Sialic Acid Mediated Endothelial and Hepatic Uptake: A Mechanism based Mathematic Model Elucidating the Complex Pharmacokinetics and Pharmacodynamics of Efmarodocokin Alfa, a Variably Glycosylated Fusion Protein.

Sialic acid (SA) is crucial for protecting glycoproteins from clearance. Efmarodocokin alfa (IL-22Fc), a fusion protein agonist that links IL-22 to the crystallizable fragment (Fc) of human IgG4, contains 8 N-glycosylation sites and exhibits heterogeneous and variable terminal sialylation biodistribution. This presents a unique challenge for Pharmacokinetic (PK) and Pharmacodynamic (PD) analysis and cross-species translation. In this study, we sought to understand how varying SA levels and heterogeneous distribution contribute to IL-22Fc's complex PKPD properties. We initially used homogenous drug material with varying SA levels to examine PKPD in mice. Population PKPD analysis based on mouse data revealed that SA was a critical covariate simultaneously accounting for the substantial between subject variability (BSV) in clearance (CL), distribution clearance (CLd), and volume of distribution (Vd). In addition to the well-established mechanism by which SA inhibits ASGPR activity, we hypothesized a novel mechanism by which decrease in SA increases the drug uptake by endothelial cells. This decrease in SA, leading to more endothelial uptake, was supported by the neonatal Fc receptor (FcRn) dependent cell-based transcytosis assay. The population analysis also suggested in vivo EC50 (IL-22Fc stimulating Reg3ß) was independent on SA, while the in-vitro assay indicated a contradictory finding of SA-in vitro potency relationship. We created a mechanism based mathematical (MBM) PKPD model incorporating the decrease in SA mediated endothelial and hepatic uptake, and successfully characterized the SA influence on IL-22Fc PK, as well as the increased PK exposure being responsible for increased PD. Thereby, the MBM model supported that SA has no direct impact on EC50, aligning with the population PKPD analysis. Subsequently, using the MBM PKPD model, we employed 5 subpopulation simulations to reconstitute the heterogeneity of drug material. The simulation accurately predicted the PKPD of heterogeneously and variably sialylated drug in mouse, monkey and human. The successful prospective validation confirmed the MBM's ability to predict IL-22Fc PK across variable SA levels, homogenous to heterogeneous material, and across species (R2=0.964 for clearance prediction). Our model prediction suggests an average of 1 mol/mol SA increase leads to a 50% increase in drug exposure. This underlines the significance of controlling sialic acid levels during lot-to-lot manufacturing.

The paradoxical role of zinc on microglia.

Zinc is an essential trace element for humans, and its homeostasis is essential for the health of the central nervous system. Microglia, the resident immune cells in the central nervous system, play the roles of sustaining, nourishing, and immune surveillance. Microglia are sensitive to microenvironment changes and are easily activated to M1 phenotype to enhance disease progression or the M2 phenotype to improve peripheral nerves injury repair. Zinc is requisite for microglial activation, However, the cytotoxicity outcome of zinc against microglia, the activated microglia phenotype, and activated microglia function are ambiguous. Herein, we have reviewed the neurological function of zinc and microglia, particularly the ambiguous role of zinc on microglia. We also pay attention to the role of zinc homeostasis on microglial function within the central nervous system disease. Finally, we observe the relationship between zinc and microglia, attempting to design new therapeutic measures against major nervous system disorders.

Tuning Redistribution of CuOx Nanoparticles on TiO2 Support.

