Change In pK Research Articles

Abstract PO1-20-06: Phase 2 study of novel HER2-targeting, TLR7/8 immune-stimulating antibody conjugate (ISAC) BDC-1001 +/- pertuzumab in patients with HER2-positive metastatic breast cancer (MBC) previously treated with trastuzumab deruxtecan

Abstract Background: Therapies to effectively manage patients (pts) with metastatic HER2+ breast cancer have significantly improved over the years, but improvement is still needed in both efficacy and tolerability. BDC-1001 is an ISAC consisting of a trastuzumab biosimilar conjugated to a proprietary cell membrane impermeable TLR7/8 agonist via a non-cleavable linker, administered IV every 2 weeks. It is designed to trigger the innate immune system and generate a durable tumor-targeted adaptive immune response. Preclinical studies indicate that HER2-targeted ISACs elicit potent and durable immune-mediated antitumor efficacy, leading to complete tumor regression in a TLR- and Fc receptor-dependent manner [1]. Moreover, preclinical studies with a murine surrogate of BDC-1001 (trastuzumab-T785 ISAC) indicate improved anti-tumor activity with trastuzumab-T785 compared with trastuzumab/pertuzumab. In these preclinical studies, the combination of trastuzumab-T785 and pertuzumab demonstrated significantly enhanced efficacy in multiple HER2-expressing tumor models, including those with lower HER2 expression [1]. The addition of pertuzumab decreased the quantity of ISAC required for anti-tumor activity in the JIMT-1 HER2 IHC2+ model. Moreover, the combination of pertuzumab with the ISAC significantly increased the cytokine and chemokine concentrations in the tumor xenografts, compared with monotherapy or trastuzumab/pertuzumab, indicating enhanced myeloid activation in the tumor. These preclinical studies suggest that this combination may enhance the clinical activity of trastuzumab-based ISACs. The completed part of the BDC-1001 dose escalation trial (NCT04278144) demonstrated safety, PK and pharmacodynamic changes compatible with the ISAC mechanism of action, and a wide range of antitumor activity (incl. cases with breast cancer); resulting in a RP2D of 20 mg/kg q2w [2]. Two trials are underway, including a Phase 2 trial in other HER2+ malignancies, and a randomized Phase 2 trial with BDC-1001 alone and in combination with pertuzumab in patients with HER2-positive MBC previously treated with 2 or more prior anti-HER2 therapies, including trastuzumab deruxtecan. Methods: The Phase 2 multicenter, open-label, randomized study (BBI-20231001) is enrolling up to 66 pts with HER2-positive (ASCO/CAP guidelines 2018) MBC previously treated with 2 or more prior anti-HER2 therapies, including trastuzumab deruxtecan as one of the prior therapies. Pts must be 18 years or older, have measurable disease (RECIST v1.1), and have Eastern Cooperative Oncology Group performance status of 0 or 1. Pts will be administered BDC-1001 20 mg/kg every 2 weeks (IV q2w) and randomized 1:1 to receive BDC-1001 as a single agent or in combination with pertuzumab. The trial has a Simon 2-stage design within each arm. The primary objective is to determine the overall response rate per RECIST v1.1 of BDC-1001 alone and in combination with pertuzumab. Secondary objectives will evaluate safety, additional efficacy parameters, pharmacokinetics, and immunogenicity of BDC-1001 alone and in combination with pertuzumab. Exploratory objectives will include pharmacodynamic biomarkers in tumor tissue (baseline and on-treatment biopsies if feasible) and in peripheral blood to elucidate the mechanism of action and seek to identify biomarkers associated with BDC-1001 biological activity with or without pertuzumab. This study is expected to initiate accrual in 2H 2023. For additional information, please contact Bolt Biotherapeutics at 1-650-665-9295 or info@boltbio.com.

Hexasodium fytate exposure-response correlations in a randomized, placebo-controlled study of patients on dialysis with cardiovascular calcification.

