. A significant (p &lt; 0.05) increase in AUC0-t (2.41-fold), AUC0-inf (3.86-fold) and AUMC0-inf (8.35-fold) of losartan was observed in hypertensive rats treated with LS + losartan. The present study affirms that interactions between CUR or LS with losartan alter both "pharmacokinetics and pharmacodynamics" of the drug. Concurrent administration of losartan with either CUR or LS would require dose adjustment and intermittent blood pressure monitoring for clinical use in hypertensive patients. Additional investigation is necessary to determine the importance of these interactions in humans and to elucidate the mechanisms of action behind these interactions.

OPTIMIZING MEDICATION RECONCILIATION AMONG OLDER ADULTS DURING COVID-19 INFECTION TREATMENT WITH PAXLOVID

Abstract COVID-19 infection treatment (CIT) has reframed optimizing medication reconciliation in older adults. In December 2021, FDA authorized Emergency Use Authorization of Paxlovid (Nirmatrelvir/Ritonavir), protease inhibitor blocking SARS-CoV-2 replication, to reduce severe COVID-19 and mortality in high-risk patients1. Pharmacodynamic and pharmacokinetic changes in geriatric population warrant a stepwise, patient-centered approach for prescribing Paxlovid by reviewing - 1) drug-drug interactions with current medications2, 2) renal dosing, 3) risks-benefits-alternatives, 4) adverse drug events (ADE), i.e. polypharmacy and prescribing cascade. Case A – Community-dwelling 65-year-old Hispanic male history of paroxysmal ventricular tachycardia and end-stage renal disease (ESRD) requiring CIT- 1) Paxlovid contraindication with Amiodarone2 2) ESRD – not candidate 3) risks outweigh benefits, 4) safer alternatives with less ADE. Case B – Long term care 80-year-old Hispanic female history of stroke, type 2 diabetes mellitus and dementia requiring CIT -1) Paxlovid contraindication with Atorvastatin2 (Atorvastatin held during Paxlovid treatment then restarted at lower dose “deprescribing”), 2) estimated glomerular filtration rate 46 with renal dosing – Paxlovid 150mg/100mg, 3) benefits outweigh risks, 4) monitored ADE in controlled setting. Optimizing medication reconciliation during CIT in older patients can decrease preventable ADE. Further research is essential to align CIT efficacy with the fundamental geriatric principles, including shared decision-making, long-term prognosis, and life care planning. 1Najjar-Debbiny R, Gronich N, Weber G, Khoury J, Amar M, Stein N, Goldstein LH, Saliba W. Effectiveness of Paxlovid in Reducing Severe COVID-19 and Mortality in High Risk Patients. Clin Infect Dis. 2022 Jun 2:ciac443. 2Lexicomp Drug Interaction Checker. Accessed August 6, 2022.

620. Pharmacokinetic-Pharmacodynamic Analysis of Oral Vancomycin and Gut Microbiome Changes in Healthy Volunteers: an Exploratory Study

Abstract Background Oral vancomycin causes profound changes to the gut microbiome due to high intra-colonic vancomycin concentrations. However, pharmacokinetics of oral vancomycin causing pharmacodynamic changes have not been explored, especially during the early dosing period. The purpose of this study was to investigate fecal vancomycin concentrations in healthy individuals in relation to gut microbiome diversity changes. Methods Healthy subjects 18-45 years with no antibiotic use for at least 28 days were given oral vancomycin 125 mg was given every 6 hours for 10 days. Stool samples were collected at baseline and during antibiotic therapy. Vancomycin concentrations were obtained through high-performance liquid chromatography (HPLC) assay. For this early pharmacokinetics analysis, stool samples from day 0 (baseline) to day 4 were included. Shotgun metagenomics sequencing was used for microbiome analysis. Descriptive analysis was performed to identify gut-microbiome phyla changes in correlation with detectable oral vancomycin fecal concentrations. Results A total of 6 healthy volunteers aged 32±5 years (Male: 100%; Caucasian: 50%; mean BMI: 26.8±4.5 kg/m2) were included. In the early dosing period (day 0-4), the mean fecal vancomycin concentrations increased daily with the highest concentration of 1,586 μg/g of stool occurring on day 4. Three of 9 subjects (50%) had undetectable oral vancomycin levels one days 1 and 2 of dosing. Within 24-48 hour of detectable vancomycin levels, subject-specific changes of gut microbiome phylum-level proportions were observable. Overall, an increase in Actinobacteria and Proteobacteria phyla and decrease in Firmicute phylum was observed within 24 hours that vancomycin was detected in the feces. Conclusion High concentrations of vancomycin are achieved in the stool by day four of dosing for all subjects; however, low concentrations are observed early in the dosing period for some subjects. Proportional, subject specific differences in gut microbiome phyla were observed within 24 hours of detectable vancomycin levels in the feces. Disclosures Kevin W. Garey, PharmD, MS, Acurx Pharmaceuticals: Grant/Research Support|Paratek Pharmaceuticals: Grant/Research Support|Seres Therapeutics: Grant/Research Support|Summit Pharmaceuticals: Grant/Research Support.

