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Purpose: To assess the preclinical efficacy, clinical safety and efficacy, and MTD of palbociclib plus nab-paclitaxel in patients with advanced pancreatic ductal adenocarcinoma (PDAC). Experimental Design: Preclinical activity was tested in patient-derived xenograft (PDX) models of PDAC. In the open-label, phase I clinical study, the dose-escalation cohort received oral palbociclib initially at 75 mg/day (range, 50‒125 mg/day; modified 3+3 design; 3/1 schedule); intravenous nab-paclitaxel was administered weekly for 3 weeks/28-day cycle at 100‒125 mg/m2. The modified dose–regimen cohorts received palbociclib 75 mg/day (3/1 schedule or continuously) plus nab-paclitaxel (biweekly 125 or 100 mg/m2, respectively). The prespecified efficacy threshold was 12-month survival probability of ≥65% at the MTD. Results: Palbociclib plus nab-paclitaxel was more effective than gemcitabine plus nab-paclitaxel in three of four PDX models tested; the combination was not inferior to paclitaxel plus gemcitabine. In the clinical trial, 76 patients (80% received prior treatment for advanced disease) were enrolled. Four dose-limiting toxicities were observed [mucositis (n = 1), neutropenia (n = 2), febrile neutropenia (n = 1)]. The MTD was palbociclib 100 mg for 21 of every 28 days and nab-paclitaxel 125 mg/m2 weekly for 3 weeks in a 28-day cycle. Among all patients, the most common all-causality any-grade adverse events were neutropenia (76.3%), asthenia/fatigue (52.6%), nausea (42.1%), and anemia (40.8%). At the MTD (n = 27), the 12-month survival probability was 50% (95% confidence interval, 29.9–67.2). Conclusions: This study showed the tolerability and antitumor activity of palbociclib plus nab-paclitaxel treatment in patients with PDAC; however, the prespecified efficacy threshold was not met. Trial Registration: Pfizer Inc (NCT02501902) Significance: In this article, the combination of palbociclib, a CDK4/6 inhibitor, and nab-paclitaxel in advanced pancreatic cancer evaluates an important drug combination using translational science. In addition, the work presented combines preclinical and clinical data along with pharmacokinetic and pharmacodynamic assessments to find alternative treatments for this patient population.

Purpose:To assess the preclinical efficacy, clinical safety and efficacy, and MTD of palbociclib plus nab-paclitaxel in patients with advanced pancreatic ductal adenocarcinoma (PDAC).Experimental Design:Preclinical activity was tested in patient-derived xenograft (PDX) models of PDAC. In the open-label, phase I clinical study, the dose-escalation cohort received oral palbociclib initially at 75 mg/day (range, 50‒125 mg/day; modified 3+3 design; 3/1 schedule); intravenous nab-paclitaxel was administered weekly for 3 weeks/28-day cycle at 100‒125 mg/m2. The modified dose–regimen cohorts received palbociclib 75 mg/day (3/1 schedule or continuously) plus nab-paclitaxel (biweekly 125 or 100 mg/m2, respectively). The prespecified efficacy threshold was 12-month survival probability of ≥65% at the MTD.Results:Palbociclib plus nab-paclitaxel was more effective than gemcitabine plus nab-paclitaxel in three of four PDX models tested; the combination was not inferior to paclitaxel plus gemcitabine. In the clinical trial, 76 patients (80% received prior treatment for advanced disease) were enrolled. Four dose-limiting toxicities were observed [mucositis (n = 1), neutropenia (n = 2), febrile neutropenia (n = 1)]. The MTD was palbociclib 100 mg for 21 of every 28 days and nab-paclitaxel 125 mg/m2 weekly for 3 weeks in a 28-day cycle. Among all patients, the most common all-causality any-grade adverse events were neutropenia (76.3%), asthenia/fatigue (52.6%), nausea (42.1%), and anemia (40.8%). At the MTD (n = 27), the 12-month survival probability was 50% (95% confidence interval, 29.9–67.2).Conclusions:This study showed the tolerability and antitumor activity of palbociclib plus nab-paclitaxel treatment in patients with PDAC; however, the prespecified efficacy threshold was not met.Trial Registration:Pfizer Inc (NCT02501902)Significance:In this article, the combination of palbociclib, a CDK4/6 inhibitor, and nab-paclitaxel in advanced pancreatic cancer evaluates an important drug combination using translational science. In addition, the work presented combines preclinical and clinical data along with pharmacokinetic and pharmacodynamic assessments to find alternative treatments for this patient population.

Supplementary Materials and Methods

Supplementary Table S3 from A Preclinical and Phase Ib Study of Palbociclib plus Nab-Paclitaxel in Patients with Metastatic Adenocarcinoma of the Pancreas

The NH3-SCO reaction mechanism over a Pt/TiO2 catalyst was transferred into the i-SCR mechanism after adding CuSO4, and thus the formation of N2 was promoted.

This phase 1, open-label, single-arm clinical trial evaluated pharmacokinetics, safety, and biomarker activity of palbociclib-letrozole as first-line treatment for estrogen receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer (ABC) in postmenopausal Chinese women to support palbociclib approval in China. Patients received palbociclib 125 mg once daily (3/1 schedule) plus letrozole 2.5 mg once daily. Blood samples were collected predose and ≤ 120 h after single and multiple doses of palbociclib. The incidence and severity of adverse events were reported. Skin biopsy tissues and blood samples were collected for biomarker assessments. By 31 July 2018, 26 patients were enrolled. After single and multiple dosing, palbociclib maximum plasma concentration was 82.14 and 139.7 ng/mL, apparent clearance was 52.40 and 49.97 L/h, AUCτ was 1217 and 2501 ng∙h/mL, and t½ was 23.46 and 27.26 h, respectively. Levels of Ki67, retinoblastoma protein, and thymidine kinase decreased after palbociclib treatment. A similar safety profile as previously reported was observed. Pharmacokinetic and pharmacodynamic effects of palbociclib were well characterized in Chinese patients with ABC. Despite higher exposure, pharmacokinetic parameters were similar to those of a previously studied non-Asian population. No palbociclib dose adjustment based on Chinese ethnicity is needed. Palbociclib-letrozole had a manageable safety profile. NCT02499146

