Population pharmacokinetics and pharmacodynamics of efmarodocokin alfa (IL-22Fc).

Efmarodocokin alfa (IL-22Fc) is a fusion protein of human IL-22 linked to the crystallizable fragment (Fc) of human IgG4. It has been tested in multiple indications including inflammatory bowel disease (IBD). The purposes of the present analyses were to describe the population pharmacokinetics (PK) of efmarodocokin alfa and perform pharmacodynamic (PD) analysis on the longitudinal changes of the PD biomarker REG3A after efmarodocokin alfa treatment as well as identify covariates that affect efmarodocokin alfa PK and REG3A PD. The data used for this analysis included 182 subjects treated with efmarodocokin alfa in two clinical studies. The population PK and PD analyses were conducted sequentially. Efmarodocokin alfa concentration-time data were analyzed using a nonlinear mixed-effects modeling approach, and an indirect response model was adopted to describe the REG3A PD data with efmarodocokin alfa serum concentration linked to the increase in REG3A. The analysis software used were NONMEM and R. A 3-compartment model with linear elimination best described the PK of efmarodocokin alfa. The estimated population-typical value for clearance (CL) was 1.12 L/day, and volume of central compartment was 6.15 L. Efmarodocokin alfa CL increased with higher baseline body weight, C-reactive protein, and CL was 27.6% higher in IBD patients compared to healthy subjects. The indirect response PD model adequately described the longitudinal changes of REG3A after efmarodocokin alfa treatment. A popPK and PD model for efmarodocokin alfa and REG3A was developed and covariates affecting the PK and PD were identified.

An Investigation in the Comparability of the Exposure and Recommended Dose of Selected Pfizer Drugs in East Asian Countries: Is Mutual Usage of Clinical Data Among East Asian Countries Feasible?

The current regulatory path for new drug registration in East Asian countries has led to significant delay of the new medicines in these countries. A unified regulatory path and allowance of mutual usage of clinical data in East Asian countries would lead to cost saving in drug development and expedite the new drug registration in these countries. The objectives of the present analysis are to compare the approval dates of a selection of products developed by Pfizer in the United States and East Asian countries (China, Japan, Korea) and compare the pharmacokinetics and recommended doses of these products in East Asian countries. Eighteen products (20 drugs, 2 products with 2 combination drugs) with exposure data available in at least 2 of the 3 East Asian countries across different therapeutic areas were included in the analyses. The results showed that most products had delayed approval in East Asian countries (up to 8 years) after US or EU approval. No distinct differences were observed in the drug exposure and recommended doses for the selected products in East Asian countries. These results together with literature data of genetic similarity of the East Asian populations support the mutual usage of the clinical data in the East Asian countries for expedited regulatory submission and approval.

Assessment of the drug-drug interaction potential for therapeutic proteins with pro-inflammatory activities.

It is well-recognized that therapeutic proteins (TPs) with pro-inflammatory activities elevate the pro-inflammatory cytokines and result in cytokine-drug interactions. In the current review, several pro-inflammatory cytokines, including IL-2, IL-6, IFN-γ, and TNF-α, as well as an anti-inflammatory cytokine IL-10, were summarized for their respective effect on major cytochrome P450 enzymes and efflux transporter PgP. Pro-inflammatory cytokines are generally associated with suppression of CYP enzymes across assay systems but have varied effect on Pgp expression levels and activities depending on the individual cytokines and assay systems, whereas IL-10 had no significant impact on CYP enzymes and P-gp. A cocktail drug-drug interaction (DDI) study design could be an ideal approach for simultaneously assess the impact of TPs with pro-inflammatory activities on multiple CYP enzymes. Clinical DDI studies using the cocktail approach have been conducted for several TPs with pro-inflammatory activities and for those TPs with pro-inflammatory activities which had no clinical DDI study conducted, languages for potential DDI risk due to cytokine-drug interaction were included in the label. Up to date drug cocktails, including clinically validated and unvalidated for DDI assessment, were summarized in this review. Most clinically validated cocktails focused either on CYP enzymes or transporters. Additional effort was needed to validate a cocktail to include both the major CYP enzymes and key transporters. In silico methods for assessment of the DDI for TPs with pro-inflammatory activities were also discussed.

Rationally Engineering a CuO/Pd@SiO2 Core-Shell Catalyst with Isolated Bifunctional Pd and Cu Active Sites for n-Butylamine Controllable Decomposition.