Nanoparticles exhibit unique catalytic performance, depending on their nanoscale size. However, controlling the particle size of the supported catalysts is still challenging. Here, we present a method for tunable redistribution of CuOx nanoparticles on rutile TiO2 support by physically adding pristine TiO2. The redistribution is driven by the work function difference (WFD) between the TiO2 support and the TiO2 additive, both of which exhibit distinct values, as determined through Kelvin probe force microscopy and electron binding energy analysis. Addition of TiO2 with lower work function (rutile) promotes electron transfer toward the CuOx/TiO2 composite, resulting in nanoparticle aggregation, while addition of TiO2 with higher work function (anatase) results in smaller CuOx on TiO2. The increase in particle size and electron density of CuOx, driven by the addition of rutile TiO2, promoted the complete conversion of nitrobenzene (100%) within 5 h. This is 2.7 times that of dispersed and degraded CuOx driven by mixing with anatase TiO2 (36.9%).

Impact of climate change on the geographical distribution and niche dynamics of Gastrodia elata.

Background: Gastrodia elata is widely used in China as a valuable herbal medicine. Owing to its high medicinal and nutrient value, wild resources of G. elata have been overexploited and its native areas have been severely damaged. Understanding the impacts of climate change on the distribution of this endangered species is important for the conservation and sustainable use of G. elata. Methods: We used the optimized maximum entropy model to simulate the potential distribution of G. elata under contemporary and future time periods (1970-2000, 2050s, 2070s, and 2090s) and different climate change scenarios (SSP1-2.6, SSP2-4.5, SSP3-7.0, and SSP5-8.5). Under these conditions, we investigated the key environmental factors influencing the distribution of G. elata as well as the spatial and temporal characteristics of its niche dynamics. Results: With high Maxent model accuracy (AUCmean = 0.947 ± 0.012, and the Kappa value is 0.817), our analysis revealed that annual precipitation, altitude, and mean temperature of driest quarter are the most important environmental factors influencing the distribution of G. elata. Under current bioclimatic conditions, the potentially suitable area for G. elata in China is 71.98 × 104 km2, while the highly suitable region for G. elata growth is 7.28 × 104 km2. Our models for three future periods under four climate change scenarios indicate that G. elata can maintain stable distributions in southern Shaanxi, southwestern Hubei, and around the Sichuan basin, as these areas are highly suitable for its growth. However, the center of the highly suitable areas of G. elata shift depending on different climatic scenarios. The values of niche overlap for G. elata show a decreasing trend over the forecasted periods, of which the niche overlap under the SSP3-7.0 scenario shows the greatest decrease. Discussions: Under the condition of global climate change in the future, our study provides basic reference data for the conservation and sustainable utilization of the valuable and endangered medicinal plant G. elata. It is important to carefully choose the protection area of G. elata wild resources according the suitable area conditions modeled. Moreover, these findings will be valuable for providing insights into the breeding and artificial cultivation of this plant, including the selection of suitable areas for planting.

Dose escalation randomised study of efmarodocokin alfa in healthy volunteers and patients with ulcerative colitis.

BACKGROUND: The interleukin-22 cytokine (IL-22) has demonstrated efficacy in preclinical colitis models with non-immunosuppressive mechanism of action. Efmarodocokin alfa (UTTR1147A) is a fusion protein agonist that links IL-22 to the crystallisable fragment (Fc) of human IgG4 for improved pharmacokinetic characteristics, but with a mutation to minimise Fc effector functions. METHODS: This randomised, phase 1b study evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of repeat intravenous dosing of efmarodocokin alfa in healthy volunteers (HVs; n=32) and patients with ulcerative colitis (n=24) at 30-90 µg/kg doses given once every 2 weeks or monthly (every 4 weeks) for 12 weeks (6:2 active:placebo per cohort). RESULTS: The most common adverse events (AEs) were on-target, reversible, dermatological effects (dry skin, erythema and pruritus). Dose-limiting non-serious dermatological AEs (severe dry skin, erythema, exfoliation and discomfort) were seen at 90 µg/kg once every 2 weeks (HVs, n=2; patients, n=1). Pharmacokinetics were generally dose-proportional across the dose levels, but patients demonstrated lower drug exposures relative to HVs at the same dose. IL-22 serum biomarkers and IL-22-responsive genes in colon biopsies were induced with active treatment, and microbiota composition changed consistent with a reversal in baseline dysbiosis. As a phase 1b study, efficacy endpoints were exploratory only. Clinical response was observed in 7/18 active-treated and 1/6 placebo-treated patients; clinical remission was observed in 5/18 active-treated and 0/6 placebo-treated patients. CONCLUSION: Efmarodocokin alfa had an adequate safety and pharmacokinetic profile in HVs and patients. Biomarker data confirmed IL-22R pathway activation in the colonic epithelium. Results support further investigation of this non-immunosuppressive potential inflammatory bowel disease therapeutic. TRIAL REGISTRATION NUMBER: NCT02749630.