AimThis phase I study investigated talazoparib pharmacokinetics (PK) and safety in patients with advanced solid tumours and varying degrees of hepatic function.MethodsPatients with advanced solid tumours and normal hepatic function or varying degrees of hepatic impairment (mild, moderate or severe, based on National Cancer Institute Organ Dysfunction Working Group classification) received talazoparib 0.5mg once daily for 22 calendar days. Plasma and urine samples after single and multiple doses were collected and analysed for talazoparib using validated assays. Plasma PK data from all patients were analysed using the population PK method. Plasma and urine PK parameters in PK-evaluable patients were calculated using noncompartmental analysis (NCA). Safety was monitored in all enrolled patients.ResultsThirty-eight patients were enrolled; 37 had ≥1 PK concentration, among which 17 were evaluable for NCA. Population PK analysis (n = 37) indicated no significant impact of hepatic function on apparent clearance (CL/F) of talazoparib. Baseline creatinine clearance was the only significant covariate on CL/F (α = 0.05). NCA of data (n = 17) showed no clear trend for increase in exposure on day 22 with worsening hepatic function. Talazoparib protein binding was comparable in patients with varying hepatic function. Talazoparib was generally well tolerated, and the safety profile observed in this study was consistent with the known safety profile of the drug.ConclusionsHepatic impairment (mild, moderate or severe) has no impact on the PK of talazoparib. No dose modification is recommended for patients with advanced solid tumours and various degrees of hepatic impairment, and this labelling language has been approved by the US Food and Drug Administration and the European Medicines Agency.

CuO@TiO2 core–shell nanostructure catalyst with CuO core and TiO2 shell was prepared by a two-step method and then used in NH3-SCR reaction. FE-SEM, TEM and element mapping were used to investigate the morphologies of the sample. Their results indicated CuO nanorods were coated with TiO2 and thus forming a core–shell nanostructure. According to the results of N2 adsorption–desorption, XRD, Raman, XPS, NH3-TPD, H2-TPR and in situ DRIFTS, the core–shell nanostructure would benefit the formation of better redox ability, more oxygen vacancies, more acid sites and abundant adsorbed NOx species on the catalyst. Thus, the core–shell nanostructure catalyst presented significantly higher activity than pure CuO and TiO2. NH3-SCR reaction on CuO@TiO2 core–shell catalyst should follow both Eley–Rideal (E-R) mechanism and Langmuir-Hinshewood (L–H) mechanism. These findings may promote the development of the new effective non-vanadium-based SCR catalysts.

The objective for the present analyses was to evaluate the utility of physiologically-based pharmacokinetic (PBPK) modeling for prediction of the pharmacokinetics (PK) in Chinese and Japanese populations with a panel of Pfizer internal compounds. Twelve compounds from Pfizer internal development pipeline with available Westerner PK data and available PK data in at least one of the subpopulations of Japanese and Chinese populations were identified and included in the current analysis. These selected compounds represent various elimination pathways across different therapeutic areas. The Simcyp® PBPK simulator was used to develop and verify the PBPK models of individual compounds. The developed models for these compounds were verified by using the clinical PK data in Westerners. The verified PBPK models were further used to predict the PK of these compounds in Chinese and Japanese populations and the predicted PK parameters were compared with the observed PK parameters. Ten of the 12 compounds had PK data in Chinese, and all the 12 compounds had PK data in Japanese. In general, the PBPK models performed well in predicting PK in Chinese and Japanese, with 8 of 10 drugs in Chinese and 7 of 12 drugs in Japanese has AAFE values less than 1.25-fold. PBPK-guided predictions of the relative PK difference were successful for 75% and 50%, respectively, between Chinese and Western and between Japanese and Western of the tested drugs using 0.8-1.25 as criteria. In conclusion, well verified PBPK models developed using data from Westerners can be used to predict the PK in Chinese and Japanese populations.

Background Palbociclib is indicated for hormone receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer (ABC). Objective Exposure-response analyses were conducted to evaluate efficacy in Asian versus non-Asian patients and in patients with versus without dose reduction in PALOMA-2. Patients and Methods PALOMA-2 compared palbociclib plus letrozole versus placebo plus letrozole in patients with ABC. Population pharmacokinetic analysis provided apparent palbociclib clearance (CL/F) for each patient. The time-varying exposure metric, Cavg,t, was calculated using average dose intensity and CL/F at the time of each progression-free survival (PFS) event. A Cox proportional model characterized PFS and palbociclib Cavg,t relationships. Significant prognostic factors for PFS were identified by univariate analysis, which were subsequently included in multivariate analyses, in addition to the Cavg,t effect on PFS. PFS profiles in Asian/non-Asian patients and patients with/without dose reduction were simulated and compared using observed palbociclib exposures and established exposure-response relationships. Results Patients (n = 421) received palbociclib plus letrozole (Asian = 64, non-Asian = 357; no dose reduction = 272, dose reduction = 149). Based on univariate analyses, significant prognostic factors were Ki67 score, age, and baseline aspartate aminotransferase (BAST), tumor size, alkaline phosphatase, and albumin levels. In multivariate analysis, only Ki67 and BAST remained significant. Palbociclib exposure did not significantly affect PFS in either univariate (P = 0.12) or multivariate (P = 0.44) analyses. Conclusions This analysis suggests that palbociclib exposure has no impact on PFS when the dose reduction algorithm from palbociclib clinical trials is used. There is no difference in efficacy between Asians and non-Asians, despite the higher level of dose reductions in Asians. Pfizer NCT01740427.