Background: Patients receiving dialysis have high cardiovascular risk in part due to extensive vascular calcification. In the CaLIPSO study, infusion of hexasodium fytate (SNF472), the hexasodium salt of inositol hexaphosphate, for 52weeks thrice weekly during hemodialysis significantly reduced progression of coronary artery calcification (CAC). This report examines pharmacokinetic/pharmacodynamic (PK/PD) and exposure-efficacy in CaLIPSO. Methods: We measured hexasodium fytate plasma concentrations (PK) by validated liquid chromatography-mass spectroscopy, and hydroxyapatite crystallization in plasma (PD) by validated spectrophotometry. Analyses included patients evaluable for PK, PD, and CAC change (per-protocol analysis). We developed a simple Emax model for maximum concentration (Cmax) and PD effect, and linear and non-linear Emax models for exposure-efficacy among individual average Cmax and absolute and percent changes in CAC score from baseline to week 52. Results: Among evaluable patients receiving placebo (n = 15), 300mg (n = 20), or 600mg (n = 20), average Cmax across visits was not quantifiable (<0.76μM), 15μM, and 46μM, respectively. These results suggest a more-than-proportional increase, without accumulation, with a Cmax ratio of approximately 3 for the doses administered. Average inhibition of hydroxyapatite crystallization was 15%, 61%, and 75%, respectively, and similar across visits. Simple Emax models described 80% maximal effect at exposures >21.9µM and a plateau in exposure-efficacy above the third quartile of Cmax (≥32µM). Conclusion: Hexasodium fytate has exposure-dependent effects on hydroxyapatite crystallization and progression of cardiovascular calcification. Simple Emax models show robust relations among exposure, inhibition of hydroxyapatite crystallization, and change in CAC volume. Clinical Trial Registration: https://www.clinicaltrials.gov; identifier NCT02966028.

The reduction in arterial pH with increased temperature is not affected by hyperoxia in toads (Rhinella marina) and pythons (Python molurus).

It is well established that arterial pH decreases with increased temperature in amphibians and reptiles through an elevation of arterial PCO2, but the underlying regulation remains controversial. The alphastat hypothesis ascribes the pH fall to a ventilatory regulation of protein ionisation, but the pH reduction with temperature is lower than predicted by the pKa change of the imidazole group on histidine. We hypothesised that arterial pH decreases at high, but not at low, temperatures when toads (Rhinella marina) and snakes (Python molurus) are exposed to hyperoxia. In toads, hyperoxia caused similar elevations of arterial PCO2at 20 and 30°C, indicative of a temperature-independent oxygen-mediated drive to breathing, whereas PCO2was unaffected by hyperoxia in snakes at 25 and 35°C. These findings do not support our hypothesis of an increased oxygen-mediated drive to breathing as body temperature increases.

10007-ACT-2 FIRST IN HUMAN STUDY OF DSP-0390, AN ORAL EMOPAMIL BINDING PROTEIN (EBP) INHIBITOR, IN RECURRENT HIGH-GRADE GLIOMA (HGG): PRELIMINARY RESULTS

Abstract BACKGROUND Cholesterol in the brain is derived wholly from de novo biosynthesis as the blood-brain barrier prevents uptake from the circulation. The overexpression of cholesterol synthesis genes is associated with decreased survival in glioblastoma (GBM), suggesting that gliomas may be sensitive to the inhibition of cholesterol biosynthesis. DSP-0390 is an investigational small molecule that inhibits EBP, a key enzyme in cholesterol biosynthesis. Preclinical studies demonstrated antitumor activity of DSP-0390 in orthotopic xenograft GBM models. METHODS This phase I dose escalation study aims to assess the safety, PK, PD, and preliminary antitumor activity of oral DSP-0390 monotherapy for recurrent HGG (NCT05023551). Key eligibility criteria include histologically confirmed grade III or IV glioma (WHO 2016); treatment with ≥1 prior therapy; no treatment options beyond standard of care; KPS ≥70. RESULTS As of 9 May 2023, 24 patients (37.5% women) were enrolled across 6 dose levels (20 mg QD to 240 mg QD) with a median age of 51 years (range 24-76) including 17 (70.8 %) with GBM, 3 (12.5%) with anaplastic astrocytoma and 2 (8.3%) with anaplastic oligodendroglioma. Ten patients (41.7%) had IDH mutant tumors. Four patients (16.7%) were on stable dose of corticosteroids at baseline, of which 2 were able to discontinue or dose reduce the corticosteroid while on DSP-0390. There were no reported DLTs. The most common treatment-related TEAEs included grade 1 or 2 nausea (7 patients [29.2%]) and alanine aminotransferase increased (6 patients [25.0%]). Only one grade 3 related AE (dry skin) was noted. Two patients with IDH mutant grade 3 glioma had tumor reduction and remain on DSP-0390 for ≥9 months. Dose dependent changes in PK and PD were observed. CONCLUSIONS DSP-0390 has been well tolerated to date with dose escalation ongoing. A dose response relationship was observed between PK and PD biomarkers.

