Assessing QTc Effects of Vericiguat Using Two Different Concentration-QTc Modeling Approaches.

BACKGROUND AND OBJECTIVES: Vericiguat is a soluble guanylate cyclase stimulator indicated to reduce the risk of cardiovascular death and hospitalization due to heart failure. A dedicated QTc study in patients with chronic coronary syndromes demonstrated no clinically relevant QTc effect of vericiguat for exposures across the therapeutic dose range (2.5-10 mg). Interval prolongation concentration-QTc (C-QTc) modeling was performed to complement the statistical evaluations of QTc in the dedicated QTc study. METHODS: Individual time-matched, baseline- and placebo-corrected Fridericia-corrected QT interval values (ΔΔQTcF) were derived. Two approaches for ΔΔQTcF calculation were investigated: (1) ΔΔQTcF correction with data from a single baseline (as in the primary statistical analysis); and (2) ΔΔQTcF correction with a modeled baseline (considering all available individual non-treatment baselines). The ΔΔQTcF values were related to observed vericiguat concentrations with linear mixed-effects modeling. RESULTS: For both modeling approaches, a positive relationship was found between ΔΔQTcF and vericiguat concentration; however, the slope for the single-baseline approach was not statistically significant, whereas the slope from the modeled-baseline approach was statistically significant. The upper bound of the two-sided 90% confidence interval for model-derived QTc was < 10 ms at the highest observed exposure (745 µg/L; investigated dose range 2.5-10 mg). CONCLUSION: By applying a single-baseline approach and a modeled-baseline approach that integrated all available QTc data across doses to characterize the QTc prolongation potential, this study showed that vericiguat 2.5-10 mg is not associated with clinically relevant QTc effects, in line with the conclusion from the primary statistical analysis. CLINICAL TRIALS REGISTRATION NUMBER: ClinicalTrials.gov NCT03504982.

Assessment of the safe and efficacious dose of the selective progesterone receptor modulator vilaprisan for the treatment of patients with uterine fibroids by exposure-response modelling and simulation.

AIMS: We report population pharmacokinetic (popPK) and exposure-response (E-R) analyses for efficacy (induced amenorrhoea [IA]) and safety (unbound oestradiol [E2] concentrations) of the selective progesterone receptor modulator vilaprisan. Results were used to inform the dose for the Phase 3 programme in patients with uterine fibroids. METHODS: A popPK model was developed using data from Phase 1 and 2 studies (including ASTEROID 1 and 2). The relationship between vilaprisan exposure (steady-state AUC) and IA after oral administration of 0.5, 1, 2 or 4 mg/day over 3 months was analysed in ASTEROID 1 using logistic regression and qualified in ASTEROID 2 by comparing simulated and observed probability for IA after 2 mg/day. The exposure-E2 relationship was analysed visually. RESULTS: Vilaprisan clearance was 22.7% lower in obese vs non-obese patients. The E-R relationship for IA in ASTEROID 1 was steep and consistent with ASTEROID 2, with a maximum probability (Pmax ) of 59% (95% CI: 49-68%). The exposure at which 50% of Pmax is obtained was 36.9 µg*h/L (95% CI: 27.7-48.7 µg*h/L). Simulations showed that 36% of the patients will be below 90% of Pmax for IA after 1 mg/day compared to 2% after 2 mg/day. E2 levels tended to decrease with increasing exposure. While E2 levels remained largely within the physiologic follicular phase range, the clinical relevance of this decrease will be evaluated in long-term studies. CONCLUSIONS: A 2 mg/day dose was selected for Phase 3 as E-R analyses show this dose results in a close to maximum probability for IA, without any safety concerns noted.

Clinical Pharmacokinetics and Pharmacodynamics of the Selective Progesterone Receptor Modulator Vilaprisan: A Comprehensive Overview.