This publication describes an evaluation of the impact of different degrees of renal impairment on the pharmacokinetics and safety of palbociclib after a single 125-mg oral dose. Thirty-one subjects were assigned to different renal function groups. Serial blood sampling for pharmacokinetics was performed up to 120 h and 168 h post-palbociclib dose for subjects with normal and impaired renal function, respectively. A separate blood sample was collected at pre-dose and 8 h after dosing to measure plasma protein binding. Plasma palbociclib was measured using a validated liquid chromatography-tandem mass spectrometry (LC–MS/MS) method. Plasma protein binding samples were processed by equilibrium dialysis and measured by a validated LC–MS/MS method. Plasma palbociclib exposure was higher in subjects with renal impairment than in subjects with normal renal function; however, there were no marked differences in exposure across subjects with mild, moderate, and severe renal impairment. Total plasma exposure AUCinf increased by 39%, 42%, and 31% with mild, moderate, and severe renal impairment, respectively, relative to subjects with normal renal function. Peak exposure Cmax increased by 17%, 12%, and 15% for mild, moderate, and severe impairment, respectively. There was no obvious trend in the mean fu with worsening renal function. The PBPK model adequately described palbociclib exposure observed in subjects with moderate or severe renal impairment from this study. Palbociclib was safe and well-tolerated in a small population of subjects with normal and impaired renal function after a single oral 125 mg dose. No dose adjustment is required in patients with renal impairment.

In the phase 3 EMBRACA trial, treatment with the poly(ADP-ribose) polymerase inhibitor, talazoparib, led to significantly improved progression-free survival (PFS) compared with chemotherapy (hazard ratio, 0.54; 95% confidence interval, 0.41-0.71; P.0001). We conducted an exposure-efficacy analysis using EMBRACA data from 285 patients who were treated with talazoparib and had available pharmacokinetic parameters to evaluate the effect of talazoparib exposure (time-varying average talazoparib concentration [C

CuSO4/TiO2 catalysts with high catalytic activity and excellent resistant to SO2 and H2O, were thought to be promising catalysts used in Selective catalytic reduction of nitrogen oxides by NH3. The performance of catalysts is largely affected by calcination temperature. Here, effects of calcination temperature on physicochemical property and catalytic activity of CuSO4/TiO2 catalysts were investigated in depth. Catalyst samples calcined at different temperatures were prepared first and then physicochemical properties of the catalyst were characterized by N2 adsorption-desorption, X-ray diffraction, thermogravimetric analysis, Raman spectra, Fourier-transform infrared spectroscopy, X-ray photoelectron spectroscopy, temperature-programmed desorption of NH3, temperature-programmed reduction of H2 and in situ diffuse reflectance infrared Fourier transform spectroscopy. Results revealed that high calcination temperature had three main effects on the catalyst. First, sintering and anatase transform into rutile with increase of calcination temperature, causing a decrement of specific surface area. Second, decomposition of CuSO4 under higher calcination temperature, resulting in disappears of Bronsted acid sites (S–OH), which had an adverse effect on surface acidity. Third, CuO from the decomposition of CuSO4 changed surface reducibility of the catalyst and favored the process of NH3 oxidation to nitrogen oxides (NOx). Thus, catalytic activity of the catalyst calcined under high temperatures (≥600°C) decreased largely.

Neutropenia is one of the most common dose-limiting toxocities associated with anticancer drug therapy. The ability to predict the probability and severity of neutropenia based on in vitro studies of drugs in early drug development will aid in advancing safe and efficacious compounds to human testing. Toward this end, a physiological model of granulopoiesis and its regulation is presented that includes the bone marrow progenitor cell cycle, allowing for a mechanistic representation of the action of relevant anticancer drugs based on in vitro studies. Model development used data from previously reported tracer kinetic studies of granulocyte disposition in healthy humans to characterize the dynamics of neutrophil margination in the presence of endogenous granulocyte-colony stimulating factor (G-CSF). In addition, previously published data from healthy volunteers following pegfilgrastim and filgrastim were used to quantify the regulatory effects of support G-CSF therapies on granulopoiesis. The model was evaluated for the cell cycle inhibitor palbociclib, using an in vitro system of human bone marrow mononuclear cells to quantify the action of palbociclib on proliferating progenitor cells, including its inhibitory effect on G1 to S phase transition. The in vitro results were incorporated into the physiological model of granulopoiesis and used to predict the time course of absolute neutrophil count (ANC) and the incidence of neutropenia observed in three previously reported clinical trials of palbociclib. The model was able to predict grade 3 and 4 neutropenia due to palbociclib treatment with 86% accuracy based on in vitro data.

The alkali metal potassium has the functions of structure promotion and electronic modulation in metal oxides. Herein, diverse potassium precursors (KOH, KNO3, K2SO4, and KCl) were introduced to α-MnO2 nanorods through a facile post-processing strategy. The presence of potassium species has a remarkable promotion effect on the catalytic performance of α-MnO2. Amongst them, the KOH/MnO2 sample has the highest activity and can destroy 90% toluene (1000 ppm) at just 226 °C with a reaction rate of 3.39 × 10−4 mol gcat−1 s−1, which is over 20 times higher than that of pure α-MnO2. Different anions in the potassium precursors bring a distinct mutation in the α-MnO2 structure, promote the formation of MnO6–K–MnO6 bridging bonds in α-MnO2, and exhibit obvious diverse abilities for balancing charge transfer. KOH is identified as the most promising precursor for alkali metal modification, which significantly improves the distribution of K species over the α-MnO2 surface and strengthens the content and activity of lattice oxygen. It is confirmed that the lattice oxygen plays a key role in the catalytic oxidation of toluene over α-MnO2, which follows the Mars–van Krevelen mechanism. Positive hole defects (Mn3+) caused by KOH treatment play an important role in the diffusion of O and enhance the reducibility of manganese oxide. In addition, the enhanced specific surface area, pore volume, and surface acidity are also conducive for the catalytic oxidation of toluene.