Utility of Physiologically Based Pharmacokinetic Modeling to Investigate the Impact of Physiological Changes of Pregnancy and Cancer on Oncology Drug Pharmacokinetics.

The treatment of cancer during pregnancy remains challenging with knowledge gaps in drug dosage, safety, and efficacy due to the under-representation of this population in clinical trials. Our aim was to investigate physiological changes reported in both pregnancy and cancer populations into a PBPK modeling framework that allows for a more accurate estimation of PK changes in pregnant patients with cancer. Paclitaxel and docetaxel were selected to validate a population model using clinical data from pregnant patients with cancer. The validated population model was subsequently used to predict the PK of acalabrutinib in pregnant patients with cancer. The Simcyp pregnancy population model reasonably predicted the PK of docetaxel in pregnant patients with cancer, while a modified model that included a 2.5-fold increase in CYP2C8 abundance, consistent with the increased expression during pregnancy, was needed to reasonably predict the PK of paclitaxel in pregnant patients with cancer. Changes in protein binding levels of patients with cancer had a minimal impact on the predicted clearance of paclitaxel and docetaxel. PBPK modeling predicted approximately 60% lower AUC and Cmax for acalabrutinib in pregnant versus non-pregnant patients with cancer. Our results suggest that PBPK modeling is a promising approach to investigate the effects of pregnancy and cancer on the PK of oncology drugs and potentially inform dosing for pregnant patients with cancer. Further evaluation and refinement of the population model are needed for pregnant patients with cancer with additional compounds and clinical PK data.

Population pharmacokinetic modeling and target attainment analyses of rezafungin for the treatment of candidemia and invasive candidiasis.

Rezafungin is a chemically and metabolically stable echinocandin with a longer half-life than other echinocandins, allowing for a once-weekly intravenous infusion versus a daily infusion. Rezafungin is approved in the US for the treatment of candidemia and/or invasive candidiasis and is in development for the prevention of invasive fungal disease caused by Candida, Aspergillus, and Pneumocystis spp. in immunosuppressed patients. A population pharmacokinetic (PPK) model was developed using data from five Phase 1, one Phase 2, and one Phase 3 study. The model found to best describe the available data was a three-compartment PPK model with first-order elimination characterized by the parameters clearance (CL), central volume (V1), peripheral volume (V23), intercompartmental clearance 1, and intercompartmental clearance 2. The variability model included correlated interindividual variability in CL, V1, and V23 and a proportional residual variability model. The following statistically significant covariates were identified: albumin concentrations on V23; body surface area (BSA) on CL, V1, and V23; and disease state on CL and V1. Disease states were defined as patients from the Phase 2 and Phase 3 studies and hepatically impaired subjects. Covariates of BSA, disease state, or albumin, included in the final model, were not associated with clinically meaningful changes in PK, nor were any other patient factors, indicating that a common dose regimen is adequate for all adult patients. Target attainment simulations were performed to estimate the probability of achieving PK/pharmacodynamic targets across the range of minimum inhibitory concentration values for six species of Candida.

CTNI-67. FIRST IN HUMAN STUDY OF DSP-0390, AN ORAL EMOPAMIL BINDING PROTEIN (EBP) INHIBITOR, IN RECURRENT HIGH-GRADE GLIOMA (HGG): PRELIMINARY RESULTS