Astegolimab or Efmarodocokin Alfa in Patients With Severe COVID-19 Pneumonia: A Randomized, Phase 2 Trial.

OBJECTIVES: Severe cases of COVID-19 pneumonia can lead to acute respiratory distress syndrome (ARDS). Release of interleukin (IL)-33, an epithelial-derived alarmin, and IL-33/ST2 pathway activation are linked with ARDS development in other viral infections. IL-22, a cytokine that modulates innate immunity through multiple regenerative and protective mechanisms in lung epithelial cells, is reduced in patients with ARDS. This study aimed to evaluate safety and efficacy of astegolimab, a human immunoglobulin G2 monoclonal antibody that selectively inhibits the IL-33 receptor, ST2, or efmarodocokin alfa, a human IL-22 fusion protein that activates IL-22 signaling, for treatment of severe COVID-19 pneumonia. DESIGN: Phase 2, double-blind, placebo-controlled study (COVID-astegolimab-IL). SETTING: Hospitals. PATIENTS: Hospitalized adults with severe COVID-19 pneumonia. INTERVENTIONS: Patients were randomized to receive IV astegolimab, efmarodocokin alfa, or placebo, plus standard of care. The primary endpoint was time to recovery, defined as time to a score of 1 or 2 on a 7-category ordinal scale by day 28. MEASUREMENTS AND MAIN RESULTS: The study randomized 396 patients. Median time to recovery was 11 days (hazard ratio [HR], 1.01 d; p = 0.93) and 10 days (HR, 1.15 d; p = 0.38) for astegolimab and efmarodocokin alfa, respectively, versus 10 days for placebo. Key secondary endpoints (improved recovery, mortality, or prevention of worsening) showed no treatment benefits. No new safety signals were observed and adverse events were similar across treatment arms. Biomarkers demonstrated that both drugs were pharmacologically active. CONCLUSIONS: Treatment with astegolimab or efmarodocokin alfa did not improve time to recovery in patients with severe COVID-19 pneumonia.

Overall Survival Benefit in Rectal Cancer After Neoadjuvant Radiotherapy and Adjuvant Chemotherapy: A Propensity-Matched Population-Based Study.

BACKGROUND: It is well known that neoadjuvant radiotherapy could reduce local recurrence followed by surgical resection. However, evidence about oncologic efficacy of radiotherapy and survival benefit of adjuvant chemotherapy after neoadjuvant radiotherapy is still lacking. METHODS: This retrospective propensity score-matched cohort study identified patients with pathologically confirmed rectal cancer and receiving surgery with curative intent from the Surveillance, Epidemiology, and End Results database from 2004 through 2014. Overall survival was compared using the stratified log-rank test. Multivariate Cox regression analysis was used for identifying risk factor and developing prediction nomogram. RESULTS: A total of 22,008 (11,004 for each group) propensity-matched patients were identified. In the context of receiving adjuvant chemotherapy after surgical resection, there was no significant difference in terms of overall survival between surgery alone group and neoadjuvant radiotherapy and surgery group, whether for stage I (log-rank test p = 0.467), stage II (log-rank test p = 0.310), or stage III (p = 0.994). In case of receiving a prior combination therapy of neoadjuvant radiotherapy and surgery, the following adjuvant chemotherapy could significantly improve overall survival for patients with stage I (log-rank test p <0.001), stage II (log-rank test p = 0.038), and stage III (log-rank test p = 0.014). Nomogram integrating clinicopathologic factors was developed to predict survival benefit associated with neoadjuvant radiotherapy. Calibration and ROC curves validated promising performance for the nomogram. CONCLUSION: Patients with rectal cancer underwent neoadjuvant radiotherapy yield acceptable outcomes and are more likely to benefit from adjuvant chemotherapy in terms of overall survival. These data would be evidential for advocating consistency in guideline adherence to the use of adjuvant chemotherapy after neoadjuvant radiotherapy.