Due to the presence of SO2 in flue gas, SCR catalysts with high SO2 tolerance are desperately required. However, except vanadium-based catalysts, most metal oxide catalysts exhibit low SO2 tolerance. In this research study, CuSO4/TiO2, Fe2(SO4)3/TiO2, MnSO4/TiO2, Ce(SO4)2/TiO2 and CoSO4/TiO2 catalysts were prepared via a sol–gel protocol and used in the NH3-SCR reaction. Low-temperature N2-sorption, XRD, FT-IR, XPS, H2-TPR, NH3-TPD and in situ DRIFTS were used to characterize the physicochemical properties of the prepared catalysts. The presence of SO2 had little influence on the activity of all metal sulfate catalyst samples. CuSO4/TiO2 showed the highest SCR activity and apparent activation energy among the metal sulfate catalysts following the sequence of CuSO4/TiO2 < Fe2(SO4)3/TiO2 < MnSO4/TiO2 < Ce(SO4)2/TiO2 < CoSO4/TiO2. Characterization results indicated that the amount of acid sites was the main factor that influenced the catalytic activity of the metal sulfate catalysts. The NH3-SCR reaction of all metal sulfate catalysts followed the Eley–Rideal mechanism: NH3 was first adsorbed at the surface acid sites (Lewis and Bronsted acid sites), and then it reacted with gaseous NO and O2 to form N2 and H2O. The metal sulfate catalysts, especially CuSO4/TiO2, should be a promising candidate for vanadium-based SCR catalysts for NO reduction.

Commercial V2O5–WO3/TiO2 (abbreviated to VWTi) SCR catalysts are modified with Ce and different contents of Cu in wet impregnation method to improve their alkali metals resistance, which is beneficial for prolonging their service life. After K poisoning, NOx conversion of VWCeCuTi sample modified with 0.30% Ce and 0.05% Cu is 89% at 350 °C, which is obviously higher than that of VWTi with a 50% NOx conversion. A series of characterization tests were conducted and verified that the ratio of V5+ and the surface-active oxygen on VWCeCuTi sample increases due to the interaction between V, Ce and Cu. Additionally, with the addition of Ce and Cu, surface acid sites are increased and their stability is strengthened. The enhanced redox property and surface acidity contribute together to the excellent K resistance of VWCeCuTi catalyst.

In this study, the deactivation of commercial V2O5-WO3/TiO2 selective catalytic reduction catalysts by Pb was discussed primarily, and the combined promotive effects of SO2 and HCl on Pb-poisoned V2O5-WO3/TiO2 catalysts were studied. The results show that the treatment with SO2 and HCl markedly improves the NOx conversion of Pb-poisoned catalysts. SO2 and HCl react with Pb chemisorbed on V2O5, which increases effectively the ratio of V5+ and active oxygen species and the amount of acid sites.

Shape effects of nanocrystal catalysts in different reactions have attracted remarkable attention. In the present work, three types of α-Fe2O3 oxides with different micromorphologies were rationally synthesized via a facile solvothermal method and adopted in deep oxidation of ethane. The physicochemical properties of prepared materials were characterized by XRD, N2 sorption, FE-SEM, HR-TEM, FTIR, in situ DRIFTS, XPS, Mössbauer spectroscopy, in situ Raman, electron energy loss spectroscopy, and H2-TPR. Moreover, the formation energy of oxygen vacancy and surface electronic structure on various crystal faces of α-Fe2O3 were explored by DFT calculations. It is shown that nanosphere-like α-Fe2O3 exhibits much higher ethane destruction activity and reaction stability than nanocube-like α-Fe2O3 and nanorod-like α-Fe2O3 due to larger amounts of oxygen vacancies and lattice defects, which greatly enhance the concentration of reactive oxygen species, oxygen transfer speed, and material redox property. In addition to this, DFT results reveal that nanosphere-like α-Fe2O3 has the lowest formation energy of oxygen vacancy on the (110) facet (Evo (110) = 1.97 eV) and the strongest adsorption energy for ethane (−0.26 eV) and O2 (−1.58 eV), which can accelerate the ethane oxidation process. This study has deepened the understanding of the face-dependent activities of α-Fe2O3 in alkane destruction.

Identification of a pharmacodynamic (PD) biomarker, which is predictive of the efficacy outcome, is of ultimate interest in drug development. The objectives of the current analyses are to develop the pharmacokinetic (PK)/PD model for biomarkers (thymidine kinase 1 [TK1] in serum and phosphor-retinoblastoma protein [pRb] and Ki67 in skin tissues) related to cyclin-dependent kinase (CDK) 4/6 inhibition by palbociclib and to explore the relationship of the biomarker response with the efficacy end point (progression-free survival). The data used for analysis consisted of extensive sampling of palbociclib PK and longitudinal rich sampling for the PD biomarkers TK1, pRb, and Ki67 in 26 patients. A 2-compartment model was used to describe the PK of palbociclib. A precursor-dependent indirect response PD model was developed to describe the pRb time course, whereas a similar PD model with an additional transit compartment to model the delayed effect on Ki67 and TK1 response was used to describe the Ki67 and TK1 time course. Palbociclib effect on biomarkers was modeled as a maximum inhibition model. A Cox proportional hazard model was used to assess the relationship of progression-free survival with the biomarker response. The PK/PD models adequately described the observed PK of palbociclib and the longitudinal change of pRb, Ki67, and TK1. Palbociclib exposure significantly correlated with the reduction of all 3 biomarkers, and the estimated concentration to achieve 50% inhibition of the synthesis rate values were 45.2, 42.4, 50.2 ng/mL, respectively, for pRb, Ki67, and TK1. The exploratory biomarker-response analyses showed that a longer PFS was associated with lower baseline TK1 and simulated minimum TK1. Such results may warrant further confirmation from future large-scale study. Clinical Trial Registration: NCT02499146.