Abstract BACKGROUND Cholesterol in the brain is derived wholly from de novo biosynthesis as the blood-brain barrier prevents uptake from the circulation. The overexpression of cholesterol synthesis genes is associated with decreased survival in glioblastoma (GBM), suggesting that gliomas may be sensitive to the inhibition of cholesterol biosynthesis. DSP-0390 is an investigational small molecule that inhibits EBP, a key enzyme in cholesterol biosynthesis. Preclinical studies demonstrated antitumor activity of DSP-0390 in orthotopic xenograft GBM models. METHODS This phase I dose escalation study aims to assess the safety, PK, PD, and preliminary antitumor activity of oral DSP-0390 monotherapy for recurrent HGG (NCT05023551). Key eligibility criteria include histologically confirmed grade III or IV glioma (WHO 2016); treatment with ≥ 1 prior therapy; no treatment options beyond standard of care; KPS ≥ 70. RESULTS As of 9 May 2023, 24 patients (37.5% women) were enrolled across 6 dose levels (20 mg QD to 240 mg QD) with a median age of 51 years (range 24-76) including 17 (70.8 %) with GBM, 3 (12.5%) with anaplastic astrocytoma and 2 (8.3%) with anaplastic oligodendroglioma. Ten patients (41.7%) had IDH mutant tumors. Four patients (16.7%) were on stable dose of corticosteroids at baseline, of which 2 were able to discontinue or dose reduce the corticosteroid while on DSP-0390. There were no reported DLTs. The most common treatment-related TEAEs included grade 1 or 2 nausea (7 patients [29.2%]) and alanine aminotransferase increased (6 patients [25.0%]). Only one grade 3 related AE (dry skin) was noted. Two patients with IDH mutant grade 3 glioma had tumor reduction and remain on DSP-0390 for ≥ 9 months. Dose dependent changes in PK and PD were observed. CONCLUSIONS DSP-0390 has been well tolerated to date with dose escalation ongoing. A dose response relationship was observed between PK and PD biomarkers.

Effect of Omeprazole Administration on the Pharmacokinetics of Oral Extended-Release Nifedipine in Healthy Subjects.

Oral extended-release (ER) dosage forms have been used to sustain blood drug levels, reduce adverse events, and improve patient compliance. We investigated potential effects of comedication on pharmacokinetic exposure of nifedipine ER products with different formulation designs and manufacturing processes. A clinical study compared a generic version of nifedipine ER tablet with pH-dependent dissolution behavior with an osmotic pump product with pH independent drug release under fasting condition. In this study, two nifedipine tablet products were tested with or without short-term omeprazole comedication in healthy subjects. Seven-day administration of omeprazole before nifedipine dosing significantly increased the gastric pH, and subsequently increased the geometric least square (LS) means of area under the concentration-time curve from time zero to the last measurable timepoint (AUC0-t ) and maximum plasma concentration (Cmax ) of nifedipine to 132.6% (90% confidence interval (CI): 120.6-145.7%) and 112.8% (90% CI: 100.8-126.3%) for pH-dependent ER tablets, and 120.6% (90% CI: 109.7-132.5%) and 122.5% (90% CI: 113.7-131.9%) for the pH-independent ER tablets, respectively. Similar extent of increase in AUC0-t and Cmax was confirmed in the subpopulations whose gastric pH was ≥ 4 or ≤ 3 in subjects with or without omeprazole administration. Given that similar increases in drug exposures were observed for both pH-dependent and pH-independent nifedipine formulations and the geometric LS mean ratios were between 112% and 133% with and without short-term omeprazole comedication, the gastric pH may have limited effects on omeprazole-induced nifedipine PK changes on the tested formulations. The inhibition of cytochrome P450 3A4 activity may play a significant role causing nifedipine exposure changes for both formulations, which would warrant additional assessment.

Physiologically Based Pharmacokinetic Model To Predict Metoprolol Disposition in Healthy and Disease Populations.

The evolution in the development of drugs has increased the popularity of physiologically based pharmacokinetic (PBPK) models. This study seeks to assess the PK of metoprolol in populations with healthy, chronic kidney disease (CKD), and acute myocardial infarction (AMI) conditions by developing and evaluating PBPK models. An extensive literature review for identifying and selecting plasma concentration vs time profile data and other drug-related parameters was undergone for their integration into the PK-Sim program followed by the development of intravenous, oral, and diseased models. The developed PBPK model of metoprolol was then evaluated using the visual predictive checks, mean observed/predicted ratios (Robs/pre), and average fold error for all PK parameters, i.e., the area under the curve (AUC), maximal plasma concentration, and clearance. The model evaluation depicted that none of the PK parameters were out of the allowed range (2-fold error) in the case of the mean Robs/pre ratios. The model anticipations were executed to determine the influence of diseases on unbound and total AUC after the application of metoprolol in healthy, moderate, and severe CKD. The dosage reductions were also suggested based on differences in unbound and total AUC in different stages of CKD. The developed PBPK models have successfully elaborated the PK changes of metoprolol occurring in healthy individuals and those with renal and heart diseases (CKD & AMI), which may be fruitful for dose optimization among diseased patients.