The Peroxisome Proliferator-Activated Receptor γ Agonist Pioglitazone Protects Vascular Endothelial Function in Hypercholesterolemic Rats by Inhibiting Myeloperoxidase.

OBJECTIVE: Hypercholesterolemia- (HC-) induced endothelial dysfunction is the first step of atherogenesis, and the peroxisome proliferator-activated receptor γ (PPARγ (PPARγ (PPARγ) has been reported to attenuate atherosclerosis formation; however, the underlying mechanisms are not fully understood. The present study was designed to determine whether myeloperoxidase (MPO) mediates HC-induced endothelial dysfunction and the role of the PPARγ agonist pioglitazone (PIO) in attenuating endothelial dysfunction. METHODS: Male Wistar rats were fed with normal or high cholesterol diets for 8 weeks. HC rats were randomized to receive dapsone (DDS, the MPO inhibitor) during the last 6 days or PIO for the remaining 4 weeks. Vascular endothelial function was determined by comparing vasorelaxation to ACh, an endothelium-dependent vasodilator, and SNP, an endothelium-independent vasodilator in vascular rings in vitro. The vascular MPO activity, NO x content, and cGMP level were measured by the MPO activity assay kit, NO assay kit, and cGMP RIA kit. RESULTS: Compared with rats fed with normal diet, endothelium-dependent vasodilation, NO x content, and cGMP level were decreased, and MPO activity was increased in thoracic aortas of rats fed with HC diet. There was a negative correlation between vascular endothelial function, NO x content or cGMP level, and MPO activity. PIO obviously reduced the MPO activity, increased NO x content and cGMP level, and improved endothelium-dependent vasodilation function in HC rats, which was essentially the same as that seen with DDS. And, there was a negative correlation between vascular endothelial function, NO x content or cGMP level, and MPO activity in the HC group and the PIO intervention group. CONCLUSION: MPO might provoke vascular endothelial dysfunction in hypercholesterolemic rats by reducing the NO biological activity and impairing the NO/cGMP/cGK signaling pathway. PIO might inhibit vascular MPO activity and increase NO bioavailability with the net result of reversing endothelial dysfunction.

Inhibition of TRIM32 Induced by miR-519d Increases the Sensitivity of Colorectal Cancer Cells to Cisplatin.

BACKGROUND: Colorectal cancer is a leading cause of cancer-related death in the world. Despite cisplatin is a commonly used chemotherapeutic drug for the colorectal cancer treatment, resistance of cancer cells to cisplatin restricts its clinical efficacy. It is important to explore the potential mechanisms and take strategies to sensitize colorectal cancer cells to cisplatin treatment. METHODS: Differences of TRIM32 and miR-519d expression between colorectal cancer cells and human normal colon epithelial cells were evaluated by qRT-PCR and Western blot assays. Cytotoxicity of cisplatin against colorectal cancer cells was tested by CCK-8 assay. Generation of reactive oxygen species (ROS), mitochondrial membrane potential and apoptosis was measured by flow cytometry. Dual-luciferase reporter assay was used to validate the association between miR-519d and TRIM32. RESULTS: Significant increase of TRIM32 expression in colorectal cancer tissues and cell lines was observed. TRIM32 negatively regulated the cisplatin sensitivity in colorectal cancer cells. Mechanically, overexpression of TRIM32 was induced by decrease of miR-519d. Exogenous miR-519d can inhibit the expression of TRIM32 and thus promoted the cisplatin-induced apoptosis through the mitochondrial pathway. CONCLUSION: Overexpression of TRIM32 was induced by the absence of miR-519d in colorectal cancer. MiR-519d can be used as a sensitizer during the cisplatin-based chemotherapy of colorectal cancer.