Non-vanadium-based catalysts with high SO2 tolerance are still interesting in selective catalytic reduction of NO by NH3 (NH3-SCR) and SO2 adsorption is the foremost step for the deactivation of catalysts. In order to alleviate the adsorption of SO2, we fabricated a series of rhenium (Re; without stable sulfate) supported TiO2 catalysts and studied their SO2 tolerance for the first time. Owing to suitable surface acidity and reducibility, ReOx/TiO2 catalysts exhibited satisfactory activity in a wide temperature range of 250–350 °C. As expected, experimental results and DFT calculations indicated that SO2 adsorption on ReOx/TiO2 catalysts was rather weak, thus the catalysts performed excellent SO2 tolerance in the NH3-SCR reaction. Moreover, in situ DRIFTS indicated that the NH3-SCR reaction on ReOx/TiO2 catalysts followed the Eley–Rideal mechanism and SO2 had little effect on the reaction mechanism. Our findings should provide new insights into the development of SCR catalysts with high SO2 tolerance.

A series of hierarchical porous carbons (HPCs) with different morphologies and well-developed porosity have been successfully synthesized via a facile and flexible template-free method using hierarchical assembly of polyimide as carbon precursor. Amongst, cornflower-like hierarchical porous carbon (FC4) displays the best CO2 capture property with an adsorption capacity up to 4.05 and 2.87 mmol g−1 at 273 and 298 K, respectively. The excellent CO2 capture capability of FC4 can be owing to the cooperative effect of moderate meso-/macropore channels and abundant framework micropores, which are conducive to diffusion and capture of CO2 adsorbate. Moreover, FC4 shows superior stability and recyclability and CO2 trapping selectivity with CO2/N2 initial and final adsorption ratios of 24 and 6.4, respectively. It can be anticipated that the FC4 is a promising adsorbent in the adsorption and separation of carbon dioxide under actual conditions.

Four kinds of carbon-based adsorbents (micro-mesoporous hybrid carbon nanosphere and N-doped hollow carbon sphere with single-, double- or ruga-shell morphology) with different structural and textural properties were prepared and systematically studied in CO2 capture. All synthesized samples possess high specific surface area (828–910 m2 g−1), large pore volume (0.71–1.81 cm3 g−1), and different micropore contents varied from 2.1% to 46.4%. Amongst, the ordered micro-mesoporous carbon nanosphere (OM-CNS) exhibits the best adsorption performance with CO2 uptake as high as 3.01 mmol g−1 under conditions of 298 K and 1.0 bar, better than most of the reported CO2 adsorbents. The excellent CO2 adsorption capacity of OM-CNS can be reasonably attributed to the synergistic effect of ordered mesopore channels and abundant structural micropores which are beneficial for the diffusion and trapping of CO2 adsorbate. Moreover, the OM-CNS shows excellent CO2 trapping selectivity and superior stability and recyclability, which endow the OM-CNS as a promising and environmental-friendly adsorbent for CO2 capture and separation under practical conditions.

Currently, Pb poisoning of heterogeneous catalysts is considered to be a key area of interest in research involved with industrial NOx reduction. As such, a series of Pb-poisoned V2O5-WO3/TiO2 catalysts were prepared by a wet impregnation method and the influence of SO2 on the performance of these poisoned catalysts for NOx reduction was assessed both experimentally and using theoretical calculations. As expected, the incorporation of Pb in these materials resulted in a significant reduction in their catalytic performance. The conversion of NOx over the Pb-V2O5-WO3/TiO2 catalyst increased from approximately 50% to 90% in presence of SO2 (2000 ppm) at 350 °C. It was postulated that in the absence of SO2, Pb reacts with surface V-OH species, which ultimately results in the destruction of Brønsted acid sites; considered to be crucial for the catalytic conversion of NOx. In the presence of SO2 however, enhanced catalytic activity was observed which was suggested to be a result of the formation of additional Brønsted sites (S-OH) via a surface bidentate sulfate intermediate species. The formation of these species was attributed to the interaction of Pb with SO2 and O2 on the surface of the catalyst. Density functional theory (DFT) calculations based on a monolayer V model on TiO2 (0 0 1) showed that SO2 absorbed selectively onto Pb sites rather than V or Ti oxides. It was subsequently determined that NH3 absorption proceeds through the formation of Pb-N species with Pb atom and H-O with SO2. We believe that the present work provides new insights into the design and application of SCR catalysts with specific relevance for application in flue gas streams which contain high quantities of Pb content.

The decomposition of tetrachlorobenzene (TeCB) emitted from simulated fly ash was studied in a low-temperature pyrolysis–catalysis coupled system. The influences of catalyst support, active component type, active phase-to-assistant ratio, vanadium loading, and catalyst calcination temperature on TeCB conversion were comprehensively investigated. The optimal catalyst composition and preparation conditions were determined through single-factor experiments. Moreover, the effects of reaction temperature, space velocity, and pollutant initial concentration on TeCB decomposition efficiency were explored by orthogonal experiments. The possible mechanism for PeCB decomposition over prepared V2O5–WO3/TiO2 catalysts was proposed based on reaction-byproduct composition and distribution. It is found that the TeCB decomposition efficiency is positively correlated with reaction temperature while being negatively correlated with gas hourly space velocity (GHSV) and TeCB initial concentration. GHSV has the most significa...