Vilaprisan is a highly potent selective progesterone receptor modulator in development for the treatment of symptomatic uterine fibroids and endometriosis. Its pharmacokinetics are characterized by rapid absorption, almost complete bioavailability, and dose-proportional exposure. The intrinsic factors of age, bodyweight, and race have no clinically relevant effect on the pharmacokinetics and pharmacodynamics of vilaprisan and do not warrant a dose adjustment. Similarly, vilaprisan can be used in patients with mild or moderate renal or hepatic impairment without dose adjustment, but its use is not recommended in patients with severe organ impairment. Vilaprisan has no perpetrator potential on cytochrome P450 (CYP) enzymes or transporters and therefore restrictions in the concomitant use of their substrates are not required. Nonetheless, because it is a sensitive CYP3A4 substrate itself, concomitant use of vilaprisan with strong CYP3A inhibitors or inducers is not recommended. However, there is no risk for QTc prolongation when vilaprisan and a strong CYP3A inhibitor are administered concomitantly, as indicated by a vilaprisan concentration-QTc response analysis across all studies with triplicate electrocardiogram measurements. Furthermore, due to its mode of action, vilaprisan is also not recommended to be used together with progestin-containing oral contraceptives. Vilaprisan shows a steep exposure-response relationship for inducing amenorrhea in patients with uterine fibroids experiencing heavy menstrual bleeding. Based on simulations, a dose of 2 mg/day is expected to induce a maximum bleeding reduction and was thus selected for phase III.

Microfabrication Enables Quantification of Interfacial Activity in Thermal Catalysis.

A myriad of heterogeneous catalysts comprises multiple phases that need to be precisely structured to exert their maximal contribution to performance through electronic and structural interactions at their peripheries. In view of the nanometric, tridimensional, and anisotropic nature of these materials, a quantification of the interface and the impact of catalytic sites located there on the global performance is a highly challenging task. Consequently, the true origin of catalysis often remains subject of debate even for widely studied materials. Herein, an integrated strategy based on microfabricated catalysts and a custom-designed reactor is introduced for determining interfacial contributions upon catalytic activity assessment under process-relevant conditions, which can be easily implemented in the common catalysis research infrastructure and will accelerate the rational design of multicomponent heterogeneous catalysts for diverse applications. The method is validated by studying the high-pressure continuous-flow hydrogenation of CO and CO2 over Cu-ZnO catalysts, revealing linear correlations between the methanol formation rate and the interface between the metal and the oxide. Characterization of fresh and used materials points to the model catalyst preparation as the current challenge of the methodology that can be addressed through further development of nanotechnological tools.

Population Pharmacokinetics and Pharmacodynamics of Vericiguat in Patients with Heart Failure and Reduced Ejection Fraction.

BACKGROUND: Vericiguat, a stimulator of soluble guanylate cyclase, has been developed as a first-in-class therapy for worsening chronic heart failure in adults with left ventricular ejection fraction < 45%. OBJECTIVE: The objective of this article was to characterize the pharmacokinetics and pharmacokinetic variability of vericiguat combined with guideline-directed medical therapy (standard of care), and identify exposure-response relationships for safety (hemodynamics) and pharmacodynamic markers of efficacy (N-terminal pro-B-type natriuretic peptide concentration [NT-proBNP]) in patients with heart failure and left ventricular ejection fraction < 45% in the SOCRATES-REDUCED study (NCT01951625). METHODS: Vericiguat and NT-proBNP plasma concentrations in 454 and 432 patients in SOCRATES-REDUCED, respectively, were analyzed using nonlinear mixed-effects modeling. RESULTS: Vericiguat pharmacokinetics were well described by a one-compartment model with apparent clearance, apparent volume of distribution, and absorption rate constant. Age, bodyweight, plasma bilirubin, and creatinine clearance were identified as significant covariates on apparent clearance; sex and bodyweight on apparent volume of distribution; and bodyweight and plasma albumin level on absorption rate constant. Pharmacokinetic/pharmacodynamic analysis showed initial minor and transient effects of vericiguat on blood pressure with low clinical impact. There were no changes in heart rate following initial or repeated vericiguat administration. An exposure-dependent and time-dependent turnover pharmacokinetic/pharmacodynamic model for NT-proBNP described production and elimination rates and an demonstrated exposure-dependent reduction in [NT-proBNP] by vericiguat plus standard of care compared with placebo plus standard of care. This effect was dependent on baseline [NT-proBNP]. CONCLUSIONS: Vericiguat has predictable pharmacokinetics, with no long-term effects on blood pressure in patients with heart failure and left ventricular ejection fraction < 45%. A pharmacokinetic/pharmacodynamic model described a vericiguat exposure-dependent reduction of NT-proBNP. CLINICAL TRIAL IDENTIFIER: NCT01951625.