Buccal Mucosa Assessed by Ultrasonography in Healthy Adults: Methodology and Determination of Normal Appearance.

The aim of the work described here was to compare intra-oral and transcutaneous ultrasonography (US) scanning and to determine the normal values of buccal mucosa thickness and echogenicity. A total of 190 volunteers underwent US examination of the buccal mucosa. The thickness of the buccal epithelial layer was recorded in 19 subjects via both intra-oral and transcutaneous methods. Overall, 171 healthy adults were examined through intra-oral US. Buccal epithelial layer measurement was unreliable via the transcutaneous method (p = 0.001). The mean time required for visualizing the buccal mucosa was 75 and 171s with intra-oral and transcutaneous US, respectively (p < 0.001). The thickness of the buccal epithelial layers significantly differed with age and sex (p < 0.001), and was positively correlated with height, weight and body surface area. Intra-oral US was proposed as a conventional method for examination of the buccal mucosa. Normal buccal epithelial thickness in adults is associated with age, sex, height, weight and body surface area.

Randomized Phase I Healthy Volunteer Study of UTTR1147A (IL-22Fc): A Potential Therapy for Epithelial Injury.

Most treatments for epithelial injury target hematopoietic mechanisms, possibly causing immunosuppression. Interleukin (IL)-22 promotes tissue regeneration, acting directly on epithelial cells. UTTR1147A, a human IL-22Fc (immunoglobulin G (IgG)4) fusion protein, activates IL-22 signaling. This phase I placebo-controlled trial of single, ascending, i.v. (1-120 µg/kg) and s.c (3-120 µg/kg) doses of UTTR1147A analyzed its effects on safety, tolerability, pharmacokinetics, and pharmacodynamic biomarkers in healthy volunteers. Most adverse events (AEs) were mild or moderate. The maximum tolerated i.v. dose in healthy volunteers was 90 µg/kg. Predominant AEs were dose-dependent reversible skin effects consistent with IL-22 pharmacology. UTTR1147A exposure increased approximately dose-proportionally, with a half-life of ~1 week. IL-22 biomarkers (regenerating islet protein 3A (REG3A), serum amyloid A (SAA), and C-reactive protein (CRP)) increased dose-dependently. Neither inflammatory symptoms and signs nor cytokines increased with CRP elevations. UTTR1147A demonstrated acceptable safety, pharmacokinetics, and IL-22R engagement, supporting further clinical development.

Capping experiments reveal multiple surface active sites in CeO2 and their cooperative catalysis.

Understanding of surface active sites (SAS) of CeO2 is crucial to its catalytic applications. In the present study, we have employed capping experiments, DFT calculations, and spectroscopic characterization to study pristine CeO2 catalyst. We find that multiple SAS coexist on the CeO2 surface: oxygen vacancies as redox sites and the coordinately unsaturated Ce cations near the oxygen vacancies and the neighboring oxygen ions as Lewis acid-base sites. Dimethylsulfoxide (DMSO), pyridine, and benzoic acid are utilized to cap the redox sites, Lewis acid sites, and base sites, respectively. Selective capping on the redox site does not have much effect on the acid-base catalysis, and vice versa, indicating the distinct surface proximity and independent catalysis of these SAS. We draw attention to a relationship between the well-known redox sites and the surface Lewis acid and Lewis base pairs on CeO2 surface, which are responsible for driving various heterogeneous catalytic reactions.