Palbociclib (PAL) is approved for the treatment of HR+, HER2- ABC in combination with an aromatase inhibitor as initial endocrine based therapy in postmenopausal women or with fulvestrant in women with disease progression following endocrine therapy based on major progression-free survival (PFS) improvement in phase III studies. An exposure response analysis was conducted to evaluate how the changes in PAL exposure (PAL-E), e.g. due to the dose modifications, would affect the PFS. Data from PALOMA 2, a phase 3 study comparing the efficacy and safety of letrozole plus PAL (PAL+L) to letrozole plus placebo (L) in ABC patients (PTs), were used. The apparent PAL clearance (CL/F) for each PT was obtained from a population pharmacokinetic analysis. The individual PAL-E over the entire treatment (Cavg) was calculated using average daily dose intensity (ADI) and CL/F. PTs in the PAL+L group were divided into 4 quantiles (Q1, Q2, Q3, and Q4) based on their Cavg, and the median PFS in each quantile was compared to that of L using Kaplan-Meier plot. To account for the changes in PAL-E over time due to dose modifications during treatment, a time-varying PAL-E (Cavgt) was calculated using ADI and CL/F at each PFS time. The relationship between PFS and Cavgt was evaluated using Cox proportional hazard model. Univariate analyses were first conducted to identify any significant prognostic factors and the effect of Cavgt on PFS. Multivariate analysis was conducted to evaluate relationship between PFS and Cavgt when all significant prognostic factors identified from the univariate analysis were included in the model to account for their potential confounding effects. The median PFS were 14.5, 24.9, 27.7, 25.7, and 24.0 months for patients in the L, Q1, Q2, Q3, and Q4, respectively, indicating similar PFS across all exposure quartiles. The identified significant prognostic factors from univariate analysis were Ki67 score, age, baseline AST, baseline tumor size, baseline alkaline phosphatase, and baseline albumin levels. The estimated coefficients for Cavgt were -0.00377 and -0.00224 in univariate and multivariate analysis, respectively. The effect of PAL-E on PFS was not statistically significant (p PFS was not found to be associated with Cavgt, suggesting that PTs with different PAL-E in P+L benefited similarly and the changes in PAL-E resulted from dose modifications in the trial would not significantly affect the efficacy. However, the impacts on efficacy are unknown for any other unstudied dose modifications algorithm. Citation Format: Zheng J, Yu Y, Durairaj C, Amantea M, Dieras V, Finn R, Wang D. Palbociclib exposure-response analyses in the treatment of hormone-receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2–) advanced breast cancer (ABC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-21-21.

MnOx oxides with different morphologies (nanowire (MnOx-W), nanocube (MnOx-C), nanorod (MnOx-R), and nanosphere (MnOx-S)) and exposed facets were synthesized via a solvothermal method. The catalytic performance of the synthesized MnOx materials for methyl ethyl ketone (MEK) destruction was investigated. Results show that the activity of MnOx-W with highly exposed {101} facets of Mn3O4 is superior to that of MnOx-C, MnOx-R, and MnOx-S exposing {321} facets of Mn2O3, {110} facets of MnO2, and {101} and {112} facets of Mn3O4, respectively. MEK can be completely mineralized into CO2 at 195 °C over MnOx-W under a relatively high gas hourly space velocity of 37 200 h−1, which is even better than some typical noble metal loaded catalysts. The lowest apparent activation energy of MnOx-W (27.7 kJ mol−1) for MEK destruction also confirms its excellent catalytic activity. Density functional theory (DFT) results reveal that the {101} facets of Mn3O4 have the highest MEK adsorption energy (0.79 eV), which indicates that MEK molecules have a high affinity to adsorb onto the MnOx-W surface, promoting the oxidation process of MEK. In situ DRIFTS and TPSR results indicate that the mineralization of MEK into CO2 over MnOx-W goes through an oxidation route with diacetyl as the primary intermediate. We found that the highly exposed {101} active facets, abundant oxygen vacancies, and excellent low-temperature reducibility are responsible for the superior oxidation performance of MnOx-W. This finding may bring new insights into the designing of highly effective catalysts and has implications for a wide range of reactions not limited to MEK oxidation.

Novel CuMCeOx (M = Y, Eu, Ho, and Sm) trimetal oxide catalysts with developed mesoporosity and an enhanced oxygen migration capability were fabricated by a reproducible self-precipitation approach for the first time. The incorporation of a rare-earth element (especially Y, Eu, and Ho) can increase the reducibility of, and mobility of surface adsorbed oxygen on, a CuCeOx catalyst, which leads to a remarkable increase in catalytic activity in the oxidation of toluene. Among these catalysts, the CuHoCeOx catalyst possesses the highest oxidation activity, with the complete mineralization of toluene at 220 °C at a relatively high GHSV of 50 000 h−1, which is ascribable to the synergetic effect of Ho and the CuCeOx framework, which creates abundant active oxygen vacancies over mixed oxides. Raman spectroscopy and density functional theory (DFT) studies reveal that Ho element is coordinated to two oxygen atoms and occupies the site of a Ce atom, which changes the π-bonding of Ce in the CuCeOx binary oxide and thus leads to the weakening of Ce–O bonds and an enhanced oxygen storage capacity. A possible reaction pathway and a mechanism for the combustion of toluene over a CuHoCeOx sample are proposed by means of in situ DRIFTS and DFT studies, which prove that the toluene oxidation process obeys the Mars–van Krevelen mechanism, with aldehydes and ketones as the primary organic intermediates, before decomposition to CO2 and H2O.

A series of highly active de-NO x catalysts, Eu-modified MnO x -TiO 2 (MnTiEu), was prepared by an inverse co-precipitation method. Their physiochemical properties were investigated by XRD, TEM, EDS, BET, XPS and H 2 -TPR in detail, and their catalytic activities were evaluated by the selective catalytic reduction (SCR) of NO with NH 3 . The results showed that the introduction of Eu with proper amount into MnO x -TiO 2 can effectively restrain the crystallization process of MnO x and TiO 2 , enhance specific surface area, increase the concentration of both surface Mn 4 + and chemisorbed oxygen species, improve the stability of Mn 4 + and Mn 3 + , reduce the amount of surface acid sites, enhance the strength of surface acid sites. The obtained MnTiEu-0.3 catalyst (the molar rate of Eu/Mn was 0.3 and the mole rate of Mn/Ti was 0.1) exhibited a 100% NO x conversion activity in a wide temperature window from 180 to 390 °C and a 100% N 2 selectivity from 120 to 390 °C under a high space velocity of 36,000 h − 1 . Furthermore, MnTiEu-0.3 catalyst presented stronger resistance to concurrent H 2 O and SO 2 poison in comparison with MnO x -TiO 2 catalyst without Eu addition. In - situ DRIFT spectra suggested that NH 3 can be adsorbed on both Lewis and Bronsted acid sites. For MnO x -TiO 2 catalyst, both coordinated NH 3 species on Lewis acid sites and NH 4 + species on Bronsted acid sites can react with gas-phase NO following E-R mechanism. As regards MnTiEu-0.3, the NH 3 -SCR of NO follows both Eley-Rideal and Langmuir-Hinshelwood mechanisms, in which the Eley-Rideal mechanism is predominated.