Gut microbiome modulates tacrolimus pharmacokinetics through the transcriptional regulation of ABCB1

BackgroundFollowing solid organ transplantation, tacrolimus (TAC) is an essential drug in the immunosuppressive strategy. Its use constitutes a challenge due to its narrow therapeutic index and its high inter- and intra-pharmacokinetic (PK) variability. As the contribution of the gut microbiota to drug metabolism is now emerging, it might be explored as one of the factors explaining TAC PK variability. Herein, we explored the consequences of TAC administration on the gut microbiota composition. Reciprocally, we studied the contribution of the gut microbiota to TAC PK, using a combination of in vivo and in vitro models.ResultsTAC oral administration in mice resulted in compositional alterations of the gut microbiota, namely lower evenness and disturbance in the relative abundance of specific bacterial taxa. Compared to controls, mice with a lower intestinal microbial load due to antibiotics administration exhibit a 33% reduction in TAC whole blood exposure and a lower inter-individual variability. This reduction in TAC levels was strongly correlated with higher expression of the efflux transporter ABCB1 (also known as the p-glycoprotein (P-gp) or the multidrug resistance protein 1 (MDR1)) in the small intestine. Conventionalization of germ-free mice confirmed the ability of the gut microbiota to downregulate ABCB1 expression in a site-specific fashion. The functional inhibition of ABCB1 in vivo by zosuquidar formally established the implication of this efflux transporter in the modulation of TAC PK by the gut microbiota. Furthermore, we showed that polar bacterial metabolites could recapitulate the transcriptional regulation of ABCB1 by the gut microbiota, without affecting its functionality. Finally, whole transcriptome analyses pinpointed, among others, the Constitutive Androstane Receptor (CAR) as a transcription factor likely to mediate the impact of the gut microbiota on ABCB1 transcriptional regulation.ConclusionsWe highlight for the first time how the modulation of ABCB1 expression by bacterial metabolites results in changes in TAC PK, affecting not only blood levels but also the inter-individual variability. More broadly, considering the high number of drugs with unexplained PK variability transported by ABCB1, our work is of clinical importance and paves the way for incorporating the gut microbiota in prediction algorithms for dosage of such drugs.5nEvj3aohpq9uU8QResbYsVideo

Inservice Music Teachers’ Vernacular Practices: A Self-Study of Curricular Application

The purpose of this self-study was to explore how a college-level vernacular music course might have played a part in shaping inservice music educators’ teaching practices. Nineteen music teachers who graduated from the same teacher preparation program completed a 23-item researcher-constructed questionnaire that identified how they viewed, incorporated, and negotiated vernacular music practices in their classrooms. Overall, participants indicated that incorporating vernacular approaches in school music programs was important and that the vernacular music course positively impacted how they conceptualized music teaching. Participants reported including a wide variety of informal learning activities that involved technology, aural learning, and student-directed music projects. Conversely, participants identified time limitations, lack of resources, classroom management, and performance tensions as distinct challenges. Future directions include documenting turning points in students’ vernacular learning, monitoring curricular changes in PK–12 music programs, and fortifying preservice music teachers’ preparation in multimusical learning.

Use of Physiologically Based Pharmacokinetic Modeling for Hepatically Cleared Drugs in Pregnancy: Regulatory Perspective

AbstractPhysiologically based pharmacokinetic modeling could be used to predict changes in exposure during pregnancy and possibly inform medicine use in pregnancy in situations in which there is currently limited or no available clinical PK data. The Medicines and Healthcare Product Regulatory Agency has been evaluating the available models for a number of medicines cleared by hepatic clearance mechanisms. Models were evaluated for metoprolol, tacrolimus, clindamycin, ondansetron, phenytoin, caffeine, fluoxetine, clozapine, carbamazepine, metronidazole, and paracetamol. The hepatic metabolism through cytochrome P450 (CYP) contributes significantly to the elimination of these drugs, and available knowledge of CYP changes during pregnancy has been implemented in the existing pregnancy physiology models. In general, models were able to capture trends in exposure changes in pregnancy to some extent, but the magnitude of pharmacokinetic change for these hepatically cleared drugs was not captured in each case, nor were models always able to capture overall exposure in the populations. A thorough evaluation was hampered by the lack of clinical data for drugs cleared by a specific clearance pathway. The limited clinical data, as well as complex elimination pathways involving CYPs, uridine 5′‐diphospho‐glucuronosyltransferase and active transporter for many drugs, currently limit the confidence in the prospective use of the models. Pregnancy‐related changes in uridine 5′‐diphospho‐glucuronosyltransferase and transport functions are emerging, and incorporation of such changes in current physiologically based pharmacokinetic modeling software is in progress. Filling this gap is expected to further enhance predictive performance of models and increase the confidence in predicting PK changes in pregnant women for hepatically cleared drugs.