Pharmacodynamic properties for inhibition of cAMP- and cGMP elimination by pentoxifylline remain unaltered in vitro during hypothermia

BackgroundRewarming from hypothermia is associated with severe complications, one of which is hypothermia-induced cardiac dysfunction. This condition is characterized by decreased cardiac output accompanied by increased total peripheral resistance. This contributes to mortality rate approaching 40%. Despite this, no pharmacological interventions are recommended for these patients below 30 °C. Raising the intracellular levels of cAMP and/or cGMP, through PDE3- and PDE5-inhibitors respectively, have showed the ability to alleviate hypothermia-induced cardiac dysfunction in vivo. Drugs that raise levels of both cAMP and cGMP could therefore prove beneficial in patients suffering from hypothermia-induced cardiac dysfunction.MethodsThe unselective PDE-inhibitor pentoxifylline was investigated to determine its ability to reach the intracellular space, inhibit PDE3 and PDE5 and inhibit cellular efflux of cAMP and cGMP at temperatures 37, 34, 30, 28, 24 and 20 °C. Recombinant human PDE-enzymes and human erythrocytes were used in the experiments. IC50-values were calculated at all temperatures to determine temperature-dependent changes.ResultsAt 20 °C, the IC50-value for PDE5-mediated enzymatic breakdown of cGMP was significantly increased compared to normothermia (IC50: 39.4 µM ± 10.9 µM vs. 7.70 µM ± 0.265 µM, p-value = 0.011). No other significant changes in IC50-values were observed during hypothermia.ConclusionsThis study shows that pentoxifylline has minimal temperature-dependent pharmacodynamic changes, and that it can inhibit elimination of both cAMP and cGMP at low temperatures. This can potentially be effective treatment of hypothermia-induced cardiac dysfunction.Trial registration: Not applicable.

A Study to Assess the Prevalence of Medication Related Problems in Elderly Patients

Medication-related problems are referred to drug therapy that interferes with or can intervene with the preferred health outcomes for a patient. The geriatric populace that almost represents 21% of the whole populace, devours a remarkable deal of drug treatments due to the age-associated physiological changes, pharmacokinetic and pharmacodynamics alterations, consequently developing into medication related problems. The high prevalence of multiple drug use with age-related changes in pharmacokinetics and pharmacodynamics makes elderly patients vulnerable to medication-related problems. A community-based observational study was conducted among the residents who met the inclusion and exclusion criteria belonging to different regions of Dakshina Kannada district. The duration of the study was 6 months and enrolled 150 elderly patients aged 60 years and above of either sex and diagnosed to have any disease except cancer and being bedridden , to assess the prevalence of medication-related problems in elderly patients. Out of 150 elderly patients enrolled in the study, 107 were identified to have Medication Related Problems (MRPs). A total of 196 MRPs were identified amongst those 107 patients. The prevalence of patients with MRPs was found to be 72% in this study. The prevalence of MRPs was found to be varying among males (68.29%) and females (75%), across different age groups &amp; others. So, the study concluded that the number of elderly patients and multiple co-morbidities are increasing consequently with the increase in the number of medications and thus leading to increase in MRPs. So, it's vital to ensure optimum care for positive outcomes in the elderly. Keywords: Medication-related problems, MRPs, elderly patients, geriatric populace