Effectiveness of metal oxide catalysts for the degradation of 1,4-dioxane.

1,4-dioxane, commonly used as a solvent stabilizer and industrial solvent, is an environmental contaminant and probable carcinogen. In this study, we explored the concept of using metal oxides to activate H2O2 catalytically at neutral pH in the dark for 1,4-dioxane degradation. Based on batch kinetics measurements, materials that displayed the most suitable characteristics (high 1,4-dioxane degradation activity and high H2O2 consumption efficiency) were ZrO2, WO x /ZrO2, and CuO. In contrast, materials like TiO2, WO3, and aluminosilicate zeolite Y exhibited both low 1,4-dioxane degradation and H2O2 consumption activities. Other materials (e.g., Fe2O3 and CeO2) consumed H2O2 rapidly, however 1,4-dioxane degradation was negligible. The supported metal oxide WO x /ZrO2 was the most active for 1,4-dioxane degradation and had higher H2O2 consumption efficiency compared to ZrO2. In situ acetonitrile poisoning and FTIR spectroscopy results indicate different surface acid sites for 1,4-dioxane and H2O2 adsorption and reaction. Electron paramagnetic resonance measurements indicate that H2O2 forms hydroxyl radicals (˙OH) in the presence of CuO, and unusually, forms superoxide/peroxyl radicals (˙O2 -) in the presence of WO x /ZrO2. The identified material properties suggest metal oxides/H2O2 as a potential advanced oxidation process in the treatment of 1,4-dioxane and other recalcitrant organic compounds.

Selective production of phase-separable product from a mixture of biomass-derived aqueous oxygenates.

Selective conversion of an aqueous solution of mixed oxygenates produced by biomass fermentation to a value-added single product is pivotal for commercially viable biomass utilization. However, the efficiency and selectivity of the transformation remains a great challenge. Herein, we present a strategy capable of transforming ~70% of carbon in an aqueous fermentation mixture (ABE: acetone-butanol-ethanol-water) to 4-heptanone (4-HPO), catalyzed by tin-doped ceria (Sn-ceria), with a selectivity as high as 86%. Water (up to 27 wt%), detrimental to the reported catalysts for ABE conversion, was beneficial for producing 4-HPO, highlighting the feasibility of the current reaction system. In a 300 h continuous reaction over 2 wt% Sn-ceria catalyst, the average 4-HPO selectivity is maintained at 85% with 50% conversion and > 90% carbon balance. This strategy offers a route for highly efficient organic-carbon utilization, which can potentially integrate biological and chemical catalysis platforms for the robust and highly selective production of value-added chemicals.

Measurement of IL-17AA and IL-17FF as Pharmacodynamic Biomarkers to Demonstrate Target Engagement in the Phase I Study of MCAF5352A.

The interleukin (IL)-17 pathway has been implicated in the pathophysiology of many autoimmune diseases. MCAF5352A is a humanized monoclonal antibody which targets both IL-17A and IL-17F, thereby inhibiting the activity of IL-17 dimers (IL-17AA, IL-17AF, and IL-17FF). The pharmacokinetic profile of MCAF5352A has been characterized in both a Phase Ia single ascending dose study and a Phase Ib multiple ascending dose study. Two qualified enzyme-linked immunosorbent assays were used to measure total IL-17AA and IL-17FF levels in serum as pharmacodynamic biomarkers in the Phase I studies. The two assays demonstrated specificity for IL-17AA or IL-17FF with sensitivity at low picogram/milliliter levels. The assay precision and accuracy also met acceptance criteria. Although total serum IL-17AA and IL-17FF levels were below the assay detection limits prior to administration of MCAF5352A, post-treatment levels in both the single and multiple dose cohorts became detectable and increased in a dose-dependent manner. These data are consistent with target engagement by MCAF5352A. Our work highlights bioanalytical challenges encountered while developing biomarker assays requiring high sensitivity and specificity. Data generated using these assays enabled the confirmation of target engagement during early clinical drug development.