Prediction of the Drug-Drug Interaction Potential between Tegoprazan and Amoxicillin/Clarithromycin Using the Physiologically Based Pharmacokinetic and Pharmacodynamic Model.

Tegoprazan is a novel potassium-competitive acid blocker. This study investigated the effect of drug-drug interaction on the pharmacokinetics and pharmacodynamics of tegoprazan co-administered with amoxicillin and clarithromycin, the first-line therapy for the eradication of Helicobacter pylori, using physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) modeling. The previously reported tegoprazan PBPK/PD model was modified and applied. The clarithromycin PBPK model was developed based on the model provided by the SimCYP® compound library. The amoxicillin model was constructed using the middle-out approach. All of the observed concentration-time profiles were covered well by the predicted profiles with the 5th and 95th percentiles. The mean ratios of predicted to observed PK parameters, including the area under the curve (AUC), maximum plasma drug concentration (Cmax), and clearance, were within the 30% intervals for the developed models. Two-fold ratios of predicted fold-changes of Cmax and AUC from time 0 to 24 h to observed data were satisfied. The predicted PD endpoints, including median intragastric pH and percentage holding rate at pH above 4 or 6 on day 1 and day 7, were close to the corresponding observed data. This investigation allows evaluation of the effects of CYP3A4 perpetrators on tegoprazan PK and PD changes, thus providing clinicians with the rationale for co-administration dosing adjustment.

Prediction for optimal dosage of pazopanib under various clinical situations using physiologically based pharmacokinetic modeling.

This study aimed to apply a physiologically based pharmacokinetic (PBPK) model to predict optimal dosing regimens of pazopanib (PAZ) for safe and effective administration when co-administered with CYP3A4 inhibitors, acid-reducing agents, food, and administered in patients with hepatic impairment. Here, we have successfully developed the population PBPK model and the predicted PK variables by this model matched well with the clinically observed data. Most ratios of prediction to observation were between 0.5 and 2.0. Suitable dosage modifications of PAZ have been identified using the PBPK simulations in various situations, i.e., 200 mg once daily (OD) or 100 mg twice daily (BID) when co-administered with the two CYP3A4 inhibitors, 200 mg BID when simultaneously administered with food or 800 mg OD when avoiding food uptake simultaneously. Additionally, the PBPK model also suggested that dosing does not need to be adjusted when co-administered with esomeprazole and administration in patients with wild hepatic impairment. Furthermore, the PBPK model also suggested that PAZ is not recommended to be administered in patients with severe hepatic impairment. In summary, the present PBPK model can determine the optimal dosing adjustment recommendations in multiple clinical uses, which cannot be achieved by only focusing on AUC linear change of PK.

94-LB: A Phase 1, Double-Blind, Placebo-Controlled Multiple Escalating Dose Study of RGT-075 Novel Small-Molecule Oral GLP-1 Receptor Agonist in Adults with Type 2 Diabetes