Volatile organic amines are a category of typical volatile organic compounds (VOCs) extensively presented in industrial exhausts causing serious harm to the atmospheric environment and human health. Monometallic Pd and Cu-based catalysts are commonly adopted for catalytic destruction of hazardous organic amines, but their applications are greatly limited by the inevitable production of toxic amide and NOx byproducts and inferior low-temperature activity. Here, a CuO/Pd@SiO2 core-shell-structured catalyst with diverse functionalized active sites was creatively developed, which realized the total decomposition of n-butylamine at 260 °C with a CO2 yield and N2 selectivity reaching up to 100% and 98.3%, respectively (obviously better than those of Pd@SiO2 and CuO/SiO2), owing to the synergy of isolated Pd and Cu sites in independent mineralization of n-butylamine and generation of N2, respectively. The formation of amide and short-chain aliphatic hydrocarbon intermediates via C-C bond cleavage tended to occur over Pd sites, while the C-N bond was prone to breakage over Cu sites, generating NH2· species and long free-N chain intermediates at low temperatures, avoiding the production of hazardous amide and NOx. The SiO2 channel collapse and H+ site production resulted in the formation of N2O via suppressing NH2· diffusion. This work provides critical guidance for a rational fabrication of catalysts with high activity and N2 selectivity for environmentally friendly destruction of nitrogen-containing VOCs.

Evaluation of pharmacokinetics and safety of talazoparib in patients with advanced cancer and varying degrees of hepatic impairment.

AIM: This phase I study investigated talazoparib pharmacokinetics (PK) and safety in patients with advanced solid tumours and varying degrees of hepatic function. METHODS: Patients 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 0.5 mg 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. RESULTS: Thirty-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. CONCLUSIONS: Hepatic 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.

Pharmacodynamic Modeling of CDK4/6 Inhibition-Related Biomarkers and the Characterization of the Relationship Between Biomarker Response and Progression-Free Survival in Patients With Advanced Breast Cancer.

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.

A Preclinical and Phase Ib Study of Palbociclib plus Nab-Paclitaxel in Patients with Metastatic Adenocarcinoma of the Pancreas.

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.

Assessment of the Utility of Physiologically-based Pharmacokinetic Model for prediction of Pharmacokinetics in Chinese and Japanese Populations.

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.

Pharmacokinetics, safety, activity, and biomarker analysis of palbociclib plus letrozole as first-line treatment for ER+/HER2- advanced breast cancer in Chinese women.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. CLINICAL TRIAL REGISTRATION: NCT02499146.

Impact of Dose Reduction on Efficacy: Implications of Exposure-Response Analysis of Palbociclib.

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.

Palbociclib (PD-0332991) pharmacokinetics in subjects with impaired renal function.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Talazoparib Exposure-Efficacy Analysis in Patients With Advanced Breast Cancer and Germline BRCA1/2 Mutations in the EMBRACA Trial.

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 [Cavg,t ]) and other baseline variables on PFS. Graphical examination of the relationship between Cavg,t and PFS and a Cox proportional model were used. Exposure-response analyses showed that higher talazoparib exposure, absence of visceral disease, lower baseline lactate dehydrogenase levels, and disease-free interval >12 months were independent covariates associated with longer PFS. The association of talazoparib exposure with PFS (higher exposure, longer PFS) suggests the recommended starting dose of 1 mg once daily (the maximum tolerated dose) is appropriate.

Exposure-Safety Analyses of Talazoparib in Patients With Advanced Breast Cancer and Germline BRCA1/2 Mutations in the EMBRACA and ABRAZO Trials.

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.

A physiological model of granulopoiesis to predict clinical drug induced neutropenia from in vitro bone marrow studies: with application to a cell cycle inhibitor.

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.

Effects of calcination temperature on physicochemical property and activity of CuSO4/TiO2 ammonia-selective catalytic reduction catalysts.

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 Brønsted 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.

Physiologically Based Pharmacokinetic Modeling and Simulation of Sunitinib in Pediatrics.

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.

Population Pharmacokinetics of Talazoparib in Patients With Advanced Cancer.

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.

Non-thermal plasma coupled with MOF-74 derived Mn-Co-Ni-O porous composite oxide for toluene efficient degradation.

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.

A Phase 1 Mass Balance Study of 14 C-Labeled Talazoparib in Patients With Advanced Solid Tumors.

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.

In-Depth Understanding of the Morphology Effect of α-Fe2O3 on Catalytic Ethane Destruction.

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.