The Synthesis of Quinazolinones from Olefins, CO, and Amines over a Heterogeneous Ru-clusters/Ceria Catalyst.

Quinazolinones, an important class of heterocyclic compounds, have been widely used in pharmaceuticals because of their biological activity. However, the efficient and economical synthesis of quinazolinones has remained a challenge. A novel synthetic approach has now been developed to produce quinazolinones from olefins, CO, and amines over heterogeneous Ru-clusters/ceria catalyst in the absence of acids, bases, and oxidants. Furthermore, H2 O is generated as the only by-product. A series of quinazolinones with aromatic or non-aromatic substituents can be obtained in yields of up to 99 %. The Ru-clusters/ceria can be reused at least four times. The analysis of the E-factor (environmental impact factor) for the synthesis of 2-ethyl quinazolinone suggests that this system is more environmentally friendly than other processes reported previously.

Acid-Promoter-Free Ethylene Methoxycarbonylation over Ru-Clusters/Ceria: The Catalysis of Interfacial Lewis Acid-Base Pair.

The interface of metal-oxide plays pivotal roles in catalytic reactions, but its catalytic function is still not clear. In this study, we report the high activity of nanostructured Ru/ceria (Ru-clusters/ceria) in the ethylene methoxycarbonylation (EMC) reaction in the absence of acid promoter. The catalyst offers 92% yield of MP with TOF of 8666 h-1, which is about 2.5 times of homogeneous Pd catalyst (∼3500 h-1). The interfacial Lewis acid-base pair [Ru-O-Ce-Vö], which consists of acidic Ce-Vö (oxygen vacancy) site and basic interfacial oxygen of Ru-O-Ce linkage, acts as active site for the dissociation of methanol and the subsequent transfer of hydrogen to the activated ethylene, which is the key step in acid-promoter-free EMC reaction. The combination of 1H MAS NMR, pyridine-IR and DFT calculations reveals the hydrogen species derived from methanol contains Brönsted acidity. The EMC reaction mechanism under acid-promoter-free condition over Ru-clusters/ceria catalyst is discussed.

Pharmacokinetic and Pharmacodynamic Modeling of Serum Etrolizumab and Circulating ß7 Receptor Occupancy in Patients With Ulcerative Colitis.

Etrolizumab, a humanized monoclonal antibody, specifically binds to the ß7 subunit of the heterodimeric integrins α4ß7 and αEß7. Pharmacokinetic (PK) and pharmacodynamic (PD) data were collected from an etrolizumab phase 1 trial in patients with moderate to severe ulcerative colitis (UC). We developed a mechanism-based model to simultaneously describe the kinetics of serum etrolizumab concentration and free ß7 receptors on circulating intestinal-homing CD4+ T lymphocytes. Included in the analysis were 38 phase 1 UC patients who received single or 3 monthly doses of etrolizumab intravenously or subcutaneously across a dose range of 0.3 to 10 mg/kg. A quasi-steady-state target-mediated drug disposition model was developed to describe the dynamic interaction between serum etrolizumab concentration and free ß7 receptors on intestinal-homing CD4+ T lymphocytes in UC patients. The time profiles of serum etrolizumab and absolute counts of ß7+ lymphocytes (expressed as percentage of baseline level) were well described by the quasi-steady-state target-mediated drug disposition model. The model was able to characterize the maximum drug occupancy of ß7 receptors on intestinal-homing CD4+ T lymphocytes and the concentration-dependent duration of occupancy. The 90% effective concentration for etrolizumab to saturate the ß7 receptors on intestinal homing CD4+ T cells was 1.3 µg/mL. PK and PD profiles predicted by the model were consistent with observations from a subsequent phase 2 study. In conclusion, an integrated PK/PD model developed in this analysis reasonably described serum etrolizumab PK profiles and the relationship between PK and PD (free ß7 receptors on circulating intestinal-homing CD4+ T lymphocytes) in UC patients.