Background: RGT-075 is a small-molecule oral GLP-1 receptor agonist (GLP1RA) in clinical development. RGT-075 (15-280 mg) was well-tolerated by healthy adults in a prior phase 1 single ascending dose study. Phase 1 multiple-ascending dose study of RGT-075 in adults with type 2 diabetes (T2DM) results are presented. Methods: A Phase 1, randomized, double-blind, placebo-controlled, inpatient study planned multiple daily doses of RGT-075 or matching placebo (6 active/2 placebo per cohort) for up to 28 days in T2DM patients (baseline HbA1c 6-10.5% and concomitant metformin &amp;gt;500 mg/d) . An adaptive study design permitted dose and titration adjustments. Assessments included safety (primary) , PK, and exploratory efficacy changes in HbA1c, fasting plasma glucose (FPG) , continuous glucose monitoring time in range (CGM-TIR) , mixed-meal tolerance test MMTT, and body weight (BW) . Results: Four Cohorts enrolled 36 patients (56%F/44%M; mean age 55yF/61yM) to receive ([Starting Dose]→[Titration Duration]→[Target Dose]) : Cohort 1 [60 mg][ no titration][60 mg]; Cohort 2 [30 mg][10 d][120 mg]; Cohort 3 [15 mg][20 d][180 mg]; Cohort 4 [15 mg][28 d][45 mg]. Adverse events (AEs) were reported by most subjects (100% C1 + C2; 88% C3; 83% C4; 78% pooled placebo) . Most AEs were of mild severity, drug-related for RGT-075 groups, and predominantly GI with no serious AEs or deaths. Baseline HbA1c was highly variable (7.2-9.0%) ; HbA1c mean changes from baseline ranged -0.6 to -1.2% across RGT-075 doses vs. -0.37% with placebo and correlated with FPG, CGM-TIR and MMTT results. BW mean change ranged -2.3 to -4.5 kg across RGT-075 doses vs -1.1 kg with placebo. RGT-075 plasma exposures increased as the dose levels increased. Conclusion: RGT-075 GLP1RA oral small molecule (15-180 mg/day) up to 28 days was safe and QD dosing showed promising exploratory efficacy trends despite high baseline variability and short treatment duration. Disclosure M. A. Pirner: Employee; Regor Pharmaceuticals, Inc. J. Lin: None. F. Liu: Employee; Regor Pharmaceuticals Inc. L. Yao: None. M. E. Zettler: Employee; Cardinal Health, Regor Pharmaceuticals Inc. D. J. Valacer: Employee; Regor Pharmaceuticals, Inc.

Changes in leaf litter decomposition of primary Korean pine forests after degradation succession into secondary broad-leaved forests.

Forest degradation succession often leads to changes in forest ecosystem functioning. Exactly how the decomposition of leaf litter is affected in a disturbed forest remains unknown. Therefore, in our study, we selected a primary Korean pine forest (PK) and a secondary broad‐leaved forest (SF) affected by clear‐cutting degradation, both in Northeast China. The aim was to explore the response to changes in the leaf litter decomposition converting PK to SF. The mixed litters of PK and SF were decomposed in situ (1 year). The proportion of remaining litter mass, main chemistry, and soil biotic and abiotic factors were assessed during decomposition, and then, we made an in‐depth analysis of the changes in the leaf litter decomposition. According to our results, leaf litter decomposition rate was significantly higher in the PK than that in the SF. Overall, the remaining percent mass of leaf litter's main chemical quality in SF was higher than in PK, indicating that leaf litter chemical turnover in PK was relatively faster. PK had a significantly higher amount of total phospholipid fatty acids (PLFAs) than SF during decomposition. Based on multivariate regression trees, the forest type influenced the soil habitat factors related to leaf litter decomposition more than decomposition time. Structural equation modeling revealed that litter N was strongly and positively affecting litter decomposition, and the changes in actinomycetes PLFA biomass played a more important role among all the functional groups. Selected soil abiotic factors were indirectly driving litter decomposition through coupling with actinomycetes. This study provides evidence for the complex interactions between leaf litter substrate and soil physical–chemical properties in affecting litter decomposition via soil microorganisms.

Altered structure and dynamics of pathogenic cytochrome c variants correlate with increased apoptotic activity.

Mutation of cytochrome c in humans causes mild autosomal dominant thrombocytopenia. The role of cytochrome c in platelet formation, and the molecular mechanism underlying the association of cytochrome c mutations with thrombocytopenia remains unknown, although a gain-of-function is most likely. Cytochrome c contributes to several cellular processes, with an exchange between conformational states proposed to regulate changes in function. Here, we use experimental and computational approaches to determine whether pathogenic variants share changes in structure and function, and to understand how these changes might occur. Three pathogenic variants (G41S, Y48H, A51V) cause an increase in apoptosome activation and peroxidase activity. Molecular dynamics simulations of these variants, and two non-naturally occurring variants (G41A, G41T), indicate that increased apoptosome activation correlates with the increased overall flexibility of cytochrome c, particularly movement of the Ω loops. Crystal structures of Y48H and G41T complement these studies which overall suggest that the binding of cytochrome c to apoptotic protease activating factor-1 (Apaf-1) may involve an 'induced fit' mechanism which is enhanced in the more conformationally mobile variants. In contrast, peroxidase activity did not significantly correlate with protein dynamics. Thus, the mechanism by which the variants increase peroxidase activity is not related to the conformational dynamics of the native hexacoordinate state of cytochrome c. Recent molecular dynamics data proposing conformational mobility of specific cytochrome c regions underpins changes in reduction potential and alkaline transition pK was not fully supported. These data highlight that conformational dynamics of cytochrome c drive some but not all of its properties and activities.