This study aims at evaluating the utility of the population pharmacokinetics approach in therapeutic protein drug-drug-interaction (DDI) assessment. Simulations were conducted for 2 representative victim drugs, methotrexate and trastuzumab, using a parallel-group design with and without the interaction drug. The effect of a perpetrator on the exposure of the victim drug is described as the ratio of clearance/apparent clearance of the victim drug given with or without the perpetrator. The power of DDI assessment was calculated as the percentage of runs with 90% confidence interval of the estimated DDI effect within 80% to 125% for the scenarios of no DDI, benchmarked with the noncompartmental approach with intensive sampling. The impact of the number of subjects, the number of sampling points per subject, sampling time error, and model misspecification on the power of DDI determination were evaluated. Results showed that with equal numbers of subjects in each arm, the population pharmacokinetics approach with sparse sampling may need about the same or a higher number of subjects compared to a noncompartmental approach in order to achieve similar power. Increasing the number of subjects, even if only in the study drug alone arm, can increase the power. Sampling or dosing time error had notable impacts on the power for methotrexate but not for trastuzumab. Model misspecification had no notable impacts on the power for trastuzumab. Overall, the population pharmacokinetics approach with sparse sampling built in phase 2/3 studies allows appropriate DDI assessment with adequate study design and analysis and can be considered as an alternative to dedicated DDI studies.

Sulfur poisoning and regeneration behavior of In/H-BEA catalyst were carried out in NOx reduction by CH4. In/H-BEA catalyst exhibited a poor resistance to sulfur dioxide after addition of 200 ppm SO2 and 10 vol.% H2O into NO reduction with CH4 at 450 °C for 45 h. Sulfur poisoning of In/H-BEA was attributed to the inhibition of NOx adsorption on Bronsted acid sites, suppression of reaction intermediates generation on the active sites, and the formation of surface sulfate species. The formation of surface sulfate reduced the availability of surface active sites, blocked the pore structure and decreased the surface area of catalyst. These changes in chemical and textural properties resulted in a severe loss in the activity of sulfated In/H-BEA catalyst for NO reduction with CH4. H2 reduction is a promising technology for regeneration of In/H-BEA deactivated by SO2 for removing NOx from lean-burn and diesel exhausts. Indium sulfate could be reduced by H2 to InO+ with In2O3 and In(OH)2+ as the intermediates. The optimal parameters of H2 reduction was regeneration temperature of 400 °C and regeneration time of 60 min which completely recovered the catalytic activity of In/H-BEA.

Poly(ADP-ribose) polymerase inhibitors, such as talazoparib, may affect hematopoiesis. This analysis characterized the relationship between talazoparib exposure and the most common grade ≥ 3 hematopoietic adverse events (AEs) leading to dose modification in the phase 2 (ABRAZO) and phase 3 (EMBRACA) trials. The relationship between time-varying average talazoparib concentration (Cavg,t ), along with other baseline variables, and grade ≥ 3 anemia, thrombocytopenia, and neutropenia were evaluated both by graphical examination and using univariate and multivariate Cox proportional hazard models. The results indicated that higher Cavg,t was associated with a higher risk of anemia and thrombocytopenia. A trend toward an association between higher Cavg,t and neutropenia was observed, although not statistically significant. Higher risk of all tested safety end points was associated with lower baseline hemoglobin. Higher risk of neutropenia was associated with lower baseline absolute neutrophil count and lower body weight. These findings support the proposed management of AEs through talazoparib dosing modification.

Using physiologically based pharmacokinetic (PBPK) modeling and simulations, this study estimated the exposure of sunitinib and its active metabolite SU012662 in pediatric patients. A PBPK simulator, SimCYP, was used to develop and validate the pharmacokinetic models. Model development employed a combined “bottom–up” and “top–down” approach to fully utilize the available in vitro or in silico experimental data and in vivo observed clinical data. First, the PBPK model for sunitinib was established, then the cytochrome P450 3A4–mediated metabolism of sunitinib was used as the input for SU012662. PBPK models were validated using pharmacokinetics of sunitinib and SU012662 from one study in adult patients with solid tumors and three clinical trials in pediatric patients with solid or gastrointestinal stromal tumors. The models were further used to predict the exposure of sunitinib and SU012662 by pediatric age groups. The PBPK models for sunitinib and SU012662 developed based on pharmacokinetic characteristics in adults successfully predicted the observed in vivo pharmacokinetics of sunitinib and SU012662 in both adults and pediatric patients. Based on the SimCYP model predictions, a daily dose of 20 mg/m2 will produce sunitinib and SU012662 total exposures in pediatric patients similar to those in adults with gastrointestinal stromal tumor treated with a clinical dose of 50 mg once daily.

Heterogeneous catalysts with single‐atom active sites offer a means of expanding the industrial application of noble metal catalysts. Herein, an atomically dispersed Pt1‐Co3O4 catalyst is presented, which exhibits an exceptionally high efficiency for the total oxidation of methanol. Experimental and theoretical investigations indicate that this catalyst consists of Pt sites with a large proportion of occupied high electronic states. These sites possess a strong affinity for inactive Co2+ sites and anchor over the surface of (111) crystal plane, which increases the metal–support interaction of the Pt1‐Co3O4 material and accelerates the rate of oxygen vacancies regeneration. In turn, this is determined to promote the coadsorption of the probe methanol molecule and O2. Density functional theory calculations confirm that the electron transfer over the oxygen vacancies reduces both the methanol adsorption energy and activation barriers for methanol oxidation, which is proposed to significantly enhance the dissociation of the CH bond in the methanol decomposition reaction. This investigation serves as a solid foundation for characterizing and understanding single‐atom catalysts for heterogeneous oxidation reactions.