Nanostructure of nickel-promoted indium oxide catalysts drives selectivity in CO2 hydrogenation.

Metal promotion in heterogeneous catalysis requires nanoscale-precision architectures to attain maximized and durable benefits. Herein, we unravel the complex interplay between nanostructure and product selectivity of nickel-promoted In2O3 in CO2 hydrogenation to methanol through in-depth characterization, theoretical simulations, and kinetic analyses. Up to 10 wt.% nickel, InNi3 patches are formed on the oxide surface, which cannot activate CO2 but boost methanol production supplying neutral hydrogen species. Since protons and hydrides generated on In2O3 drive methanol synthesis rather than the reverse water-gas shift but radicals foster both reactions, nickel-lean catalysts featuring nanometric alloy layers provide a favorable balance between charged and neutral hydrogen species. For nickel contents >10 wt.%, extended InNi3 structures favor CO production and metallic nickel additionally present produces some methane. This study marks a step ahead towards green methanol synthesis and uncovers chemistry aspects of nickel that shall spark inspiration for other catalytic applications.

Methanol as a Hydrogen Carrier: Kinetic and Thermodynamic Drivers for its CO2 -Based Synthesis and Reforming over Heterogeneous Catalysts.

Methanol is an attractive energy vector in a closed loop including its synthesis from CO2 and H2 and on-demand reforming to the starting feedstocks. Catalytic materials for the two reactions were mostly studied separately, with very few works assessing the feasibility of the same system for both. Here, key kinetic drivers of methanol synthesis (MS) and methanol steam reforming (MSR) were identified for the main catalyst families, with special focus on Cu-ZnO-Al2 O3 , In2 O3 , and Pd/ZrO2 . It was shown that the relative activity level was preserved in either direction, whereas the distinctly favored (reverse) water-gas shift modulated selectivity differently. Low selectivity in kinetically controlled MS could be overcome in MSR by exploiting thermodynamics as the driving force, with many catalysts unfit for MS still comprising appealing candidates for MSR and only few being suited for MS as well as MSR. Overall, readily identifiable properties describing catalyst behavior in the forward and backward reactions were highlighted, effectively linking research in the two fields and setting a stronger basis for developing a methanol-based hydrogen storage unit with a single reactor.

Development of In2O3-based Catalysts for CO2-based Methanol Production.

CO2 valorization into chemicals and fuels is a key area in current academic and industrial research, with thermocatalytic hydrogenation to methanol comprising one of the most advanced routes. Life-cycle analysis coupled to the framework of planetary boundaries has recently confirmed the sustainability of this process in absolute terms, emphasizing the need for cheaper CO2 and renewable H2 and for a catalytic system embracing high activity, selectivity, and durability to meet economic requirements. Herein, our research efforts aimed to gather atomic-level understanding of electronic and geometric properties of active sites in breakthrough In2O3-based catalytic systems guiding their development are reviewed. In-depth mechanistic elucidations identified limited hydrogen activation ability as well as water-driven sintering as limitations of pure In2O3. The former aspect was successfully addressed by adding through coprecipitation a minimal amount of palladium, forming tiny clusters strongly anchored to the oxide lattice leading to an unprecedented sustained methanol productivity. The use of monoclinic zirconia as a carrier, enabling high In2O3 dispersion in two-dimensional nanostructures, inducing the formation of additional active sites on In2O3, and contributing to CO2 activation, offered an efficient way to further boost activity and tackle In2O3 sintering. Overall, our findings set solid grounds to rationally design a supported and promoted In2O3 catalyst holding bright prospects for use at a large scale.