Evaluation of the clinical molecule anti-human-PD-L1/IL-15 KD033 in the human-PD-1/PD-L1-expressing murine model demonstrates PD-L1 targeting of IL-15 in vivo

KD033 is a clinical-stage immunocytokine composed of a high-affinity anti-human-PD-L1 antibody and the human IL-15/ IL-15 receptor sushi-domain complex. We have previously shown that KD033-surrogate, the anti-mouse-PD-L1/IL-15 immunocytokine, was efficacious in several syngeneic murine tumor models including those that were refractory to anti-PD-1/PD-L1 checkpoint blockers. KD033-surrogate showed better efficacy than the combination treatment of its component, anti-PD-L1 antibody with the non-targeting IL-15. KD033-surrogate was also efficacious in both low and high PD-L1-expressing tumors. In this study, we have utilized double knock-in mice expressing functional human PD-1/PD-L1 to show that the clinical molecule, KD033, reproduced the anti-tumor efficacy observed with KD033-surrogate in the syngeneic models. KD033 was equally efficacious in reducing the growth of human-PD-L1 positive (hPDL1+) and negative (hPDL1-) MC38 murine tumors. We observed similar peripheral pharmacodynamics changes in KD033-treated mice bearing either hPDL1+ or hPDL1- MC38 tumors. However, different transcriptomic profiles were observed between KD033-treated hPDL1+ and hPDL1- MC38 tumors with marked changes involving mostly downregulated genes in hPDL1- tumors in addition to the immune-related genes changes observed in both hPDL1+ and hPDL1- MC38 tumors. Cytotoxic and myeloid cell signatures were upregulated in both tumors with relatively greater increases observed in hPDL1- MC38 tumors. These effects of KD033 treatment in PD-L1 positive and negative tumors demonstrate the role of PD-L1 in targeting of IL-15 cytokine in vivo.

Prevalence and factors associated with potentially inappropriate medication and medication complexity for older adults in the emergency department of a secondary teaching hospital in Indonesia.

Older adults experience progressive decline in various organs and changes in pharmacokinetics and pharmacodynamics of the drugs in the body which lead to an increased risk of medication-related problems. Potentially inappropriate medications (PIMs) and medication complexity are key factors contributing to adverse drug events in the emergency department (ED). To estimate the prevalence and investigate the risk factors of PIMs and medication complexity among older adults admitted to the ED. A retrospective observational study was conducted among patients aged > 60 years admitted to the ED of Universitas Airlangga Teaching Hospital in January - June 2020. PIMs and medication complexity were measured using the 2019 American Geriatrics Society Beers Criteria® and Medication Regimen Complexity Index (MRCI), respectively. A total of 1005 patients were included and 55.0% (95% confidence interval [CI]: 52 - 58%) of them received at least one PIM. Whereas, the pharmacological therapy prescribed to older adults had a high complexity index (mean MRCI 17.23 + 11.15). Multivariate analysis showed that those with polypharmacy (OR= 6.954; 95% CI: 4.617 - 10.476), diseases of the circulatory system (OR= 2.126; 95% CI: 1.166 - 3.876), endocrine, nutritional, and metabolic diseases (OR= 1.924; 95% CI: 1.087 - 3.405), and diseases of the digestive system (OR= 1.858; 95% CI: 1.214 - 2.842) had an increased risk of receiving PIM prescriptions. Meanwhile, disease of the respiratory system (OR = 7.621; 95% CI: 2.833 - 15.150), endocrine, nutritional and metabolic diseases (OR = 6.601; 95% CI: 2.935 - 14.847), and polypharmacy (OR = 4.373; 95% CI: 3.540 - 5.401) were associated with higher medication complexity. In our study, over one in every two older adults admitted to the ED had PIMs, and a high medication complexity was observed. Endocrine, nutritional and metabolic disease was the leading risk factors for receiving PIMs and high medication complexity.