Is it time to move away from polymyxins?: evidence and alternatives.

Increasing burden of carbapenem resistance and resultant difficult-to-treat infections are of particular concern due to the lack of effective and safe treatment options. More recently, several new agents with activity against certain multidrug-resistant (MDR) and extensive drug-resistant (XDR) Gram-negative pathogens have been approved for clinical use. These include ceftazidime-avibactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam, plazomicin, and cefiderocol. For the management of MBL infections, clinically used triple combination comprising ceftazidime-avibactam and aztreonam is hindered due to non-availability of antimicrobial susceptibility testing methods and lack of information on potential drug-drug interaction leading to PK changes impacting its safety and efficacy. Moreover, in several countries including Indian subcontinent and developing countries, these new agents are yet to be made available. Under these circumstances, polymyxins are the only last resort for the treatment of carbapenem-resistant infections. With the recent evidence of suboptimal PK/PD particularly in lung environment, limited efficacy and increased nephrotoxicity associated with polymyxin use, the Clinical and Laboratory Standards Institute (CLSI) has revised both colistin and polymyxin B breakpoints. Thus, polymyxins 'intermediate' breakpoint for Enterobacterales, P. aeruginosa, and Acinetobacter spp. are now set at ≤ 2mg/L, implying limited clinical efficacy even for isolates with the MIC value 2mg/L. This change has questioned the dependency on polymyxins in treating XDR infections. In this context, recently approved cefiderocol and phase 3 stage combination drug cefepime-zidebactam assume greater significance due to their potential to act as polymyxin-supplanting therapies.

Differences in Utilization of Lower Limb Muscle Power in Squat Jump With Positive and Negative Load.

Jump performance is related to the ability of lower limb muscles to produce power during the push-off phase. However, it is not known if the power associated with the action of active and passive elements of the lower limb muscles change significantly in jumps with positive and negative loads. In this study, the power associated with the action of passive and active components of lower limb muscles as a whole in squat jumps (SJ) with increase and decrease in the external load is analyzed Fourteen trained male subjects (22.5 ± 2.1 years; 176.5 ± 5.4 cm; 75.8 ± 5.8 kg; BMI 24.3 ± 1.8) performed SJ on a force plate. A functional electromechanical dynamometer (FEMD) system was used to change the external load in a range of −30 to +30% of the subject’s body weight. A model comprising a mass, a spring, an active element, and a damper was used. We applied an optimization principle to determine power in center of mass (CoM) (ptot), the powers associated with active element (pact), damper (pƔ), and spring (pk) during the push-off phase. Significant differences between loading conditions for each variable were tested by repeated-measures one-way ANOVA with Bonferroni post hoc analysis, p < 0.05. Shapes of the average curves for instantaneous variation of pact, pƔ, pk, and ptot during push-off with positive loads were closer to 0% than with negative loads. As the load increased, maximum values of ptot, pƔ, and pk decreased. Only with a negative load of −30% did ptot increase significantly, this was not accompanied by changes in pact, pƔ, and pk. The load of one’s own body provides conditions for develop high pact peaks, although the maximum ptot is not achieved in that condition. The increase in negative loads produces a significant increase in ptot, but not in pact and can be interpreted as a situation in which the power delivered to the system by the action of active components is better used. The SJ with positive load, although more similar to the instantaneous changes that occur to the SJ with body weight are not gestures where high power is developed.

Preliminary Report of MANIFEST, a Phase 2 Study of CPI-0610, a Bromodomain and Extraterminal Domain Inhibitor (BETi), in Combination with Ruxolitinib, in JAK Inhibitor (JAKi) Treatment Naïve Myelofibrosis Patients

Preliminary Report of MANIFEST, a Phase 2 Study of CPI-0610, a Bromodomain and Extraterminal Domain Inhibitor (BETi), in Combination with Ruxolitinib, in JAK Inhibitor (JAKi) Treatment Naïve Myelofibrosis Patients