Application of Physiologically-Based and Population Pharmacokinetic Modeling for Dose Finding and Confirmation During the Pediatric Development of Moxifloxacin.

Moxifloxacin is a widely used fluoroquinolone for the treatment of complicated intra-abdominal infections. We applied physiologically-based pharmacokinetic (PBPK) and population pharmacokinetic (popPK) modeling to support dose selection in pediatric patients. We scaled an existing adult PBPK model to children based on prior physiological knowledge. The resulting model proposed an age-dependent dosing regimen that was tested in a phase I study. Refined doses were then tested in a phase III study. A popPK analysis of all clinical pediatric data confirmed the PBPK predictions, including the proposed dosing schedule in children, and supported pharmacokinetics-related safety/efficacy questions. The pediatric PBPK model adequately predicted the doses necessary to achieve antimicrobial efficacy while maintaining safety in the phase I and III pediatric studies. Altogether, this study retroactively demonstrated the robustness and utility of modeling to support dose finding and confirmation in pediatric drug development for moxifloxacin.

Atomic-scale engineering of indium oxide promotion by palladium for methanol production via CO2 hydrogenation.

Metal promotion is broadly applied to enhance the performance of heterogeneous catalysts to fulfill industrial requirements. Still, generating and quantifying the effect of the promoter speciation that exclusively introduces desired properties and ensures proximity to or accommodation within the active site and durability upon reaction is very challenging. Recently, In2O3 was discovered as a highly selective and stable catalyst for green methanol production from CO2. Activity boosting by promotion with palladium, an efficient H2-splitter, was partially successful since palladium nanoparticles mediate the parasitic reverse water-gas shift reaction, reducing selectivity, and sinter or alloy with indium, limiting metal utilization and robustness. Here, we show that the precise palladium atoms architecture reached by controlled co-precipitation eliminates these limitations. Palladium atoms replacing indium atoms in the active In3O5 ensemble attract additional palladium atoms deposited onto the surface forming low-nuclearity clusters, which foster H2 activation and remain unaltered, enabling record productivities for 500 h.

Odour impact from farms with animal husbandry and biogas facilities.

Agricultural biogas facilities are usually combined with animal husbandry. Their siting near residential areas can lead to odour complaints by residents. The aim of this study was to identify relevant odour sources, to record odour impact, and to determine the main variables influencing odour impact. Therefore, a combined approach was designed to account for individual odour sources as well as the farms as a whole. On eight farms with cattle husbandry and biogas facilities, two of which kept pigs and poultry, the odour-relevant area sources ranged between 475 and 1810 m2. Solid manure from poultry, cattle and horses as well as grass cuttings, vegetable peelings, liquid-silage effluent and fermentation residues figured among the odour-intensive sources, in addition to biogas. Odour-plume inspections were performed at various distances from the farm, and assessors determined their odour perception and -intensities. The odour intensity in the downwind plume axis was explainable in a linear mixed-effects model by distance (p < 0.001), emitting surface area (p = 0.002) and wind speed (p = 0.018). As distance increased, odour intensity decreased by a factor of two per 50 m. Higher odour intensities resulted from larger surface areas in the animal enclosure, substrate storage, or especially odour-relevant sources. A mixture of odours was frequently perceived in the odour plume. If biogas escaped, an increase in odour impact was recognisable (p = 0.021). Biogas leakage should be avoided with a sufficiently large storage capacity, process optimisation, and regular servicing. In summary, animal husbandry and biogas facilities are to be viewed as an entire plant in terms of downwind odour perception. In planning processes for biogas facilities with animal husbandry, great care in the choice of site is called for, as are structural-technical and organisational measures for abatement.