A novel strategy for removal of toluene by non-thermal plasma (NTP) coupled with metal-organic frameworks (MOFs) derived catalyst was proposed in this work. The MOF-derived porous trimetallic oxide catalyst (MnCoNiOx, MCNO) was prepared by simple pyrolysis of a MOF-74(Mn-Co-Ni) precursor. We found that the MCNO material can well synergy with NTP in total decomposition of toluene owing to its high specific surface area, regular porous structure and excellent reducibility, which endow superior catalytic activity and CO2 selectivity of NTP-MCNO system compared to that of NTP-MnOx, NTP-CoOx and NTP-NiOx. For instance, the toluene degradation efficiency can reach up to 75.7% in NTP-MCNO system with a low specific input energy of 101 J/L, much higher than that of NTP-MnOx (59.3%), NTP-CoOx (70.9%), NTP-NiOx (65.0%) and NTP alone (42.9%). Moreover, the formed ozone (O3) can be well-controlled by the NTP-MCNO system due to the spinel-type oxides (MCNO) derived from MOF could generate more open-formwork structure and improve the mobility of oxygen. The results of this work would shed light on rational design and preparation of spinel-type oxides for oxidation applications, which provides guidance for further improvement of plasma-catalysis system.

Poly(ADP-ribose) polymerase (PARP) inhibitors have been developed to treat cancers associated with somatic BRCA mutations and germline genetic aberrations involved in the DNA damage response. The efficacy, tolerability, and pharmacokinetic/pharmacodynamic (PK/PD) profile of talazoparib, a potent small-molecule PARP inhibitor, was established in 4 clinical studies in cancer patients (2 phase 1 studies PRP-001 and PRP-002, the phase 2 ABRAZO trial, and the phase 3 EMBRACA trial). The current study aimed to describe the population PK of talazoparib and identify covariates that affect talazoparib PK in patients with advanced cancers using pooled data from these 4 studies. Talazoparib PK was well characterized by a 2-compartment model with first-order absorption and absorption lag time. Based on covariate analysis, no dose adjustment for talazoparib is required based on a patient's age, sex, baseline body weight, Asian race, the presence of mild renal or hepatic impairment, or use of acid-reducing agents. A reduced 0.75-mg daily dose is recommended for patients taking a potent P-glycoprotein inhibitor and those with moderate renal impairment. Insufficient data were available to establish dosing recommendations for patients with severe renal and moderate or severe hepatic impairment. The PK of a single 1-mg talazoparib capsule is comparable with 4 0.25-mg capsules. Talazoparib can be taken with or without food. These data provide support for dosing recommendations and labeling information for talazoparib.

This paper describes the pharmacokinetics (PK), mass balance, metabolic profiling, and safety of talazoparib after a single oral dose of 14 C-talazoparib in 6 patients with advanced solid tumors. Patients were aged ≥18 years, with a histologically confirmed advanced solid tumor at screening. A single 1-mg dose of talazoparib oral solution supplemented with 100 µCi of 14 C-labeled talazoparib was administered. Blood, urine, and feces samples were collected at various time points and analyzed for talazoparib and 14 C radioactivity. Metabolic profiling and identification were also carried out. Mean recovery of 14 C radioactivity was 68.7% in urine and 19.7% in feces. Talazoparib was minimally metabolized. Renal excretion of unchanged talazoparib was a major route of elimination, with mean recovery of 54.6% of the administered dose, whereas fecal excretion of talazoparib was limited, with mean recovery of 13.6% of the administered dose. No major metabolites of talazoparib were identified in plasma, and no metabolites that individually represented more than 10% of the administered dose were recovered in urine or feces. The concentration-time profiles of unchanged talazoparib, total 14 C radioactivity in plasma, and total 14 C radioactivity in whole blood were similar, with a median time at peak concentrations of 30 minutes and mean half-life of 89.8, 96.2, and 77.6 hours, respectively. Talazoparib was minimally metabolized, and renal excretion of unchanged talazoparib was the major route of elimination.

Due to high catalytic activity and excellent resistance to SO2 and H2O, sulfate materials are considered to be promising vanadium-free catalysts for selective catalytic reduction of NOx with NH3 (NH3-SCR). Despite this, investigations about thermal stability of sulfate SCR catalysts are limited, which is surprising given that sulfates are typically susceptible to thermal decomposition. In this work, the thermal stability of Fe2(SO4)3/TiO2 catalysts was investigated. It was determined that the thermal decomposition of Fe2(SO4)3 resulted in NOx conversion decreased from 90% to 60% at 350 °C. Interestingly however, the introduction of SO2 into the gas stream was found to reverse the effects of the thermal deactivation and the NOx conversion of 90% (350 °C) was once again observed. Extensive characterization of each catalyst sample and density functional theory (DFT) calculations were subsequently conducted. The reduction in catalytic activity after the thermal treatment was attributed to the transformation of Fe2(SO4)3 to α-Fe2O3, which reduced the quantity of Bronsted acid sites on the catalyst. The presence of SO2 in the gas stream was found to reverse this phase transformation which ultimately led to the recovery of Bronsted acid sites. DFT calculations indicated that SO2 adsorbed selectively on Fe atoms of the thermal deactivated catalysts and S-Fe bond should mainly be formed by electrons from p orbitals of S and Fe atoms. Then NH3 could be adsorbed on the surface by N-S bond with SO2. The recoverable property of this catalyst provides a promising outlook for the commercial application, especially given that industrial flue gas streams regularly contain SO2.