Pharmacokinetics and Exposure-Response Analysis of RG7667, a Combination of Two Anticytomegalovirus Monoclonal Antibodies, in a Phase 2a Randomized Trial To Prevent Cytomegalovirus Infection in High-Risk Kidney Transplant Recipients.

RG7667, a novel combination of two anticytomegalovirus (anti-CMV) monoclonal IgG1 antibodies (MCMV5322A and MCMV3068A), was designed to block CMV entry into host cells. It was developed as a potential therapy for preventing CMV infection and disease in transplant recipients. RG7667 was assessed for preventing CMV infection in a phase 2a trial with CMV-seronegative recipients of kidney transplants from CMV-seropositive donors. The patients received 4 intravenous doses of RG7667 (10 mg/kg of body weight of each antibody, n = 60) or placebo (n = 60) at the time of the transplant and at 1, 4, and 8 weeks after the transplant. Serum samples were collected for pharmacokinetic (PK) analysis and antidrug antibody (ADA) evaluation. To guide future dose selection, the relationships between RG7667 exposure and pharmacological activity were evaluated. MCMV5322A and MCMV3068A exposures were confirmed in all RG7667-treated patients. Mean clearances for MCMV5322A and MCMV3068A were 2.97 and 2.65 ml/day/kg, respectively, and the terminal half-lives of MCMV5322A and MCMV3068A were 26.9 and 27.4 days, respectively. The ADA incidence was low and was not associated with lower drug exposure. Patients with RG7667 or component antibody exposures greater than the respective median values had a lower incidence of viremia at 12 weeks and 24 weeks after transplantation and a longer delayed time to detectable CMV viremia than patients with exposures less than the median values. MCMV5322A and MCMV3068A exhibited expected IgG1 PK profiles in high-risk kidney transplant recipients, consistent with the earlier PK behavior of RG7667 in healthy subjects. Higher drug exposure was associated with better anti-CMV pharmacological activity. (This study has been registered at ClinicalTrials.gov under identifier NCT01753167.).

PPARγ Agonist Ameliorates the Impaired Fluidity of the Myocardial Cell Membrane and Cardiac Injury in Hypercholesterolemic Rats.

Hypercholesterolemia can increase the risk of cardiac injury, but the underlying mechanisms are not fully understood. The present study aimed to determine whether changes in the fluidity of the cardiomyocyte membrane may contribute to the increased susceptibility to myocardial ischemia/reperfusion (MI/R) injury observed in hypercholesterolemic rats. Male Wistar rats were fed a normal (n = 24) or high-cholesterol diet (n = 32) for 10 weeks. At the 6th week, the rats in the high-cholesterol diet group were treated with vehicle (n = 16, HC + V) or pioglitazone (n = 16, HC + PIO), a peroxisome proliferator-activated receptor-γ (PPARγ) agonist, and treatment lasted for the next 4 weeks. Rats in HC + V group displayed less membrane fluidity, a greater membrane cholesterol-to-phospholipid ratio (C/P), less Na+-K+-ATPase activity, and less cAMP content in their myocardial cells than rats fed a normal diet. A strong positive correlation was observed between membrane fluidity and cardiac injury, i.e., the myocardial infarct size when subjected to MI/R (30 min/24 h). Treatment with PIO restored much of the lost hypercholesterolemia-induced myocardial cell membrane fluidity, decreased membrane C/P ratio, increased Na+-K+-ATPase activity and cardiac cell cAMP content, improved cardiac function, and reduced the sizes of myocardial infarcts. Results demonstrated that hypercholesterolemia-induced decreased myocardial cell membrane fluidity may contribute to the increased susceptibility to cardiac injury, and PPARγ agonists may have therapeutic value in patients with hypercholesterolemia.